Phase 3 trial Design of the Hepatocyte Growth Factor Mimetic ANG-3777 in Renal Transplant Recipients With Delayed Graft Function

Abstract

Introduction One-third of kidney transplantation patients experience acute kidney injury (AKI) resulting in delayed graft function (DGF), associated with increased risk of graft failure and mortality. Preclinical and phase 2 data indicate that treatment with ANG-3777 (formerly BB3), a hepatocyte growth factor (HGF) mimetic, may improve long-term kidney function and reduce health care resource use and cost, but these data require validation in a phase 3 randomized controlled trial. Methods The Graft Improvement Following Transplant (GIFT) trial is a multicenter, double-blind randomized controlled trial, designed to determine the efficacy and safety of ANG-3777 in renal transplantation patients showing signs of DGF. Subjects are randomized 1:1 to ANG-3777 (2 mg/kg) administered intravenously once daily for 3 consecutive days starting within 30 hours after transplantation, or to placebo. Results The primary endpoint is estimated glomerular filtration rate (eGFR) at 12 months. Secondary endpoints include proportion of subjects with eGFR >30 at days 30, 90, 180, and 360; proportion of subjects whose graft function is slow, delayed, or primary nonfunction; length of hospitalization; and duration of dialysis through day 30. Adverse events are assessed throughout the study. Conclusion GIFT will generate data that are important to advancing treatment of DGF in this medically complex population.

Optimizing the Design and Analysis of Future AKI Trials

“…In this regard, longer-term changes in the eGFR might be considered as an end point in clinical trials. 43 An approach for pragmatic trials with very large sample sizes to consider is to have two coprimary end points, and these may be a combination of superiority in a nonmortality outcome and noninferiority in mortality.…”

“…There may also be room for investigation of potential intermediate or surrogate outcomes, such as renal recovery and the risk of progression toward CKD. In this regard, longer-term changes in the eGFR might be considered as an end point in clinical trials 43 . An approach for pragmatic trials with very large sample sizes to consider is to have two coprimary end points, and these may be a combination of superiority in a nonmortality outcome and noninferiority in mortality.…”

Pathogenesis of intrinsic acute kidney injury

“…HGF is nephro-protective in animal models of AKI, and recent studies have explored the effects of BB3/ ANG3777, a small molecule with strong HGF-like activity, which, when administered at 24 h after kidney ischemia in rats, improved survival and kidney function. BB3/ANG3777 is currently being tested in human AKI [18]. Human trials with recombinant IGF-1 have not demonstrated a beneficial effect.…”

Innovative immunosuppression in kidney transplantation: A challenge for unmet needs

“…In a randomized, placebo-controlled phase 2 trial on oliguric patients after kidney transplantation, patients treated with ANG-3777 had a larger increase in urine output, a greater reduction in C reactive protein and neutrophil gelatinase-associated lipocalin and a higher estimated glomerular filtration rate (eGFR)[ 24 ]. More recently, Vincenti et al [ 25 ] started the Graft Improvement Following Transplant (GIFT) trial, which is a phase 3 trial on the hepatocyte growth factor mimetic ANG-3777 in kidney transplant recipients with DGF. The aim of GIFT is to generate data to advance the treatment of DGF.…”