Which of the Commonly Available and Approved Drugs in Addition to Standard of Care Can Significantly Improve the Slope of Estimated Glomerular Filtration Rate at Two Years When Compared to Standard of Care Alone in South-Asian Kidney Biopsy-proven Adult (≥18 Years) Primary IgA Nephropathy?

NCT06676384 | Recruiting Phase 4 DMC

• 3 other identifiers: IA/CPHS/22/1/50654115811[INTERVEN] dated 25.10.23CTRI/2024/11/076794
• Study Type: interventional
• Target: 585
• Locations: 1 country
• Sites: 12

Brief Summary

Global Burden of Diseases ranks chronic kidney disease (CKD) as the 12th leading cause of death, with an estimated 20% increase from 2010 to 2019. India is the most populous country in South Asia, with one-fourth of the global population. CKD prevalence has reached epidemic proportions in South Asia, with 1 in 7 adults affected by it. Glomerular diseases are the most common cause of CKD after diabetes and hypertension. IgAN is the most common primary glomerular disease in adults. In the Caucasian and East Asian populations, IgAN results in end-stage kidney disease (ESKD) in 15-20% of patients within 15-20 years after the first clinical presentation. Our first prospective observational (GRACE-IgANI) cohort since 2015 showed that South Asians have severe and progressive IgAN, with 39% having a rapid fall in eGFR, 25% having non-remission of proteinuria, and 36% reaching an adverse kidney outcome at three years. Our group has shown that South Asian ethnicity is associated with a severe phenotype, rapid progression, and significant ethnic differences in biomarkers. Over the last few years, newer anti-proteinuric agents and immunomodulatory drugs have either been approved by the FDA or are in the late phases of clinical trials for various proteinuric kidney diseases. The results of the STOP-IgAN and the recent TESTING trial have shown that the short-term beneficial effects of steroids on proteinuria and eGFR slope at six months wane over time, and there is a need for effective longer-term agents. The KDIGO guidelines development body on glomerular diseases has actively advocated enrolling patients prospectively in 'Clinical Trials'. Platform trials are Multi-Arm and Multi-Stage (MAMS) randomised CTs comparing multiple parallel interventional groups against standardised common control groups with central coordination. It allows new interventions to be added, the control group to be updated throughout the trial, and the use of prespecified interim analysis plans for statistical efficiencies. Interventional groups can be introduced after the trial has started based on pre-specified criteria, and futile interventions may be stopped based on pre-specified interim analyses and trial-stopping rules. This is a randomised controlled single-blind (outcome assessor) Platform trial, Multi-Arm and Multi-Stage. There is a single overarching protocol called a Master protocol. The master protocol, the common concurrent control arm for multiple interventions,the within-trial adaptations, the pre-specified interim analyses, and the pragmatic nature ensure greater acceptability and allow key trial characteristics to evolve. The overall strategy of the study relies strongly on pragmatic 'real world clinical situations' faced by practising nephrologists when treating adult patients with kidney biopsy-proven primary IgAN in South Asia. It will establish the 'GRACE Clinical Trial Network'. The overarching trial hypothesis is that commonly available and approved generic drugs (low-dose oral prednisolone, gut-directed budesonide, mycophenolate mofetil, and hydroxychloroquine) in addition to Standard of Care (SoC), which is the maximal labelled or tolerated dose of renin-angiotensin system blockers (ACEi/ ARB) and a steady dose of sodium-glucose cotransporter 2 inhibitors (SGLT2i) can significantly improve the kidney outcomes at two years when compared to Standard of Care (SoC) alone in South Asian kidney biopsy-proven adult (≥18 years) primary IgAN who 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. SoC is defined as a maximal labelled or tolerated dose of ACEi/ ARB and a steady dose of SGLT2i with a goal BP \<140/90 mmHg for at least three months.

Conditions

IgA Nephropathy; Renal Insufficiency, Chronic; IgA Vasculitis; IGA Glomerulonephritis

Keywords

Platform Trial; Randomised Embedded Trial; MAMS Trial; IgA Nephropathy; Chronic kidney disease; Glomerulonephritis; IgA Vasculitis; Single blind; Treatment

Outcome Measures

Primary Outcomes (1)

• To evaluate the mean change in annualized eGFR slope (ml/min/1.73m2) in the interventional and the active comparator arms.

  Mean change in eGFR slope in ml/min/1.73m2/year

  Baseline, 3, 6, 9, 12, 15, 18 and 24 months

Secondary Outcomes (12)

• To evaluate the mean change in UPCR ratio in the interventional and the active comparator arms.

  Baseline, 6, 12, 18 and 24 months

• To evaluate the mean change in time averaged proteinuria in the interventional and the active comparator arms.

  Baseline, 6, 12, 18 and 24 months

• Proportion of participants reaching the composite endpoint

  From enrollment to the end of treatment at 24 months

• Proportion of participants having rapidly progressive kidney disease

  From enrollment to the end of treatment at 24 months

• Proportion of participants reaching eGFR <15 ml/min/1.73 m2

  From enrollment to the end of treatment at 24 months

Other Outcomes (1)

• Serum biomarker profile

  Baseline, 12, 24 months

Study Arms (6)

Standard of Care (SoC)

ACTIVE COMPARATOR

This intervention arm will start with the randomisation of the first participant.

Drug: SoC defined as maximal labelled or tolerated dose of angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker (ACEi/ARB) & steady dose of sodium-glucose cotransporter-2 inhibitor (SGLT2i)

SoC and Oral prednisolone

EXPERIMENTAL

This intervention arm will start with randomisation of the first participant.

Drug: Oral prednisolone and SoC

SoC and Gut-directed budesonide

EXPERIMENTAL

This intervention arm will start with the randomisation of the first participant.

Drug: Gut-directed budesonide and SoC

SoC and Mycophenolate mofetil (MMF)

EXPERIMENTAL

This intervention arm will start with the randomisation of the first participant.

Drug: Mycophenolate mofetil (MMF) and SoC

SoC and Hydroxychloroquine

EXPERIMENTAL

This intervention arm will start with the randomisation of the first participant.

Drug: Hydroxychloroquine and SoC

SoC and Non-steroidal mineralocorticoid receptor antagonist

EXPERIMENTAL

The sixth arm may begin after the planned interim analysis conditional to the availability of the generic drug in the Indian market and will recruit an additional 117 participants with a concurrent comparator arm.

Drug: Non-steroidal mineralocorticoid receptor antagonist and SoC

Interventions

Oral prednisolone and SoC DRUG

Oral prednisolone 0.5 mg/kg per day (maximum, 40 mg/day) for two months, followed by dose tapering by 5mg per day each month for six to nine months. All participants in this arm will receive SoC and oral cotrimoxazole prophylaxis.

Also known as: Wysolone® by Pfizer Ltd.

SoC and Oral prednisolone

Gut-directed budesonide and SoC DRUG

Gut-directed Budesonide 12 mg once daily for nine months and tapered to 9mg once daily for the next three months, 6mg once daily for the next three months and 3mg once daily for the next three months and stopped (total 18 months). All participants in this arm will receive SoC.

Also known as: IgANEF® by MediART Life Sciences Pvt. Ltd.

SoC and Gut-directed budesonide

Mycophenolate mofetil (MMF) and SoC DRUG

Mycophenolate mofetil (MMF) 1.5g/ day for twelve months, followed by 1g/ day for six months (total 18 months). All participants in this arm will receive SoC.

Also known as: Mycept® by Panacea Biotec Ltd.

SoC and Mycophenolate mofetil (MMF)

Hydroxychloroquine and SoC DRUG

Hydroxychloroquine (HCQ) 6.5 mg/kg/day (maximum 400 mg daily) for 24 months. All participants in this arm will receive SoC.

Also known as: Ipca HCQ® by IPCA Laboratories Ltd.

SoC and Hydroxychloroquine

Non-steroidal mineralocorticoid receptor antagonist and SoC DRUG

Generic drug not available currently. All participants in this arm will receive SoC.

SoC and Non-steroidal mineralocorticoid receptor antagonist

SoC defined as maximal labelled or tolerated dose of angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker (ACEi/ARB) & steady dose of sodium-glucose cotransporter-2 inhibitor (SGLT2i) DRUG

Maximal labelled or tolerated dose of ACEi/ ARB and a steady dose of SGLT2i (10mg/d of dapagliflozin).

Also known as: Dapmed® by Medgenix Pharma India Pvt. Ltd.

Standard of Care (SoC)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be able to provide a written informed consent form, which must be obtained before the initiation of study assessments.
• Adults between 18-65 years of age.
• Males or Females.
• Diagnosis of primary IgAN as demonstrated by renal biopsy of any vintage if eGFR ≥45 mL/min/1.73 m2 or within the last ten years if eGFR \<45 mL/min/1.73 m2. If diabetic, the biopsy vintage should be less than five years.
• eGFR ≥20 mL/min/1.73 m2 at screening, as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
• Total urine protein excretion ≥1 g per 24-hour or UPCR ≥ 0.75 g/g from an adequately measured 24-hour urine sample (24HUP) during the Screening Period.
• Patient on the maximum labelled or tolerated dose of ACEi or ARB AND 10mg/d of Dapagliflozin (SGLT2i) for at least 12 weeks at screening and from screening to study Day 1.
• Systolic blood pressure ≤140 mmHg and diastolic blood pressure ≤90 mmHg at randomisation. Other anti-hypertensives can be optimised during the screening period to achieve the BP goal.
• A female is eligible if she is not pregnant and consents to avoid pregnancy during the study duration.

You may not qualify if:

• IgAN secondary to another condition (e.g., liver cirrhosis) or other causes of mesangial IgA deposition such as systemic lupus erythematosus (SLE), dermatitis herpetiformis, ankylosing spondylitis, etc. IgA vasculitis (i.e., Henoch-Schonlein purpura) with biopsy-proven mesangial IgA deposition and no active skin vasculitis for the last year can be included.
• Evidence of nephrotic syndrome at screening (serum albumin \<3g/dL AND UPCR \>3.5 g/g).
• Evidence of rapidly progressive glomerulonephritis defined as loss of ≥ 50% of eGFR in three months before screening.
• Concomitant kidney disease in addition to IgAN in kidney biopsy (e.g., diabetic nephropathy, primary focal segmental glomerulosclerosis, membranous nephropathy, C3 glomerulopathy, lupus nephritis).
• Female patients planning pregnancy.
• Concomitant co-morbidities like systemic autoimmune disorders, chronic active infections like tuberculosis, hepatitis B, hepatitis C and human immunodeficiency virus infection, chronic liver disease, and chronic obstructive pulmonary disease.
• Renal or other organ transplantation before, or expected during, the study, except for corneal transplants.
• Morbid obesity defined as BMI ≥ 40 kg/m2 at screening.
• Uncontrolled diabetes as defined by HbA1c \> 8% at screening.
• History or diagnosis of demyelinating diseases such as multiple sclerosis or optic neuritis.
• Prohibited medications:
• Participants who received oral steroids over two weeks within 12 weeks before screening.
• Immunosuppressive medications (e.g., MMF, azathioprine, cyclophosphamide, hydroxychloroquine) for treating IgAN within 12 weeks before screening.
• Use of B-cell-directed biologic therapies, including belimumab, rituximab, and ocrelizumab, within six months before screening.
• Use of other biologics (e.g., anti-TNF, abatacept, anti-IL-6) and investigational biologics within the last four weeks or five half-lives, whichever is longer, before the screening.

Sponsors & Collaborators

• Christian Medical College, Vellore, India: lead
• Medical Research Council: collaborator
• India Alliance: collaborator

Study Sites (12)

Muljibhai Patel Urological Hospital

Nadiād, Gujarat, 387001, India

NOT YET RECRUITING

JSS Medical College

Mysuru, Karnataka, 570004, India

NOT YET RECRUITING

Kasturba Medical College, Manipal

Udupi, Karnataka, 576104, India

NOT YET RECRUITING

KEM Hospital

Mumbai, Maharashtra, 400012, India

NOT YET RECRUITING

Safdarjung Hospital, Ansari Nagar East

Delhi, New Delhi, 110029, India

NOT YET RECRUITING

AIIMS Bhubaneswar

Bhubaneswar, Odisha, 751019, India

NOT YET RECRUITING

JIPMER, JIPMER Campus

Puducherry, Puducherry, 605006, India

NOT YET RECRUITING

Madras Medical College

Chennai, Tamil Nadu, 600003, India

NOT YET RECRUITING

Christian Medical College Vellore

Vellore, Tamil Nadu, 632004, India

RECRUITING

Nizams Institute of Medical Sciences

Hyderabad, Telangana, 500082, India

NOT YET RECRUITING

Osmania Medical College

Hyderabad, Telangana, 500095, India

NOT YET RECRUITING

Sanjay Gandhi Post Graduate Institute of Medical Sciences

Lucknow, Uttar Pradesh, 226014, India

NOT YET RECRUITING

MeSH Terms

Conditions

Glomerulonephritis, IGA; Renal Insufficiency, Chronic; IgA Vasculitis; Glomerulonephritis

Interventions

Prednisolone; Mycophenolic Acid; Hydroxychloroquine; Angiotensin Receptor Antagonists

Condition Hierarchy (Ancestors)

Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Autoimmune Diseases; Immune System Diseases; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Purpura; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemostatic Disorders; Hemorrhagic Disorders; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Immune Complex Diseases; Hypersensitivity; Hemorrhage; Skin Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Jonathan Barratt, PhD, FRCP

  University of Leicester

  STUDY CHAIR

• George T John, DM, FRCP, FRACP

  Royal Brisbane and Women's Hospital

  STUDY CHAIR

Central Study Contacts

Suceena Alexander, DM, PhD.

CONTACT

+91-417-; suceena@cmcvellore.ac.in

Selvin Sundar Raj, MD, DM

CONTACT

+91-417-; selvinsr@cmcvellore.ac.in

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The statistician/ outcome assessor will be blinded to the drug allocation and use coded data.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and HoU (Nephrology Unit III)

Model Details: This is a Phase 4 multi-arm, multi-stage (MAMS) platform trial. It is a multicenter, randomised, single-blind (outcome assessor), active comparator trial. The participants will be randomised 1:1 to the comparator and each of the four interventional arms. The sample size of 585 participants is for five arms, including the active comparator. The sixth arm may begin after the planned interim analysis conditional to the availability of the generic drug in the Indian market and will recruit additional 117 participants with concurrent comparator arm.

Study Record Dates

• First Submitted: October 26, 2024
• First Posted: November 6, 2024
• Study Start: February 15, 2025
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): August 1, 2029
• Last Updated: July 14, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Within 6 months of data lock at the end of the trial and for a period of five years thereafter.
• Access Criteria: Upon providing a draft hypothesis and analysis plan.

Locations

IN (12)