Health Effects (Renal) of Extra Strength Avmacol (HEROES) Study: Interim Update from the Phase 2 Randomized Double-Blind Placebo-Controlled Trial

Background: Progression of chronic kidney disease (CKD) is associated with increased oxidative stress (OS). The common null allele of the glutathione S-transferase μ-1 (GSTM1) gene, which encodes an antioxidant enzyme and is a downstream target of nuclear factor erythroid 2-related factor 2 (Nrf2), has been shown to be associated with elevated oxidative stress and increased risk of CKD progression in clinical studies. We hypothesize that upregulating antioxidant enzymes by activating the Nrf2 pathway via supplementation with sulforaphane (SFN) would decrease markers of OS and inflammation and slow CKD progression. We are testing this hypothesis using Avmacol Extra Strength (ES) in a Phase 2 randomized double-blind placebo-controlled safety and feasibility trial. Methods: Adult subjects with CKD Stage 3-4 (eGFR 15-60 mL/min/1.73m2) and progressive GFR decline are recruited from the Kidney Clinic at the University of Rochester Medical Center. Subjects are randomized to take 4 tablets daily of either Avmacol ES or a matching placebo for 6 months. Blood and urine are obtained for markers of OS and inflammation at baseline, and at 1, 3, and 6 months, in addition to standard of care clinical labs. GSTM1 genotype is also determined. Results: As of May 1, 2024, 59 subjects have enrolled and completed a baseline visit, of which 28 have completed the 6-month study. By RT-PCR genotyping, 27 have at least 1 active Gstm1 allele (1/0 or 1/1, 45.8%). In total, there have been 149 reported side effects (SEs), including 101 related to the gastrointestinal (GI) system, and 3 serious adverse events (SAEs), all GI-related. While 1 arm of the study has a slightly higher proportion of subjects without any SEs (21.2% vs. 12.0%), the number of SEs per subject with at least 1 SE is similar (2.5 vs 2.7). One subject with a GI SAE was discontinued from the study due to safety concerns, while another 7 subjects have voluntarily withdrawn from the study. Conclusion: As of this interim report, there is no significant difference in SE or SAE rate between the arms of the study, with most being relatively mild. The GSTM1 genotypes of the study participants are within the expected proportions. This study is on pace to complete recruitment (100 subjects total) in ~6 months. Funding: NIDDK Support - NIDDK Support, NIDDK Support