RANDOMIZED EMBEDDED ADAPTIVE PLATFORM CLINICAL TRIAL IN SOUTH ASIAN KIDNEY BIOPSY-PROVEN PRIMARY GLOMERULAR DISEASES: MULTI-CENTER, MULTI-ARM AND MULTI-STAGE- THE STORY SO FAR.

Glomerular diseases are the most common cause of CKD after diabetes and hypertension and IgAN is the most common primary glomerular disease in adults. India is the most populous country in the South Asian region which has one-fourth of the global population. Our group has shown that South Asian ethnicity is associated with much severe phenotype, rapid progression in the first prospective longitudinal IgAN (GRACE-IgANI) cohort. There is a dearth of funded academic pragmatic clinical trials looking at commonly available and approved generic drugs that can be effective long term strategies for better clinical outcomes in the South Asian region. The KDIGO guidelines advocate enrolling patients prospectively in ‘Clinical Trials’ especially to understand region specific treatment effectiveness.

Hypothesis: The overarching study hypothesis is that commonly available and approved drugs (oral steroids, gut-directed budesonide hydroxychloroquine, mycophenolate mofetil, or nsMRA) in addition to maximally tolerated RAASi and SGLT2i (SoC) can significantly improve the kidney outcomes at 2 years when compared to SoC alone in South-Asian kidney biopsy proven adult (≥18 years) primary IgAN who are on SOC and on follow-up remain at high risk of progression defined as UPCR ≥0.75g/g and baseline eGFR ≥20ml/min/1.73m2 despite good BP control. The investigators are allowed to use IS regime of their choice and there will be at least a three month wash out period between end of IS and inclusion in the trial.

Phase IV Randomized Embedded Adaptive MAMS Platform Trial with Concurrent Comparator arm and four Interventional arms in two stages inclusion and exclusion criteria. Inclusion criteria: 1. Adults between 18-65 years of age 2. Males or Females 3. eGFR ≥20 ml/min/1.73m2 4. UPCR ≥0.75 g/g  or 24HUP ≥ 1g/day 5. Renal biopsy proven primary IgA nephropathy 6. Patient on maximum tolerated dose of RAASi and SGLT2i (SoC) for at least 3 months with a goal BP of <140/90 mmHg. Exclusion criteria: 1. Patients who received immunosuppressive treatment in the preceding 6 months 2. Secondary IgAN 3. Female patients planning pregnancy 4. Concomitant co-morbidities like systemic autoimmune disorders, chronic infections, chronic liver disease etc. 5. Evidence of rapidly progressive glomerulonephritis 6. Concomitant chronic renal disease in addition to IgAN in kidney biopsy 7. Uncontrolled diabetes. Sample size: A total of 585 patients (allocation 1:1 in control arm; ~117 in each of the interventional arms) over approximately two years. Sample size calculations were based on change in eGFR slope at 2 years in the intervention compared to control group with 90% power and a one-sided type I error of 2.5% for each pair-wise comparison.

This trial is funded by DBT Wellcome UK India Alliance Senior Fellowship [IA/CPHS/22/1/506541] granted to the PI [SA].

The trial is a pragmatic Platform Trial. Milestones achieved:

1. Ethics submission and approval in 11 sites completed 2. CTRI [CTRI/2024/11/076794] and ClinicalTrials.gov [NCT06676384] registered. 3. Master Protocol version 1.62 approved in all sites 4. First Participant randomised in CMC Vellore on 15.02.2025. 5. All 11 sites have randomised their first patient by Jan 2025. 6. Two in-person investigators’ and TSC meetings in Nov 2023 and Nov 2025 along with patient representatives. 7.  >50% of the participant recruitment expected to be completed by March 2026.  

Total screened: 784

Date of First Participant Randomised: 01/02/2025

Number Randomised till 14/01/2026: 205 (35% of total N) 

 Allocation ratio 1:1 into 5 arms

Baseline parameters (n=205): Median age- 38 (IQR: 31-46) yrs; Gender: Male (111, 53.9%), Female (95, 46.1%); BMI: 24.7 (IQR: 22.43-27.1) kg/m2; Mean SBP: 121.18± 9.35 mmHg, Mean DBP: 81.57±6.88 mmHg; Diabetes: n= 23 (11.2%); Mean eGFR: 48.96± 23.79 ml/min/1.73m2; Mean serum albumin: 4.14± 0.36 mg/dL; median UPCR 1.37 (IQR: 1-2.08) g/g.

Three months in-centre follow-up till 14/01/2026: 125/205 (61%)

Six months in-centre follow-up till 14/01/2026: 51/205 (25%)

Nine months in-centre follow-up till 14/01/2026: 17/205 (8.3%)

 Adverse events so far: 105

Serious Adverse Events: 03

 Early Treatment Discontinuation: 03 (1.73 %)

Lost to follow up: 02 (1.15 %)

The IDMC has finished the first safety review for the trial. The interim analysis for the percentage reduction in proteinuria will be conducted after 50% of the total participants have completed 9 months of follow-up. Based on the pre-specified futility analysis, the TSC will decide whether to stop interventions and introduce new interventional arms, as recommended by the IDMC. The primary efficacy endpoint, change in eGFR slope, will be determined at 2 years of follow-up. Adverse events, PROM and glucocorticoid toxicity indices the other secondary endpoints. Sample biobanking is being undertaken at baseline and at each 6-monthly in-centre visit. We will be able to generate primary evidence of clinical efficacy and toxicity of anti-proteinuric and immunomodulatory therapies in primary glomerular diseases in the South Asian population. The Platform MAMS trial design is being used for the first time in IgAN therapeutics, and it will help establish the ‘GRACE- Clinical Trial Network’ for similar studies in glomerular diseases.