Elsevier

American Heart Journal

Volume 235, May 2021, Pages 1-11
American Heart Journal

Trial Designs
Cardiovascular safety and efficacy of vadadustat for the treatment of anemia in non-dialysis-dependent CKD: Design and baseline characteristics

https://doi.org/10.1016/j.ahj.2020.10.068Get rights and content

Current clinical practice guidelines for anemia management in non–dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N = 1751) had hemoglobin <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (N = 1725) had hemoglobin between 8 and 11 g/dL (US) or 9 and 12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include (1) correction/conversion (weeks 0-23); (2) maintenance (weeks 24-52); (3) long-term treatment (week 53 to end of treatment); and (4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics are similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD.

Section snippets

METHODS

The PRO2TECT trials are two ongoing randomized, Phase 3, open-label, active-controlled clinical trials evaluating the safety and efficacy of oral vadadustat vs injectable darbepoetin alfa: PRO2TECT-Correction (previously ESA untreated; NCT02648347) and PRO2TECT-Conversion (previously ESA treated; NCT02680574). Target enrollment for each was approximately 1,850 patients recruited at approximately 390 and 480 sites in North America, Latin America, Europe, and the Asia Pacific for the

RESULTS

In total, 4,708 patients were screened for the ESA-untreated NDD-CKD trial, and 1,751 were randomized. Most (n = 1,061, 60.6%) were from the United States; the remainder were from Europe or non-US/non-Europe. A total of 2,961 patients were screened for the ESA-treated NDD-CKD trial, 1,725 of whom were randomized. Most (n = 1,060, 61.5%) were from Europe or non-US/non-Europe countries, and the remainder were from the United States. The most common reason for screen failure in both trials was an

DISCUSSION

The PRO2TECT program is designed to compare the safety and efficacy of oral vadadustat to injectable darbepoetin alfa in patients with anemia of NDD-CKD.

Although ESAs have helped to correct anemia and typically maintain hemoglobin concentrations in patients with CKD, resulting in lower rates of red blood cell transfusion, concerns about cardiovascular safety have lessened the enthusiasm of healthcare providers to prescribe these agents, particularly for patients with NDD-CKD, whose anemia tends

Disclosures

GMC reports grants from NIDDK and Amgen and personal fees from Akebia Therapeutics, Inc., Satellite Healthcare, Ardelyx, AstraZeneca, Baxter, Cricket, DiaMedica, Gilead, Reata, Sanifit, Vertex, Angion, Bayer, and ReCor. PEP reports personal fees from Akebia Therapeutics, Inc., Astra-Zeneca, Bayer, Reata, Gilead, Corvidia, FibroGen, Tricida, and Ardelyx. PEP's institution, Renal Associates (PA), has received support from multiple pharmaceutical companies, including Akebia Therapeutics, Inc. RA

Funding

Akebia Therapeutics, Inc. and Otsuka Pharmaceuticals.

References (27)

  • J Portolés et al.

    The development of anemia is associated to poor prognosis in NKF/KDOQI stage 3 chronic kidney disease

    BMC Nephrol

    (2013)
  • A Covic et al.

    Real-world impact of cardiovascular disease and anemia on quality of life and productivity in patients with non-dialysis-dependent chronic kidney disease

    Adv Ther

    (2017)
  • TB Drüeke et al.

    Normalization of hemoglobin level in patients with chronic kidney disease and anemia

    N Engl J Med

    (2006)
  • Cited by (0)

    1

    Was an employee of Akebia Therapeutics, Inc. at the time the trial was conducted.

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