Novel Renal Autologous Cell Therapy for Type 2 Diabetes Mellitus Chronic Diabetic Kidney Disease: Clinical Trial Design

Abstract

<b><i>Background:</i></b> Cell therapies explore unmet clinical needs of patients with chronic kidney disease with the potential to alter the pathway toward end-stage kidney disease. We describe the design and baseline patient characteristics of a phase II multicenter clinical trial utilizing the novel renal autologous cell therapy (REACT), by direct kidney parenchymal injection via the percutaneous approach in adults with type 2 diabetic kidney disease (T2DKD), to delay or potentially avoid renal replacement therapy. <b><i>Design:</i></b> The study conducted a prospective, multicenter, randomized control, open-label, phase II clinical trial between an active treatment group (ATG) receiving REACT from the beginning of the trial and a contemporaneous deferred treatment group (DTG) receiving standard of care for 12 months before crossing over to receive REACT. <b><i>Objectives:</i></b> The objective of this study was to establish the safety and efficacy of 2 REACT injections with computed tomography guidance, into the renal cortex of patients with T2DKD administered 6 months apart, and to compare the longitudinal change in renal function between the ATG and the DTG. <b><i>Setting:</i></b> This was a multicenter study conducted in major US hospitals. <b><i>Patients:</i></b> We enrolled eighty-three adult patients with T2DKD, who have estimated glomerular filtration rates (eGFRs) between 20 and 50 mL/min/1.73 m<sup>2</sup>. <b><i>Methods:</i></b> All patients undergo an image-guided percutaneous kidney biopsy to obtain epithelial phenotype selective renal cells isolated from the kidney tissue that is then expanded ex vivo over 4–6 weeks, resulting in the REACT biologic product. Patients are randomized 1:1 into the ATG or the DTG. Primary efficacy endpoints for both study groups include eGFR measurements at baseline and at 3-month intervals, through 24 months after the last REACT injection. Safety analyses include biopsy-related complications, REACT injection, and cellular-related adverse events. The study utilizes Good Clinical and Manufacturing Practices and a Data and Safety Monitoring Board. The sample size confers a statistical power of 80% to detect an eGFR change in the ATG compared to the DTG at 24 months with an α = 0.05. <b><i>Limitations:</i></b> Blinding cannot occur due to the intent to treat procedure, biopsy in both groups, and open trial design. <b><i>Conclusion:</i></b> This multicenter phase II randomized clinical trial is designed to determine the efficacy and safety of REACT in improving or stabilizing renal function among patients with T2DKD stages 3a–4.

<i>Rilparencel</i> (Renal Autologous Cell Therapy-REACT^®) for Chronic Kidney Disease and Type 1 and Type 2 Diabetes: Phase 2 Trial Design Evaluating Bilateral Kidney Dosing and Redosing Triggers

“…An outpatient percutaneous kidney biopsy is performed with an automated device under ultrasound or CT image guidance. A minimum of two cores using a 16-gauge or four cores using an 18-gauge biopsy needle are collected to supply sufficient material for cell manufacturing as previously described [ 4 ]. An additional biopsy may be obtained for local pathologic analysis at the discretion of the investigator.…”

“…On the day of the scheduled injection, participants are admitted to the outpatient hospital/clinical research center for the procedure. After warming the cells to room temperature, the investigational product is injected into the kidney cortex region using a percutaneous co-axial needle approach by CT image guidance and with conscious sedation as described previously [ 4 ]. We conduct real-time assessment of needle location and cell deposition with intermittent CT scanning to identify potential perinephric bleeding.…”

“…Cell-based therapies (CBT) for this population have the potential to preserve kidney function and forestall dialysis, offering reductions in short-and long-term care costs and an improved quality of life. Early-phase investigative CBT trials in the kidney are underway, but there is limited evaluation of optimal delivery methods and dosing schedules to assess treatment durability and safety [3][4][5][6]. Most dose data for kidney CBTs are under-reported and widely variable, and beyond a few reported dose escalation studies for cell target safety, the dosing frequency for treatment durability offers unique trial challenges caused by CKD heterogeneity and nonlinear rates of disease progression [7].…”

Renal Autologous Cell Therapy in Type 2 Diabetes with Late Stage 4 Diabetes-Related Chronic Kidney Disease: Trial Design and Early Analysis

“…The REACT dose is 3 × 10 6 cells/g estimated kidney weight, determined by renal volume analysis, with a dose range of 3–8 mL. All injections are performed as outpatient procedures under conscious sedation [ 10 , 11 ]. Post-injection renal ultrasounds, hemoglobin, hematocrit, and chemistry levels are obtained during the recovery period and at 24 h, to detect adverse events.…”

“…Findings in our preceding animal studies led to FDA-approved phase I and II clinical trials utilizing an admixture of ex vivo expanded homologous autologous selected renal cells (SRCs) obtained from a percutaneous kidney biopsy, which form the product called Renal Autologous Cell Therapy (REACT) [ 7 , 8 , 9 , 10 ]. Injection procedures have been well tolerated among patients with type 2 diabetes [ 11 ].…”