Journal: N Engl J Med

Sorted by: date / impact
Abstract
<div><h4>Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.</h4><i>National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Shapiro NI, ... Yealy DM, Self WH</i><br /><b>Background</b><br />Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited.<br /><b>Methods</b><br />In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed.<br /><b>Results</b><br />A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups.<br /><b>Conclusions</b><br />Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 21 Jan 2023; epub ahead of print</small></div>
National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Shapiro NI, ... Yealy DM, Self WH
N Engl J Med: 21 Jan 2023; epub ahead of print | PMID: 36688507
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture.</h4><i>Major Extremity Trauma Research Consortium (METRC), O\'Toole RV, Stein DM, O\'Hara NN, ... Marvel D, Castillo RC</i><br /><b>Background</b><br />Clinical guidelines recommend low-molecular-weight heparin for thromboprophylaxis in patients with fractures, but trials of its effectiveness as compared with aspirin are lacking.<br /><b>Methods</b><br />In this pragmatic, multicenter, randomized, noninferiority trial, we enrolled patients 18 years of age or older who had a fracture of an extremity (anywhere from hip to midfoot or shoulder to wrist) that had been treated operatively or who had any pelvic or acetabular fracture. Patients were randomly assigned to receive low-molecular-weight heparin (enoxaparin) at a dose of 30 mg twice daily or aspirin at a dose of 81 mg twice daily while they were in the hospital. After hospital discharge, the patients continued to receive thromboprophylaxis according to the clinical protocols of each hospital. The primary outcome was death from any cause at 90 days. Secondary outcomes were nonfatal pulmonary embolism, deep-vein thrombosis, and bleeding complications.<br /><b>Results</b><br />A total of 12,211 patients were randomly assigned to receive aspirin (6101 patients) or low-molecular-weight heparin (6110 patients). Patients had a mean (±SD) age of 44.6±17.8 years, 0.7% had a history of venous thromboembolism, and 2.5% had a history of cancer. Patients received a mean of 8.8±10.6 in-hospital thromboprophylaxis doses and were prescribed a median 21-day supply of thromboprophylaxis at discharge. Death occurred in 47 patients (0.78%) in the aspirin group and in 45 patients (0.73%) in the low-molecular-weight-heparin group (difference, 0.05 percentage points; 96.2% confidence interval, -0.27 to 0.38; P<0.001 for a noninferiority margin of 0.75 percentage points). Deep-vein thrombosis occurred in 2.51% of patients in the aspirin group and 1.71% in the low-molecular-weight-heparin group (difference, 0.80 percentage points; 95% CI, 0.28 to 1.31). The incidence of pulmonary embolism (1.49% in each group), bleeding complications, and other serious adverse events were similar in the two groups.<br /><b>Conclusions</b><br />In patients with extremity fractures that had been treated operatively or with any pelvic or acetabular fracture, thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin in preventing death and was associated with low incidences of deep-vein thrombosis and pulmonary embolism and low 90-day mortality. (Funded by the Patient-Centered Outcomes Research Institute; PREVENT CLOT ClinicalTrials.gov number, NCT02984384.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 19 Jan 2023; 388:203-213</small></div>
Major Extremity Trauma Research Consortium (METRC), O'Toole RV, Stein DM, O'Hara NN, ... Marvel D, Castillo RC
N Engl J Med: 19 Jan 2023; 388:203-213 | PMID: 36652352
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Bivalent Omicron BA.1-Adapted BNT162b2 Booster in Adults Older than 55 Years.</h4><i>Winokur P, Gayed J, Fitz-Patrick D, Thomas SJ, ... Kitchin N, C4591031 Clinical Trial Group</i><br /><b>Background</b><br />The emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019.<br /><b>Methods</b><br />In an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-μg doses of the BNT162b2 vaccine were randomly assigned to receive 30 μg or 60 μg of BNT162b2, 30 μg or 60 μg of monovalent B.1.1.529 (omicron) BA.1-adapted BNT162b2 (monovalent BA.1), or 30 μg (15 μg of BNT162b2 + 15 μg of monovalent BA.1) or 60 μg (30 μg of BNT162b2 + 30 μg of monovalent BA.1) of BA.1-adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT<sub>50</sub>] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 μg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants.<br /><b>Results</b><br />A total of 1846 participants underwent randomization. At 1 month after vaccination, bivalent BA.1 (30 μg and 60 μg) and monovalent BA.1 (60 μg) showed neutralizing activity against BA.1 superior to that of BNT162b2 (30 μg), with NT<sub>50</sub> geometric mean ratios (GMRs) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3.15 (95% CI, 2.38 to 4.16), respectively. Bivalent BA.1 (both doses) and monovalent BA.1 (60 μg) were also noninferior to BNT162b2 (30 μg) with respect to seroresponse against BA.1; between-group differences ranged from 10.9 to 29.1 percentage points. Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain, with NT<sub>50</sub> GMRs of 0.99 (95% CI, 0.82 to 1.20) and 1.30 (95% CI, 1.07 to 1.58), respectively. BA.4-BA.5 and BA.2.75 neutralizing titers were numerically higher with 30-μg bivalent BA.1 than with 30-μg BNT162b2. The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 μg). Adverse events were more common in the 30-μg monovalent-BA.1 (8.5%) and 60-μg bivalent-BA.1 (10.4%) groups than in the other groups (3.6 to 6.6%).<br /><b>Conclusions</b><br />The candidate monovalent or bivalent omicron BA.1-adapted vaccines had a safety profile similar to that of BNT162b2 (30 μg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 19 Jan 2023; 388:214-227</small></div>
Winokur P, Gayed J, Fitz-Patrick D, Thomas SJ, ... Kitchin N, C4591031 Clinical Trial Group
N Engl J Med: 19 Jan 2023; 388:214-227 | PMID: 36652353
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Futibatinib for -Rearranged Intrahepatic Cholangiocarcinoma.</h4><i>Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, ... Bridgewater JA, FOENIX-CCA2 Study Investigators</i><br /><b>Background</b><br />Alterations in fibroblast growth factor receptor 2 (<i>FGFR2</i>) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with <i>FGFR</i>-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors.<br /><b>Methods</b><br />In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic <i>FGFR2</i> fusion-positive or <i>FGFR2</i> rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes.<br /><b>Results</b><br />Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring <i>TP53</i> mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment.<br /><b>Conclusions</b><br />In previously treated patients with <i>FGFR2</i> fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 19 Jan 2023; 388:228-239</small></div>
Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW, ... Bridgewater JA, FOENIX-CCA2 Study Investigators
N Engl J Med: 19 Jan 2023; 388:228-239 | PMID: 36652354
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Psychosocial Functioning in Transgender Youth after 2 Years of Hormones.</h4><i>Chen D, Berona J, Chan YM, Ehrensaft D, ... Tishelman AC, Olson-Kennedy J</i><br /><b>Background</b><br />Limited prospective outcome data exist regarding transgender and nonbinary youth receiving gender-affirming hormones (GAH; testosterone or estradiol).<br /><b>Methods</b><br />We characterized the longitudinal course of psychosocial functioning during the 2 years after GAH initiation in a prospective cohort of transgender and nonbinary youth in the United States. Participants were enrolled in a four-site prospective, observational study of physical and psychosocial outcomes. Participants completed the Transgender Congruence Scale, the Beck Depression Inventory-II, the Revised Children\'s Manifest Anxiety Scale (Second Edition), and the Positive Affect and Life Satisfaction measures from the NIH (National Institutes of Health) Toolbox Emotion Battery at baseline and at 6, 12, 18, and 24 months after GAH initiation. We used latent growth curve modeling to examine individual trajectories of appearance congruence, depression, anxiety, positive affect, and life satisfaction over a period of 2 years. We also examined how initial levels of and rates of change in appearance congruence correlated with those of each psychosocial outcome.<br /><b>Results</b><br />A total of 315 transgender and nonbinary participants 12 to 20 years of age (mean [±SD], 16±1.9) were enrolled in the study. A total of 190 participants (60.3%) were transmasculine (i.e., persons designated female at birth who identify along the masculine spectrum), 185 (58.7%) were non-Latinx or non-Latine White, and 25 (7.9%) had received previous pubertal suppression treatment. During the study period, appearance congruence, positive affect, and life satisfaction increased, and depression and anxiety symptoms decreased. Increases in appearance congruence were associated with concurrent increases in positive affect and life satisfaction and decreases in depression and anxiety symptoms. The most common adverse event was suicidal ideation (in 11 participants [3.5%]); death by suicide occurred in 2 participants.<br /><b>Conclusions</b><br />In this 2-year study involving transgender and nonbinary youth, GAH improved appearance congruence and psychosocial functioning. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 19 Jan 2023; 388:240-250</small></div>
Chen D, Berona J, Chan YM, Ehrensaft D, ... Tishelman AC, Olson-Kennedy J
N Engl J Med: 19 Jan 2023; 388:240-250 | PMID: 36652355
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>The Safety of Inpatient Health Care.</h4><i>Bates DW, Levine DM, Salmasian H, Syrowatka A, ... Reynolds ME, Mort E</i><br /><b>Background</b><br />Adverse events during hospitalization are a major cause of patient harm, as documented in the 1991 Harvard Medical Practice Study. Patient safety has changed substantially in the decades since that study was conducted, and a more current assessment of harm during hospitalization is warranted.<br /><b>Methods</b><br />We conducted a retrospective cohort study to assess the frequency, preventability, and severity of patient harm in a random sample of admissions from 11 Massachusetts hospitals during the 2018 calendar year. The occurrence of adverse events was assessed with the use of a trigger method (identification of information in a medical record that was previously shown to be associated with adverse events) and from review of medical records. Trained nurses reviewed records and identified admissions with possible adverse events that were then adjudicated by physicians, who confirmed the presence and characteristics of the adverse events.<br /><b>Results</b><br />In a random sample of 2809 admissions, we identified at least one adverse event in 23.6%. Among 978 adverse events, 222 (22.7%) were judged to be preventable and 316 (32.3%) had a severity level of serious (i.e., caused harm that resulted in substantial intervention or prolonged recovery) or higher. A preventable adverse event occurred in 191 (6.8%) of all admissions, and a preventable adverse event with a severity level of serious or higher occurred in 29 (1.0%). There were seven deaths, one of which was deemed to be preventable. Adverse drug events were the most common adverse events (accounting for 39.0% of all events), followed by surgical or other procedural events (30.4%), patient-care events (which were defined as events associated with nursing care, including falls and pressure ulcers) (15.0%), and health care-associated infections (11.9%).<br /><b>Conclusions</b><br />Adverse events were identified in nearly one in four admissions, and approximately one fourth of the events were preventable. These findings underscore the importance of patient safety and the need for continuing improvement. (Funded by the Controlled Risk Insurance Company and the Risk Management Foundation of the Harvard Medical Institutions.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 12 Jan 2023; 388:142-153</small></div>
Bates DW, Levine DM, Salmasian H, Syrowatka A, ... Reynolds ME, Mort E
N Engl J Med: 12 Jan 2023; 388:142-153 | PMID: 36630622
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19.</h4><i>Cao Z, Gao W, Bao H, Feng H, ... Gao Y, Zhao R</i><br /><b>Background</b><br />Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).<br /><b>Methods</b><br />We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir).<br /><b>Results</b><br />A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%).<br /><b>Conclusions</b><br />Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 28 Dec 2022; epub ahead of print</small></div>
Cao Z, Gao W, Bao H, Feng H, ... Gao Y, Zhao R
N Engl J Med: 28 Dec 2022; epub ahead of print | PMID: 36577095
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis.</h4><i>Dellon ES, Rothenberg ME, Collins MH, Hirano I, ... Giannelou A, Shabbir A</i><br /><b>Background</b><br />Dupilumab, a fully human monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, which have key roles in eosinophilic esophagitis.<br /><b>Methods</b><br />We conducted a three-part, phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo (Part A) or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo (Part B) up to week 24. Eligible patients who completed Part A or Part B continued the trial in Part C, in which those who completed Part A received dupilumab at a weekly dose of 300 mg up to week 52 (the Part A-C group); Part C that included the eligible patients from Part B is ongoing. The two primary end points at week 24 were histologic remission (≤6 eosinophils per high-power field) and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score (range, 0 to 84, with higher values indicating more frequent or more severe dysphagia).<br /><b>Results</b><br />In Part A, histologic remission occurred in 25 of 42 patients (60%) who received weekly dupilumab and in 2 of 39 patients (5%) who received placebo (difference, 55 percentage points; 95% confidence interval [CI], 40 to 71; P<0.001). In Part B, histologic remission occurred in 47 of 80 patients (59%) with weekly dupilumab, in 49 of 81 patients (60%) with dupilumab every 2 weeks, and in 5 of 79 patients (6%) with placebo (difference between weekly dupilumab and placebo, 54 percentage points; 95% CI, 41 to 66 [P<0.001]; difference between dupilumab every 2 weeks and placebo, 56 percentage points; 95% CI, 43 to 69 [not significant per hierarchical testing]). The mean (±SD) DSQ scores at baseline were 33.6±12.41 in Part A and 36.7±11.22 in Part B; the scores improved with weekly dupilumab as compared with placebo, with differences of -12.32 (95% CI, -19.11 to -5.54) in Part A and -9.92 (95% CI, -14.81 to -5.02) in Part B (both P<0.001) but not with dupilumab every 2 weeks (difference in Part B, -0.51; 95% CI, -5.42 to 4.41). Serious adverse events occurred in 9 patients during the Part A or B treatment period (in 7 who received weekly dupilumab, 1 who received dupilumab every 2 weeks, and 1 who received placebo) and in 1 patient in the Part A-C group during the Part C treatment period who received placebo in Part A and weekly dupilumab in Part C.<br /><b>Conclusions</b><br />Among patients with eosinophilic esophagitis, subcutaneous dupilumab administered weekly improved histologic outcomes and alleviated symptoms of the disease. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03633617.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 22 Dec 2022; 387:2317-2330</small></div>
Dellon ES, Rothenberg ME, Collins MH, Hirano I, ... Giannelou A, Shabbir A
N Engl J Med: 22 Dec 2022; 387:2317-2330 | PMID: 36546624
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.</h4><i>Nyang\'wa BT, Berry C, Kazounis E, Motta I, ... Fielding K, TB-PRACTECAL Study Collaborators</i><br /><b>Background</b><br />In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed.<br /><b>Methods</b><br />We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points.<br /><b>Results</b><br />Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%).<br /><b>Conclusions</b><br />In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 22 Dec 2022; 387:2331-2343</small></div>
Nyang'wa BT, Berry C, Kazounis E, Motta I, ... Fielding K, TB-PRACTECAL Study Collaborators
N Engl J Med: 22 Dec 2022; 387:2331-2343 | PMID: 36546625
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Lentiviral Gene Therapy for Artemis-Deficient SCID.</h4><i>Cowan MJ, Yu J, Facchino J, Fraser-Browne C, ... McIvor RS, Puck JM</i><br /><b>Background</b><br />The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in <i>DCLRE1C</i>, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation.<br /><b>Methods</b><br />We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing <i>DCLRE1C</i>, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months.<br /><b>Results</b><br />Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor β chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report.<br /><b>Conclusions</b><br />Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 22 Dec 2022; 387:2344-2355</small></div>
Cowan MJ, Yu J, Facchino J, Fraser-Browne C, ... McIvor RS, Puck JM
N Engl J Med: 22 Dec 2022; 387:2344-2355 | PMID: 36546626
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Recombinant ADAMTS13 for Hereditary Thrombotic Thrombocytopenic Purpura.</h4><i>Asmis LM, Serra A, Krafft A, Licht A, ... Tinguely M, Kremer Hovinga JA</i><br /><AbstractText>A 27-year-old patient with a history of severe obstetrical complications and arterial thrombosis received a diagnosis of hereditary thrombotic thrombocytopenic purpura (TTP) due to severe ADAMTS13 deficiency when she presented with an acute episode in the 30th week of her second pregnancy. When the acute episode of hereditary TTP became plasma-refractory and fetal death was imminent, weekly injections of recombinant ADAMTS13 at a dose of 40 U per kilogram of body weight were initiated. The patient\'s platelet count normalized, and the growth of the fetus stabilized. At 37 weeks 1 day of gestation, a small-for-gestational-age boy was delivered by cesarean section. At the time of this report, the patient and her son were well, and she continued to receive injections of recombinant ADAMTS13 every 2 weeks. (Funded by the Swiss National Science Foundation.).</AbstractText><br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 22 Dec 2022; 387:2356-2361</small></div>
Asmis LM, Serra A, Krafft A, Licht A, ... Tinguely M, Kremer Hovinga JA
N Engl J Med: 22 Dec 2022; 387:2356-2361 | PMID: 36546627
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Sotorasib in p.G12C-Mutated Advanced Pancreatic Cancer.</h4><i>Strickler JH, Satake H, George TJ, Yaeger R, ... Tran Q, Hong DS</i><br /><b>Background</b><br /><i>KRAS</i> p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with <i>KRAS</i> p.G12C-mutated pancreatic cancer are unknown.<br /><b>Methods</b><br />We conducted a single-group, phase 1-2 trial to assess the safety and efficacy of sotorasib treatment in patients with <i>KRAS</i> p.G12C-mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed.<br /><b>Results</b><br />The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation.<br /><b>Conclusions</b><br />Sotorasib showed anticancer activity and had an acceptable safety profile in patients with <i>KRAS</i> p.G12C-mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 21 Dec 2022; epub ahead of print</small></div>
Strickler JH, Satake H, George TJ, Yaeger R, ... Tran Q, Hong DS
N Engl J Med: 21 Dec 2022; epub ahead of print | PMID: 36546651
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated G12C.</h4><i>Yaeger R, Weiss J, Pelster MS, Spira AI, ... Der-Torossian H, Klempner SJ</i><br /><b>Background</b><br />Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.<br /><b>Methods</b><br />In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.<br /><b>Results</b><br />As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.<br /><b>Conclusions</b><br />Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 21 Dec 2022; epub ahead of print</small></div>
Yaeger R, Weiss J, Pelster MS, Spira AI, ... Der-Torossian H, Klempner SJ
N Engl J Med: 21 Dec 2022; epub ahead of print | PMID: 36546659
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa.</h4><i>Guide SV, Gonzalez ME, Bağcı IS, Agostini B, ... Krishnan S, Marinkovich MP</i><br /><b>Background</b><br />Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations in <i>COL7A1</i>, which encodes type VII collagen (C7). Beremagene geperpavec (B-VEC) is a topical investigational herpes simplex virus type 1 (HSV-1)-based gene therapy designed to restore C7 protein by delivering <i>COL7A1</i>.<br /><b>Methods</b><br />We conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain).<br /><b>Results</b><br />Primary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P = 0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P<0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was -0.88 with B-VEC and -0.71 with placebo (adjusted least-squares mean difference, -0.61; 95% CI, -1.10 to -0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills.<br /><b>Conclusions</b><br />Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 15 Dec 2022; 387:2211-2219</small></div>
Guide SV, Gonzalez ME, Bağcı IS, Agostini B, ... Krishnan S, Marinkovich MP
N Engl J Med: 15 Dec 2022; 387:2211-2219 | PMID: 36516090
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.</h4><i>Ishani A, Cushman WC, Leatherman SM, Lew RA, ... Ferguson RE, Diuretic Comparison Project Writing Group</i><br /><b>Background</b><br />Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear.<br /><b>Methods</b><br />In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed.<br /><b>Results</b><br />A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001).<br /><b>Conclusions</b><br />In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 14 Dec 2022; epub ahead of print</small></div>
Ishani A, Cushman WC, Leatherman SM, Lew RA, ... Ferguson RE, Diuretic Comparison Project Writing Group
N Engl J Med: 14 Dec 2022; epub ahead of print | PMID: 36516076
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Randomized Trial of Vaccines for Zaire Ebola Virus Disease.</h4><i>PREVAC Study Team, Kieh M, Richert L, Beavogui AH, ... Neaton J, Yazdanpanah Y</i><br /><b>Background</b><br />Questions remain concerning the rapidity of immune responses and the durability and safety of vaccines used to prevent Zaire Ebola virus disease.<br /><b>Methods</b><br />We conducted two randomized, placebo-controlled trials - one involving adults and one involving children - to evaluate the safety and immune responses of three vaccine regimens against Zaire Ebola virus disease: Ad26.ZEBOV followed by MVA-BN-Filo 56 days later (the Ad26-MVA group), rVSVΔG-ZEBOV-GP followed by placebo 56 days later (the rVSV group), and rVSVΔG-ZEBOV-GP followed by rVSVΔG-ZEBOV-GP 56 days later (the rVSV-booster group). The primary end point was antibody response at 12 months, defined as having both a 12-month antibody concentration of at least 200 enzyme-linked immunosorbent assay units (EU) per milliliter and an increase from baseline in the antibody concentration by at least a factor of 4.<br /><b>Results</b><br />A total of 1400 adults and 1401 children underwent randomization. Among both adults and children, the incidence of injection-site reactions and symptoms (e.g., feverishness and headache) was higher in the week after receipt of the primary and second or booster vaccinations than after receipt of placebo but not at later time points. These events were largely low-grade. At month 12, a total of 41% of adults (titer, 401 EU per milliliter) and 78% of children (titer, 828 EU per milliliter) had a response in the Ad26-MVA group; 76% (titer, 992 EU per milliliter) and 87% (titer, 1415 EU per milliliter), respectively, had a response in the rVSV group; 81% (titer, 1037 EU per milliliter) and 93% (titer, 1745 EU per milliliter), respectively, had a response in the rVSV-booster group; and 3% (titer, 93 EU per milliliter) and 4% (titer, 67 EU per milliliter), respectively, had a response in the placebo group (P<0.001 for all comparisons of vaccine with placebo). In both adults and children, antibody responses with vaccine differed from those with placebo beginning on day 14.<br /><b>Conclusions</b><br />No safety concerns were identified in this trial. With all three vaccine regimens, immune responses were seen from day 14 through month 12. (Funded by the National Institutes of Health and others; PREVAC ClinicalTrials.gov number, NCT02876328; EudraCT numbers, 2017-001798-18 and 2017-001798-18/3rd; and Pan African Clinical Trials Registry number, PACTR201712002760250.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 14 Dec 2022; epub ahead of print</small></div>
PREVAC Study Team, Kieh M, Richert L, Beavogui AH, ... Neaton J, Yazdanpanah Y
N Engl J Med: 14 Dec 2022; epub ahead of print | PMID: 36516078
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Deep Intronic GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.</h4><i>Pellerin D, Danzi MC, Wilke C, Renaud M, ... Zuchner S, Brais B</i><br /><b>Background</b><br />The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.<br /><b>Methods</b><br />We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines.<br /><b>Results</b><br />In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of <i>FGF14</i>, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]<sub>≥250</sub>). There was significant association between <i>FGF14</i> (GAA)<sub>≥250</sub> expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an <i>FGF14</i> (GAA)<sub>≥250</sub> expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of <i>FGF14</i> RNA and protein.<br /><b>Conclusions</b><br />A dominantly inherited deep intronic GAA repeat expansion in <i>FGF14</i> was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 14 Dec 2022; epub ahead of print</small></div>
Pellerin D, Danzi MC, Wilke C, Renaud M, ... Zuchner S, Brais B
N Engl J Med: 14 Dec 2022; epub ahead of print | PMID: 36516086
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia.</h4><i>Brown JR, Eichhorst B, Hillmen P, Jurczak W, ... Cohen A, Shadman M</i><br /><b>Background</b><br />In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton\'s tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available.<br /><b>Methods</b><br />We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05.<br /><b>Results</b><br />At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a <i>TP53</i> mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death.<br /><b>Conclusions</b><br />In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 13 Dec 2022; epub ahead of print</small></div>
Brown JR, Eichhorst B, Hillmen P, Jurczak W, ... Cohen A, Shadman M
N Engl J Med: 13 Dec 2022; epub ahead of print | PMID: 36511784
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.</h4><i>Dickinson MJ, Carlo-Stella C, Morschhauser F, Bachy E, ... Humphrey K, Hutchings M</i><br /><b>Background</b><br />The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is poor. Glofitamab is a bispecific antibody that recruits T cells to tumor cells.<br /><b>Methods</b><br />In the phase 2 part of a phase 1-2 study, we enrolled patients with relapsed or refractory DLBCL who had received at least two lines of therapy previously. Patients received pretreatment with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles total). The primary end point was complete response according to assessment by an independent review committee. Key secondary end points included duration of response, survival, and safety.<br /><b>Results</b><br />Of the 155 patients who were enrolled, 154 received at least one dose of any study treatment (obinutuzumab or glofitamab). At a median follow-up of 12.6 months, 39% (95% confidence interval [CI], 32 to 48) of the patients had a complete response according to independent review. Results were consistent among the 52 patients who had previously received chimeric antigen receptor T-cell therapy (35% of whom had a complete response). The median time to a complete response was 42 days (95% CI, 42 to 44). The majority (78%) of complete responses were ongoing at 12 months. The 12-month progression-free survival was 37% (95% CI, 28 to 46). Discontinuation of glofitamab due to adverse events occurred in 9% of the patients. The most common adverse event was cytokine release syndrome (in 63% of the patients). Adverse events of grade 3 or higher occurred in 62% of the patients, with grade 3 or higher cytokine release syndrome in 4% and grade 3 or higher neurologic events in 3%.<br /><b>Conclusions</b><br />Glofitamab therapy was effective for DLBCL. More than half the patients had an adverse event of grade 3 or 4. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT03075696.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 11 Dec 2022; epub ahead of print</small></div>
Dickinson MJ, Carlo-Stella C, Morschhauser F, Bachy E, ... Humphrey K, Hutchings M
N Engl J Med: 11 Dec 2022; epub ahead of print | PMID: 36507690
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma.</h4><i>Chari A, Minnema MC, Berdeja JG, Oriol A, ... Goldberg JD, Krishnan A</i><br /><b>Background</b><br />G protein-coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells.<br /><b>Methods</b><br />In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 μg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 μg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points - the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities - were assessed in order to select the recommended doses for a phase 2 study.<br /><b>Results</b><br />At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 μg per kilogram weekly [30 patients] and 800 μg per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-μg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-μg dose level) and 4.2 months (in those who had received it at the 800-μg dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively.<br /><b>Conclusions</b><br />Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 10 Dec 2022; epub ahead of print</small></div>
Chari A, Minnema MC, Berdeja JG, Oriol A, ... Goldberg JD, Krishnan A
N Engl J Med: 10 Dec 2022; epub ahead of print | PMID: 36507686
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.</h4><i>Rohaan MW, Borch TH, van den Berg JH, Met Ö, ... Svane IM, Haanen JBAG</i><br /><b>Background</b><br />Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.<br /><b>Methods</b><br />In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×10<sup>9</sup> TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival.<br /><b>Results</b><br />A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression.<br /><b>Conclusions</b><br />In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 08 Dec 2022; 387:2113-2125</small></div>
Rohaan MW, Borch TH, van den Berg JH, Met Ö, ... Svane IM, Haanen JBAG
N Engl J Med: 08 Dec 2022; 387:2113-2125 | PMID: 36477031
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only.</h4><i>Hugosson J, Månsson M, Wallström J, Axcrona U, ... Hellström M, GÖTEBORG-2 Trial Investigators</i><br /><b>Background</b><br />Screening for prostate cancer is burdened by a high rate of overdiagnosis. The most appropriate algorithm for population-based screening is unknown.<br /><b>Methods</b><br />We invited 37,887 men who were 50 to 60 years of age to undergo regular prostate-specific antigen (PSA) screening. Participants with a PSA level of 3 ng per milliliter or higher underwent magnetic resonance imaging (MRI) of the prostate; one third of the participants were randomly assigned to a reference group that underwent systematic biopsy as well as targeted biopsy of suspicious lesions shown on MRI. The remaining participants were assigned to the experimental group and underwent MRI-targeted biopsy only. The primary outcome was clinically insignificant prostate cancer, defined as a Gleason score of 3+3. The secondary outcome was clinically significant prostate cancer, defined as a Gleason score of at least 3+4. Safety was also assessed.<br /><b>Results</b><br />Of the men who were invited to undergo screening, 17,980 (47%) participated in the trial. A total of 66 of the 11,986 participants in the experimental group (0.6%) received a diagnosis of clinically insignificant prostate cancer, as compared with 72 of 5994 participants (1.2%) in the reference group, a difference of -0.7 percentage points (95% confidence interval [CI], -1.0 to -0.4; relative risk, 0.46; 95% CI, 0.33 to 0.64; P<0.001). The relative risk of clinically significant prostate cancer in the experimental group as compared with the reference group was 0.81 (95% CI, 0.60 to 1.1). Clinically significant cancer that was detected only by systematic biopsy was diagnosed in 10 participants in the reference group; all cases were of intermediate risk and involved mainly low-volume disease that was managed with active surveillance. Serious adverse events were rare (<0.1%) in the two groups.<br /><b>Conclusions</b><br />The avoidance of systematic biopsy in favor of MRI-directed targeted biopsy for screening and early detection in persons with elevated PSA levels reduced the risk of overdiagnosis by half at the cost of delaying detection of intermediate-risk tumors in a small proportion of patients. (Funded by Karin and Christer Johansson\'s Foundation and others; GÖTEBORG-2 ISRCTN Registry number, ISRCTN94604465.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 08 Dec 2022; 387:2126-2137</small></div>
Hugosson J, Månsson M, Wallström J, Axcrona U, ... Hellström M, GÖTEBORG-2 Trial Investigators
N Engl J Med: 08 Dec 2022; 387:2126-2137 | PMID: 36477032
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.</h4><i>Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, ... de Boode WP, BeNeDuctus Trial Investigators</i><br /><b>Background</b><br />Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain.<br /><b>Methods</b><br />In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks\' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell\'s stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks\' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points.<br /><b>Results</b><br />A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups.<br /><b>Conclusions</b><br />Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks\' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Dec 2022; epub ahead of print</small></div>
Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, ... de Boode WP, BeNeDuctus Trial Investigators
N Engl J Med: 06 Dec 2022; epub ahead of print | PMID: 36477458
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Buprenorphine versus Methadone for Opioid Use Disorder in Pregnancy.</h4><i>Suarez EA, Huybrechts KF, Straub L, Hernández-Díaz S, ... Mogun H, Bateman BT</i><br /><b>Background</b><br />Opioid agonist therapy is strongly recommended for pregnant persons with opioid use disorder. Buprenorphine may be associated with more favorable neonatal and maternal outcomes than methadone, but existing data are limited.<br /><b>Methods</b><br />We conducted a cohort study involving pregnant persons who were enrolled in public insurance programs in the United States during the period from 2000 through 2018 in which we examined outcomes among those who received buprenorphine as compared with those who received methadone. Exposure to the two medications was assessed in early pregnancy (through gestational week 19), late pregnancy (gestational week 20 through the day before delivery), and the 30 days before delivery. Risk ratios for neonatal and maternal outcomes were adjusted for confounders with the use of propensity-score overlap weights.<br /><b>Results</b><br />The data source for the study consisted of 2,548,372 pregnancies that ended in live births. In early pregnancy, 10,704 pregnant persons were exposed to buprenorphine and 4387 to methadone. In late pregnancy, 11,272 were exposed to buprenorphine and 5056 to methadone (9976 and 4597, respectively, in the 30 days before delivery). Neonatal abstinence syndrome occurred in 52.0% of the infants who were exposed to buprenorphine in the 30 days before delivery as compared with 69.2% of those exposed to methadone (adjusted relative risk, 0.73; 95% confidence interval [CI], 0.71 to 0.75). Preterm birth occurred in 14.4% of infants exposed to buprenorphine in early pregnancy and in 24.9% of those exposed to methadone (adjusted relative risk, 0.58; 95% CI, 0.53 to 0.62); small size for gestational age in 12.1% and 15.3%, respectively (adjusted relative risk, 0.72; 95% CI, 0.66 to 0.80); and low birth weight in 8.3% and 14.9% (adjusted relative risk, 0.56; 95% CI, 0.50 to 0.63). Delivery by cesarean section occurred in 33.6% of pregnant persons exposed to buprenorphine in early pregnancy and 33.1% of those exposed to methadone (adjusted relative risk, 1.02; 95% CI, 0.97 to 1.08), and severe maternal complications developed in 3.3% and 3.5%, respectively (adjusted relative risk, 0.91; 95% CI, 0.74 to 1.13). Results of exposure in late pregnancy were consistent with results of exposure in early pregnancy.<br /><b>Conclusions</b><br />The use of buprenorphine in pregnancy was associated with a lower risk of adverse neonatal outcomes than methadone use; however, the risk of adverse maternal outcomes was similar among persons who received buprenorphine and those who received methadone. (Funded by the National Institute on Drug Abuse.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Dec 2022; 387:2033-2044</small></div>
Suarez EA, Huybrechts KF, Straub L, Hernández-Díaz S, ... Mogun H, Bateman BT
N Engl J Med: 01 Dec 2022; 387:2033-2044 | PMID: 36449419
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Trial of Deferiprone in Parkinson\'s Disease.</h4><i>Devos D, Labreuche J, Rascol O, Corvol JC, ... Moreau C, FAIRPARK-II Study Group</i><br /><b>Background</b><br />Iron content is increased in the substantia nigra of persons with Parkinson\'s disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson\'s disease, but its effects on disease progression are unclear.<br /><b>Methods</b><br />We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson\'s disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson\'s Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.<br /><b>Results</b><br />A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.<br /><b>Conclusions</b><br />In participants with early Parkinson\'s disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Dec 2022; 387:2045-2055</small></div>
Devos D, Labreuche J, Rascol O, Corvol JC, ... Moreau C, FAIRPARK-II Study Group
N Engl J Med: 01 Dec 2022; 387:2045-2055 | PMID: 36449420
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Trial of Training to Reduce Driver Inattention in Teens with ADHD.</h4><i>Epstein JN, Garner AA, Kiefer AW, Peugh J, ... Simon JO, Fisher DL</i><br /><b>Background</b><br />Teens with attention deficit-hyperactivity disorder (ADHD) are at increased risk for motor vehicle collisions. A computerized skills-training program to reduce long glances away from the roadway, a contributor to collision risk, may ameliorate driving risks among teens with ADHD.<br /><b>Methods</b><br />We evaluated a computerized skills-training program designed to reduce long glances (lasting ≥2 seconds) away from the roadway in drivers 16 to 19 years of age with ADHD. Participants were randomly assigned in a 1:1 ratio to undergo either enhanced Focused Concentration and Attention Learning, a program that targets reduction in the number of long glances (intervention) or enhanced conventional driver\'s education (control). The primary outcomes were the number of long glances away from the roadway and the standard deviation of lane position, a measure of lateral movements away from the center of the lane, during two 15-minute simulated drives at baseline and at 1 month and 6 months after training. Secondary outcomes were the rates of long glances and collisions or near-collisions involving abrupt changes in vehicle momentum (g-force event), as assessed with in-vehicle recordings over the 1-year period after training.<br /><b>Results</b><br />During simulated driving after training, participants in the intervention group had a mean of 16.5 long glances per drive at 1 month and 15.7 long glances per drive at 6 months, as compared with 28.0 and 27.0 long glances, respectively, in the control group (incidence rate ratio at 1 month, 0.64; 95% confidence interval [CI], 0.52 to 0.76; P<0.001; incidence rate ratio at 6 months, 0.64; 95% CI, 0.52 to 0.76; P<0.001). The standard deviation of lane position (in feet) was 0.98 SD at 1 month and 0.98 SD at 6 months in the intervention group, as compared with 1.20 SD and 1.20 SD, respectively, in the control group (difference at 1 month, -0.21 SD; 95% CI, -0.29 to -0.13; difference at 6 months, -0.22 SD; 95% CI, -0.31 to -0.13; P<0.001 for interaction for both comparisons). During real-world driving over the year after training, the rate of long glances per g-force event was 18.3% in the intervention group and 23.9% in the control group (relative risk, 0.76; 95% CI, 0.61 to 0.92); the rate of collision or near-collision per g-force event was 3.4% and 5.6%, respectively (relative risk, 0.60, 95% CI, 0.41 to 0.89).<br /><b>Conclusions</b><br />In teens with ADHD, a specially designed computerized simulated-driving program with feedback to reduce long glances away from the roadway reduced the frequency of long glances and lessened variation in lane position as compared with a control program. During real-world driving in the year after training, the rate of collisions and near-collisions was lower in the intervention group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02848092.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Dec 2022; 387:2056-2066</small></div>
Epstein JN, Garner AA, Kiefer AW, Peugh J, ... Simon JO, Fisher DL
N Engl J Med: 01 Dec 2022; 387:2056-2066 | PMID: 36449421
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Lecanemab in Early Alzheimer\'s Disease.</h4><i>van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, ... Kramer LD, Iwatsubo T</i><br /><b>Background</b><br />The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer\'s disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer\'s disease.<br /><b>Methods</b><br />We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer\'s disease (mild cognitive impairment or mild dementia due to Alzheimer\'s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer\'s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer\'s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer\'s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).<br /><b>Results</b><br />A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.<br /><b>Conclusions</b><br />Lecanemab reduced markers of amyloid in early Alzheimer\'s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer\'s disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 29 Nov 2022; epub ahead of print</small></div>
van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, ... Kramer LD, Iwatsubo T
N Engl J Med: 29 Nov 2022; epub ahead of print | PMID: 36449413
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Lifting Universal Masking in Schools - Covid-19 Incidence among Students and Staff.</h4><i>Cowger TL, Murray EJ, Clarke J, Bassett MT, ... Linos N, Hall KT</i><br /><b>Background</b><br />In February 2022, Massachusetts rescinded a statewide universal masking policy in public schools, and many Massachusetts school districts lifted masking requirements during the subsequent weeks. In the greater Boston area, only two school districts - the Boston and neighboring Chelsea districts - sustained masking requirements through June 2022. The staggered lifting of masking requirements provided an opportunity to examine the effect of universal masking policies on the incidence of coronavirus disease 2019 (Covid-19) in schools.<br /><b>Methods</b><br />We used a difference-in-differences analysis for staggered policy implementation to compare the incidence of Covid-19 among students and staff in school districts in the greater Boston area that lifted masking requirements with the incidence in districts that sustained masking requirements during the 2021-2022 school year. Characteristics of the school districts were also compared.<br /><b>Results</b><br />Before the statewide masking policy was rescinded, trends in the incidence of Covid-19 were similar across school districts. During the 15 weeks after the statewide masking policy was rescinded, the lifting of masking requirements was associated with an additional 44.9 cases per 1000 students and staff (95% confidence interval, 32.6 to 57.1), which corresponded to an estimated 11,901 cases and to 29.4% of the cases in all districts during that time. Districts that chose to sustain masking requirements longer tended to have school buildings that were older and in worse condition and to have more students per classroom than districts that chose to lift masking requirements earlier. In addition, these districts had higher percentages of low-income students, students with disabilities, and students who were English-language learners, as well as higher percentages of Black and Latinx students and staff. Our results support universal masking as an important strategy for reducing Covid-19 incidence in schools and loss of in-person school days. As such, we believe that universal masking may be especially useful for mitigating effects of structural racism in schools, including potential deepening of educational inequities.<br /><b>Conclusions</b><br />Among school districts in the greater Boston area, the lifting of masking requirements was associated with an additional 44.9 Covid-19 cases per 1000 students and staff during the 15 weeks after the statewide masking policy was rescinded.<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 09 Nov 2022; epub ahead of print</small></div>
Cowger TL, Murray EJ, Clarke J, Bassett MT, ... Linos N, Hall KT
N Engl J Med: 09 Nov 2022; epub ahead of print | PMID: 36351262
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe\'s Disease.</h4><i>Cohen JL, Chakraborty P, Fung-Kee-Fung K, Schwab ME, ... Kishnani PS, MacKenzie TC</i><br /><AbstractText>Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe\'s disease. The family history was positive for infantile-onset Pompe\'s disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.</AbstractText><br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 09 Nov 2022; epub ahead of print</small></div>
Cohen JL, Chakraborty P, Fung-Kee-Fung K, Schwab ME, ... Kishnani PS, MacKenzie TC
N Engl J Med: 09 Nov 2022; epub ahead of print | PMID: 36351280
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection.</h4><i>Yuen MF, Lim SG, Plesniak R, Tsuji K, ... Theodore D, B-Clear Study Group</i><br /><b>Background</b><br />Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.<br /><b>Methods</b><br />We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Groups 1, 2, and 3 received loading doses of bepirovirsen. The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication.<br /><b>Results</b><br />The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4).<br /><b>Conclusions</b><br />In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HBV infection. Larger and longer trials are required to assess the efficacy and safety of bepirovirsen. (Funded by GSK; B-Clear ClinicalTrials.gov number, NCT04449029.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 08 Nov 2022; epub ahead of print</small></div>
Yuen MF, Lim SG, Plesniak R, Tsuji K, ... Theodore D, B-Clear Study Group
N Engl J Med: 08 Nov 2022; epub ahead of print | PMID: 36346079
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.</h4><i>Freeman MW, Halvorsen YD, Marshall W, Pater M, ... Brown MJ, BrigHTN Investigators</i><br /><b>Background</b><br />Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels.<br /><b>Methods</b><br />In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group.<br /><b>Results</b><br />A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level of 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug.<br /><b>Conclusions</b><br />Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 07 Nov 2022; epub ahead of print</small></div>
Freeman MW, Halvorsen YD, Marshall W, Pater M, ... Brown MJ, BrigHTN Investigators
N Engl J Med: 07 Nov 2022; epub ahead of print | PMID: 36342143
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.</h4><i>Farber A, Menard MT, Conte MS, Kaufman JA, ... Rosenfield K, BEST-CLI Investigators</i><br /><b>Background</b><br />Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes.<br /><b>Methods</b><br />In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause.<br /><b>Results</b><br />In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts.<br /><b>Conclusions</b><br />Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 07 Nov 2022; epub ahead of print</small></div>
Farber A, Menard MT, Conte MS, Kaufman JA, ... Rosenfield K, BEST-CLI Investigators
N Engl J Med: 07 Nov 2022; epub ahead of print | PMID: 36342173
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Progression of Atrial Fibrillation after Cryoablation or Drug Therapy.</h4><i>Andrade JG, Deyell MW, Macle L, Wells GA, ... Verma A, EARLY-AF Investigators</i><br /><b>Background</b><br />Atrial fibrillation is a chronic, progressive disorder, and persistent forms of atrial fibrillation are associated with increased risks of thromboembolism and heart failure. Catheter ablation as initial therapy may modify the pathogenic mechanism of atrial fibrillation and alter progression to persistent atrial fibrillation.<br /><b>Methods</b><br />We report the 3-year follow-up of patients with paroxysmal, untreated atrial fibrillation who were enrolled in a trial in which they had been randomly assigned to undergo initial rhythm-control therapy with cryoballoon ablation or to receive antiarrhythmic drug therapy. All the patients had implantable loop recorders placed at the time of trial entry, and evaluation was conducted by means of downloaded daily recordings and in-person visits every 6 months. Data regarding the first episode of persistent atrial fibrillation (lasting ≥7 days or lasting 48 hours to 7 days but requiring cardioversion for termination), recurrent atrial tachyarrhythmia (defined as atrial fibrillation, flutter, or tachycardia lasting ≥30 seconds), the burden of atrial fibrillation (percentage of time in atrial fibrillation), quality-of-life metrics, health care utilization, and safety were collected.<br /><b>Results</b><br />A total of 303 patients were enrolled, with 154 patients assigned to undergo initial rhythm-control therapy with cryoballoon ablation and 149 assigned to receive antiarrhythmic drug therapy. Over 36 months of follow-up, 3 patients (1.9%) in the ablation group had an episode of persistent atrial fibrillation, as compared with 11 patients (7.4%) in the antiarrhythmic drug group (hazard ratio, 0.25; 95% confidence interval [CI], 0.09 to 0.70). Recurrent atrial tachyarrhythmia occurred in 87 patients in the ablation group (56.5%) and in 115 in the antiarrhythmic drug group (77.2%) (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). The median percentage of time in atrial fibrillation was 0.00% (interquartile range, 0.00 to 0.12) in the ablation group and 0.24% (interquartile range, 0.01 to 0.94) in the antiarrhythmic drug group. At 3 years, 8 patients (5.2%) in the ablation group and 25 (16.8%) in the antiarrhythmic drug group had been hospitalized (relative risk, 0.31; 95% CI, 0.14 to 0.66). Serious adverse events occurred in 7 patients (4.5%) in the ablation group and in 15 (10.1%) in the antiarrhythmic drug group.<br /><b>Conclusions</b><br />Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 07 Nov 2022; epub ahead of print</small></div>
Andrade JG, Deyell MW, Macle L, Wells GA, ... Verma A, EARLY-AF Investigators
N Engl J Med: 07 Nov 2022; epub ahead of print | PMID: 36342178
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial.</h4><i>Hill KD, Kannankeril PJ, Jacobs JP, Baldwin HS, ... Li JS, STRESS Network Investigators</i><br /><b>Background</b><br />Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown.<br /><b>Methods</b><br />We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes.<br /><b>Results</b><br />A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P<0.001).<br /><b>Conclusions</b><br />Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Nov 2022; epub ahead of print</small></div>
Hill KD, Kannankeril PJ, Jacobs JP, Baldwin HS, ... Li JS, STRESS Network Investigators
N Engl J Med: 06 Nov 2022; epub ahead of print | PMID: 36342116
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Duration of Device-Based Fever Prevention after Cardiac Arrest.</h4><i>Hassager C, Schmidt H, Møller JE, Grand J, ... Meyer MAS, Kjaergaard J</i><br /><b>Background</b><br />Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking.<br /><b>Methods</b><br />We randomly assigned comatose patients who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause to device-based temperature control targeting 36°C for 24 hours followed by targeting of 37°C for either 12 or 48 hours (for total intervention times of 36 and 72 hours, respectively) or until the patient regained consciousness. The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category of 3 or 4 (range, 1 to 5, with higher scores indicating more severe disability; a category of 3 or 4 indicates severe cerebral disability or coma) within 90 days after randomization. Secondary outcomes included death from any cause and the Montreal Cognitive Assessment score (range, 0 to 30, with higher scores indicating better cognitive ability) at 3 months.<br /><b>Results</b><br />A total of 393 patients were randomly assigned to temperature control for 36 hours, and 396 patients were assigned to temperature control for 72 hours. At 90 days after randomization, a primary end-point event had occurred in 127 of 393 patients (32.3%) in the 36-hour group and in 133 of 396 patients (33.6%) in the 72-hour group (hazard ratio, 0.99; 95% confidence interval, 0.77 to 1.26; P = 0.70) and mortality was 29.5% in the 36-hour group and 30.3% in the 72-hour group. At 3 months, the median Montreal Cognitive Assessment score was 26 (interquartile range, 24 to 29) and 27 (interquartile range, 24 to 28), respectively. There was no significant between-group difference in the incidence of adverse events.<br /><b>Conclusions</b><br />Active device-based fever prevention for 36 or 72 hours after cardiac arrest did not result in significantly different percentages of patients dying or having severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Nov 2022; epub ahead of print</small></div>
Hassager C, Schmidt H, Møller JE, Grand J, ... Meyer MAS, Kjaergaard J
N Engl J Med: 06 Nov 2022; epub ahead of print | PMID: 36342119
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Defibrillation Strategies for Refractory Ventricular Fibrillation.</h4><i>Cheskes S, Verbeek PR, Drennan IR, McLeod SL, ... Dorian P, Scales DC</i><br /><b>Background</b><br />Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation.<br /><b>Methods</b><br />We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge.<br /><b>Results</b><br />A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% confidence interval [CI], 1.33 to 3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01 to 2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26 to 3.88] and 1.48 [95% CI, 0.81 to 2.71], respectively).<br /><b>Conclusions</b><br />Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF ClinicalTrials.gov number, NCT04080986.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Nov 2022; epub ahead of print</small></div>
Cheskes S, Verbeek PR, Drennan IR, McLeod SL, ... Dorian P, Scales DC
N Engl J Med: 06 Nov 2022; epub ahead of print | PMID: 36342151
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.</h4><i>O\'Donoghue ML, Rosenson RS, Gencer B, López JAG, ... Sabatine MS, OCEAN(a)-DOSE Trial Investigators</i><br /><b>Background</b><br />Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver.<br /><b>Methods</b><br />We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed.<br /><b>Results</b><br />Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain.<br /><b>Conclusions</b><br />Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 06 Nov 2022; epub ahead of print</small></div>
O'Donoghue ML, Rosenson RS, Gencer B, López JAG, ... Sabatine MS, OCEAN(a)-DOSE Trial Investigators
N Engl J Med: 06 Nov 2022; epub ahead of print | PMID: 36342163
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Trial of an Intervention to Improve Acute Heart Failure Outcomes.</h4><i>Lee DS, Straus SE, Farkouh ME, Austin PC, ... Ross HJ, COACH Trial Investigators</i><br /><b>Background</b><br />Patients with acute heart failure are frequently or systematically hospitalized, often because the risk of adverse events is uncertain and the options for rapid follow-up are inadequate. Whether the use of a strategy to support clinicians in making decisions about discharging or admitting patients, coupled with rapid follow-up in an outpatient clinic, would affect outcomes remains uncertain.<br /><b>Methods</b><br />In a stepped-wedge, cluster-randomized trial conducted in Ontario, Canada, we randomly assigned 10 hospitals to staggered start dates for one-way crossover from the control phase (usual care) to the intervention phase, which involved the use of a point-of-care algorithm to stratify patients with acute heart failure according to the risk of death. During the intervention phase, low-risk patients were discharged early (in ≤3 days) and received standardized outpatient care, and high-risk patients were admitted to the hospital. The coprimary outcomes were a composite of death from any cause or hospitalization for cardiovascular causes within 30 days after presentation and the composite outcome within 20 months.<br /><b>Results</b><br />A total of 5452 patients were enrolled in the trial (2972 during the control phase and 2480 during the intervention phase). Within 30 days, death from any cause or hospitalization for cardiovascular causes occurred in 301 patients (12.1%) who were enrolled during the intervention phase and in 430 patients (14.5%) who were enrolled during the control phase (adjusted hazard ratio, 0.88; 95% confidence interval [CI], 0.78 to 0.99; P = 0.04). Within 20 months, the cumulative incidence of primary-outcome events was 54.4% (95% CI, 48.6 to 59.9) among patients who were enrolled during the intervention phase and 56.2% (95% CI, 54.2 to 58.1) among patients who were enrolled during the control phase (adjusted hazard ratio, 0.95; 95% CI, 0.92 to 0.99). Fewer than six deaths or hospitalizations for any cause occurred in low- or intermediate-risk patients before the first outpatient visit within 30 days after discharge.<br /><b>Conclusions</b><br />Among patients with acute heart failure who were seeking emergency care, the use of a hospital-based strategy to support clinical decision making and rapid follow-up led to a lower risk of the composite of death from any cause or hospitalization for cardiovascular causes within 30 days than usual care. (Funded by the Ontario SPOR Support Unit and others; COACH ClinicalTrials.gov number, NCT02674438.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 05 Nov 2022; epub ahead of print</small></div>
Lee DS, Straus SE, Farkouh ME, Austin PC, ... Ross HJ, COACH Trial Investigators
N Engl J Med: 05 Nov 2022; epub ahead of print | PMID: 36342109
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.</h4><i>Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, ... Ridker PM, PROMINENT Investigators</i><br /><b>Background</b><br />High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.<br /><b>Methods</b><br />In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.<br /><b>Results</b><br />Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.<br /><b>Conclusions</b><br />Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 05 Nov 2022; epub ahead of print</small></div>
Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, ... Ridker PM, PROMINENT Investigators
N Engl J Med: 05 Nov 2022; epub ahead of print | PMID: 36342113
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Empagliflozin in Patients with Chronic Kidney Disease.</h4><i>EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Wanner C, ... Baigent C, Haynes R</i><br /><b>Background</b><br />The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients.<br /><b>Methods</b><br />We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m<sup>2</sup> of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m<sup>2</sup> with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m<sup>2</sup>, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes.<br /><b>Results</b><br />A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups.<br /><b>Conclusions</b><br />Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 04 Nov 2022; epub ahead of print</small></div>
EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Wanner C, ... Baigent C, Haynes R
N Engl J Med: 04 Nov 2022; epub ahead of print | PMID: 36331190
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.</h4><i>Goodwin GM, Aaronson ST, Alvarez O, Arden PC, ... Zisook S, Malievskaia E</i><br /><b>Background</b><br />Psilocybin is being studied for use in treatment-resistant depression.<br /><b>Methods</b><br />In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).<br /><b>Results</b><br />A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.<br /><b>Conclusions</b><br />In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Nov 2022; 387:1637-1648</small></div>
Goodwin GM, Aaronson ST, Alvarez O, Arden PC, ... Zisook S, Malievskaia E
N Engl J Med: 03 Nov 2022; 387:1637-1648 | PMID: 36322843
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin\'s Lymphoma.</h4><i>Castellino SM, Pei Q, Parsons SK, Hodgson D, ... Keller FG, Kelly KM</i><br /><b>Background</b><br />In adults with advanced-stage Hodgkin\'s lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin\'s lymphoma is unclear.<br /><b>Methods</b><br />We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin\'s lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed.<br /><b>Results</b><br />Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.<br /><b>Conclusions</b><br />The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Nov 2022; 387:1649-1660</small></div>
Castellino SM, Pei Q, Parsons SK, Hodgson D, ... Keller FG, Kelly KM
N Engl J Med: 03 Nov 2022; 387:1649-1660 | PMID: 36322844
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years.</h4><i>Bloomfield FH, Jiang Y, Harding JE, Crowther CA, Cormack BE, ProVIDe Trial Group</i><br /><b>Background</b><br />Whether higher parenteral amino acid intake improves outcomes in infants with extremely low birth weight is unclear.<br /><b>Methods</b><br />In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned infants with birth weights of less than 1000 g at 8 neonatal intensive care units to receive amino acids at a dose of 1 g per day (intervention group) or placebo in addition to usual nutrition for the first 5 days after birth. The primary outcome was survival free from neurodisability as assessed with the Bayley Scales of Infant and Toddler Development and neurologic examination at 2 years, corrected for gestational age at birth. Secondary outcomes were the components of the primary outcome as well as the presence or absence of neonatal disorders, the rate of growth, and nutritional intake.<br /><b>Results</b><br />We enrolled 434 infants (217 per group) in this trial. Survival free from neurodisability was observed in 97 of 203 children (47.8%) in the intervention group and in 102 of 205 (49.8%) in the placebo group (adjusted relative risk, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P = 0.56). Death before the age of 2 years occurred in 39 of 217 children (18.0%) in the intervention group and 42 of 217 (19.4%) in the placebo group (adjusted relative risk, 0.93; 95% CI, 0.63 to 1.36); neurodisability occurred in 67 of 164 children (40.9%) in the intervention group and 61 of 163 (37.4%) in the placebo group (adjusted relative risk, 1.16; 95% CI, 0.90 to 1.50). Neurodisability was moderate to severe in 27 children (16.5%) in the intervention group and 14 (8.6%) in the placebo group (adjusted relative risk, 1.95; 95% CI, 1.09 to 3.48). More children in the intervention group than in the placebo group had patent ductus arteriosus (adjusted relative risk, 1.65; 95% CI, 1.11 to 2.46). In a post hoc analysis, refeeding syndrome occurred in 42 of 172 children in the intervention group and 26 of 166 in the placebo group (adjusted relative risk, 1.64; 95% CI, 1.09 to 2.47). Eight serious adverse events occurred.<br /><b>Conclusions</b><br />In infants with extremely low birth weight, extra parenteral amino acids at a dose of 1 g per day for 5 days after birth did not increase the number who survived free from neurodisability at 2 years. (Funded by the New Zealand Health Research Council and others; ProVIDe Australian New Zealand Clinical Trials Registry number, ACTRN12612001084875.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Nov 2022; 387:1661-1672</small></div>
Bloomfield FH, Jiang Y, Harding JE, Crowther CA, Cormack BE, ProVIDe Trial Group
N Engl J Med: 03 Nov 2022; 387:1661-1672 | PMID: 36322845
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease.</h4><i>Bhandari S, Mehta S, Khwaja A, Cleland JGF, ... Cockwell P, STOP ACEi Trial Investigators</i><br /><b>Background</b><br />Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline.<br /><b>Methods</b><br />In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m<sup>2</sup> of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.<br /><b>Results</b><br />At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m<sup>2</sup> in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m<sup>2</sup> in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P = 0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22).<br /><b>Conclusions</b><br />Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISTRCTN number, 62869767.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Nov 2022; epub ahead of print</small></div>
Bhandari S, Mehta S, Khwaja A, Cleland JGF, ... Cockwell P, STOP ACEi Trial Investigators
N Engl J Med: 03 Nov 2022; epub ahead of print | PMID: 36326117
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Covid-19 Vaccine Protection among Children and Adolescents in Qatar.</h4><i>Chemaitelly H, AlMukdad S, Ayoub HH, Altarawneh HN, ... Bertollini R, Abu-Raddad LJ</i><br /><b>Background</b><br />The BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) has been authorized for use in children 5 to 11 years of age and adolescents 12 to 17 years of age but in different antigen doses.<br /><b>Methods</b><br />We assessed the real-world effectiveness of the BNT162b2 vaccine against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children and adolescents in Qatar. To compare the incidence of SARS-CoV-2 infection in the national cohort of vaccinated participants with the incidence in the national cohort of unvaccinated participants, we conducted three matched, retrospective, target-trial, cohort studies - one assessing data obtained from children 5 to 11 years of age after the B.1.1.529 (omicron) variant became prevalent and two assessing data from adolescents 12 to 17 years of age before the emergence of the omicron variant (pre-omicron study) and after the omicron variant became prevalent. Associations were estimated with the use of Cox proportional-hazards regression models.<br /><b>Results</b><br />Among children, the overall effectiveness of the 10-μg primary vaccine series against infection with the omicron variant was 25.7% (95% confidence interval [CI], 10.0 to 38.6). Effectiveness was highest (49.6%; 95% CI, 28.5 to 64.5) right after receipt of the second dose but waned rapidly thereafter and was negligible after 3 months. Effectiveness was 46.3% (95% CI, 21.5 to 63.3) among children 5 to 7 years of age and 16.6% (95% CI, -4.2 to 33.2) among those 8 to 11 years of age. Among adolescents, the overall effectiveness of the 30-μg primary vaccine series against infection with the omicron variant was 30.6% (95% CI, 26.9 to 34.1), but many adolescents had been vaccinated months earlier. Effectiveness waned over time since receipt of the second dose. Effectiveness was 35.6% (95% CI, 31.2 to 39.6) among adolescents 12 to 14 years of age and 20.9% (95% CI, 13.8 to 27.4) among those 15 to 17 years of age. In the pre-omicron study, the overall effectiveness of the 30-μg primary vaccine series against SARS-CoV-2 infection among adolescents was 87.6% (95% CI, 84.0 to 90.4) and waned relatively slowly after receipt of the second dose.<br /><b>Conclusions</b><br />Vaccination in children was associated with modest, rapidly waning protection against omicron infection. Vaccination in adolescents was associated with stronger, more durable protection, perhaps because of the larger antigen dose. (Funded by Weill Cornell Medicine-Qatar and others.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 02 Nov 2022; epub ahead of print</small></div>
Chemaitelly H, AlMukdad S, Ayoub HH, Altarawneh HN, ... Bertollini R, Abu-Raddad LJ
N Engl J Med: 02 Nov 2022; epub ahead of print | PMID: 36322837
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Once-Weekly Semaglutide in Adolescents with Obesity.</h4><i>Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, ... Arslanian S, STEP TEENS Investigators</i><br /><b>Background</b><br />A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking.<br /><b>Methods</b><br />In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68.<br /><b>Results</b><br />A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16.7 percentage points; 95% confidence interval [CI], -20.3 to -13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group.<br /><b>Conclusions</b><br />Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 02 Nov 2022; epub ahead of print</small></div>
Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, ... Arslanian S, STEP TEENS Investigators
N Engl J Med: 02 Nov 2022; epub ahead of print | PMID: 36322838
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract
<div><h4>Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali.</h4><i>Kayentao K, Ongoiba A, Preston AC, Healy SA, ... Crompton PD, Mali Malaria mAb Trial Team</i><br /><b>Background</b><br />CIS43LS is a monoclonal antibody that was shown to protect against controlled <i>Plasmodium falciparum</i> infection in a phase 1 clinical trial. Whether a monoclonal antibody can prevent <i>P. falciparum</i> infection in a region in which the infection is endemic is unknown.<br /><b>Methods</b><br />We conducted a phase 2 trial to assess the safety and efficacy of a single intravenous infusion of CIS43LS against <i>P. falciparum</i> infection in healthy adults in Mali over a 6-month malaria season. In Part A, safety was assessed at three escalating dose levels. In Part B, participants were randomly assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first <i>P. falciparum</i> infection detected on blood-smear examination, which was performed at least every 2 weeks for 24 weeks. At enrollment, all the participants received artemether-lumefantrine to clear possible <i>P. falciparum</i> infection.<br /><b>Results</b><br />In Part B, 330 adults underwent randomization; 110 were assigned to each trial group. The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo. <i>P. falciparum</i> infections were detected on blood-smear examination in 39 participants (35.5%) who received 10 mg of CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and 86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS per kilogram as compared with placebo was 88.2% (adjusted 95% confidence interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.001).<br /><b>Conclusions</b><br />CIS43LS was protective against <i>P. falciparum</i> infection over a 6-month malaria season in Mali without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04329104.).<br /><br />Copyright © 2022 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 31 Oct 2022; epub ahead of print</small></div>
Kayentao K, Ongoiba A, Preston AC, Healy SA, ... Crompton PD, Mali Malaria mAb Trial Team
N Engl J Med: 31 Oct 2022; epub ahead of print | PMID: 36317783
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.