Phase 3 trial: Vadadustat noninferior to darbepoetin alfa in hemoglobin maintenance
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Vadadustat is noninferior to darbepoetin alfa in preserving hemoglobin levels in patients with nondialysis-dependent chronic kidney disease and anemia who were or were not treated with erythropoiesis-stimulating agents prior, a study shows.
However, vadadustat did not meet the trial’s noninferiority criterion for cardiovascular safety compared with darbepoetin alfa.
“In terms of efficacy for both trials, vadadustat met its noninferiority target,” Glenn M. Chertow, MD, MPH, Norman S. Coplon satellite health care professor of medicine, epidemiology and population health, chief of the nephrology division at Stanford University Health, said at ASN Kidney Week, which was held as a virtual event. “There were a number of treatment-emergent adverse events” that were “similarly balanced across the two groups.”
Chertow and colleagues conducted two randomized, open-label, sponsor-blind, parallel group, active-controlled noninferiority trials that compared vadadustat with darbepoetin alfa. They randomized 1,751 patients, including 1,061 U.S. patients, for the ESA untreated trial and 1,725 patients, including 1,060 from Europe, for the ESA treated trial. For both trials, the ratio of patients randomized to vadadustat or darbepoetin alfa was 1:1.
All patients had NDD-CKD and anemia. No patients received a red blood cell transfusion within 8 weeks of randomization. Chertow said during the presentation that baseline hemoglobin eligibility criteria for the ESA treated trial varied between the United States and Europe “to maintain region-specific, guideline-driven targets.” In the U.S., baseline hemoglobin concentrations needed to be from 8 g/dL to 11 g/dL and in Europe, the concentration needed to be from 9 g/dL to 12 g/dL. Chertow said target hemoglobin concentrations are 10 g/dL to 11 g/dL in the United States and 10 g/dL to 12 g/dL in other regions.
The primary safety endpoint was time to first adverse cardiovascular event, including all-cause mortality, nonfatal myocardial infarction or nonfatal stroke (MACE), with a noninferiority margin upper bound of 1.25. Researchers combined safety data from both trials for analysis. The primary efficacy endpoint was the change in average hemoglobin from baseline to the end of the primary evaluation period, which was weeks 24 to 36. The lower bound of the efficacy noninferiority measure was 0.75 g/dL. Researchers measured hemoglobin changes from baseline during weeks 24 to 36 and weeks 40 to 52 and compared data from patients treated with vadadustat with darbepoetin alfa.
“We just received these data just 3 or 4 weeks ago, so we’re still conducting analyses of a number of issues trying to better understand the findings and we are working to expeditiously publish these main results,” Chertow said.
Initial results showed vadadustat met noninferiority efficacy targets. In patients who were not previously treated with ESAs, the vadadustat group had a greater hemoglobin change from baseline at weeks 24 to 36 (1.43 vs. 1.38), as well as weeks 40 to 52 (1.52 vs. 1.48) compared with darbepoetin alfa. Patients who were transitioned from ESAs to vadadustat for the trial had lower hemoglobin changes with darbepoetin alfa at weeks 24 to 36 (0.41 vs. 0.42) and weeks 40 to 52 (0.43 vs. 0.44).
Chertow said adverse events “were similarly balanced across the two groups.” Nonetheless, vadadustat did not meet the prespecified cardiovascular safety noninferiority criterion. The initial safety analysis dichotomized age into younger than or equal to 65 years and older than 65 years. Chertow said that “does not yield the most precise treatment estimate because of poor suggesting for a 63-year-old vs. a 33-year-old.” An analysis that implemented age as a continuous variable found lower hazard ratios for MACE (HR = 1.17 vs. 1.14), MACE plus hospitalization for heart failure or thromboembolic events excluding vascular access failure (HR = 1.11 vs. 1.09), all-cause mortality (HR= 1.09 vs. 1.06), MACE adjudicated for cardiovascular mortality, nonfatal myocardial infarction or nonfatal stroke (HR = 1.16 vs. 1.14) and cardiovascular mortality (HR = 1.01 vs. 0.99). Risk for cardiovascular events was similar in the United States, but was higher in patients randomized to vadadustat in regions that used a hemoglobin target of 10 g/dL to 12 g/dL.
Chertow said data analysis is ongoing.
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Chertow GM, et al. Paper FR-OR54. Presented at: ASN Kidney Week. Oct. 22-25, 2020 (virtual meeting).
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