A Decentralized Phase II Open-Label Trial Assessing the Safety and Efficacy of Dapagliflozin in Renal AL Amyloidosis (FLORAL)

Background and Significance: In renal amyloid light chain amyloidosis (AL), the severity of proteinuria is a risk factor for progression to end-stage renal disease (ESRD) and the need for hemodialysis, impacting prognosis. Despite the incorporation of daratumumab into the regimen of cyclophosphamide, bortezomib, and dexamethasone achieving deeper and durable hematologic responses, roughly half of AL patients (pts) fail to exhibit renal response within six months. While several preclinical studies and clinical trials indicate that sodium-glucose cotransporter 2 inhibitors (SGLT2i) can reduce proteinuria in chronic kidney disease, their potential utility as therapy for renal AL remains unexplored.

Clinical trials are central to evidence-based medicine but face recruitment and retention challenges, with 20% of sites failing to enroll pts, a 30% dropout rate, and geographic distance hindering participation. Decentralized Clinical Trials (DCTs) offer a promising solution by using digital health technology to streamline processes, reduce costs, and improve efficiency. Although studies have begun validating the DCT framework, no amyloidosis trial has implemented a fully virtual, decentralized approach. Our project has two-fold significance: first, to evaluate the potential of SGLT2i as anti-proteinuric agents in AL. If effective, this could introduce a novel approach to preventing renal dysfunction, potentially postponing or mitigating the onset of renal failure and the need for hemodialysis. Second, to demonstrate the feasibility of decentralized clinical trials in hematology, enhancing inclusivity by reaching a geographically diverse participant population.

Study Design and Methods: This investigator-initiated, Phase II, open-label, single-arm, decentralized clinical trial (NCT06420167) aims to evaluate the efficacy and safety of dapagliflozin in patients with renal AL amyloidosis and the practical viability of implementing the DCT framework. Eligible participants are adult Michigan residents with ECOG Performance Status of 0-2, biopsy-confirmed renal AL, and >1.0 g/day proteinuria without other identifiable causes, with a plateau in renal response. Pts are not eligible if they are still undergoing first-line induction or post-induction maintenance with anti-plasma cell therapy for less than six months before enrollment. The primary objective is to evaluate the efficacy of dapagliflozin in reducing proteinuria in renal AL pts, measured by the proportion achieving a 30% reduction in daily proteinuria at any point within six months of starting protocol therapy. The secondary objective is to assess the feasibility of the DCT approach through completion rates of tele-visits and post-trial feedback. The exploratory objective is to assess cardiac and renal deterioration, with endpoints including significant declines in eGFR, onset of ESRD, or death from renal disease-related or cardiovascular causes, and the incidence of dialysis-dependent ESRD in patients with Pavia Renal AL Stage II or III.

The trial will recruit patients throughout Michigan via local healthcare provider communications, colleague referrals, and self-referrals through a study website. Potential participants will be prescreened online and screened for eligibility via direct phone outreach. Informed consent will be obtained electronically using Adobe Sign, supplemented with a video presentation. The recruitment process follows a fully decentralized pathway for determination of eligibility, consent, enrollment, and study execution. Study supplies, including the study drug, will be mailed to participants. After a baseline telehealth visit, participants will start dapagliflozin 10 mg once daily in addition to standard care for six months, with regular virtual visits and data collection at 1, 3, and 6 months. Lab work will be completed at patients' preferred local labs and drug adherence will be monitored via a pill-reminder app or pill diary screenshots. Study closure will commence after the final visit of the last participant. Using A'Hern's single-arm design with a one-sided type I error rate (α) of 0.05 and a power of 0.90, 16 pts are needed. Anticipating a 20% dropout rate, 20 pts will be enrolled. Descriptive statistics will summarize patient characteristics as median with interquartile range for continuous variables, and count with percentage for categorical variables.