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? (IA-GRACE-IgANT)

July 10, 2025 updated by: Suceena Alexander, Christian Medical College, Vellore, India

Randomized Embedded Adaptive Platform Clinical Trial in South Asian Kidney Biopsy-Proven Primary IgA Nephropathy: Multi-center, Multi-arm and Multi-stage

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

585

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • India
    • Gujarat
      • Nadiad, Gujarat, India, 387001
        • Not yet recruiting
        • Muljibhai Patel Urological Hospital
        • Contact:
        • Principal Investigator:
          • Umapati Hegde
    • Karnataka
      • Mysuru, Karnataka, India, 570004
        • Not yet recruiting
        • JSS Medical College
        • Contact:
        • Principal Investigator:
          • Manjunath S Shetty
      • Udupi, Karnataka, India, 576104
        • Not yet recruiting
        • Kasturba Medical College, Manipal
        • Contact:
        • Principal Investigator:
          • Ravindra Prabhu A
    • Maharashtra
      • Mumbai, Maharashtra, India, 400012
        • Not yet recruiting
        • KEM Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Tukaram Jamale
        • Sub-Investigator:
          • Sreyashi Bose
        • Sub-Investigator:
          • Tulsi Modi
    • New Delhi
      • Delhi, New Delhi, India, 110029
        • Not yet recruiting
        • Safdarjung Hospital, Ansari Nagar East
        • Contact:
        • Principal Investigator:
          • Pallavi Prasad
    • Odisha
      • Bhubaneswar, Odisha, India, 751019
        • Not yet recruiting
        • AIIMS Bhubaneswar
        • Contact:
        • Principal Investigator:
          • Sandip Panda
    • Tamil Nadu
      • Chennai, Tamil Nadu, India, 600003
        • Not yet recruiting
        • Madras Medical College
        • Contact:
        • Principal Investigator:
          • Jayalakshmi Seshadri
      • Vellore, Tamil Nadu, India, 632004
        • Recruiting
        • Christian Medical College Vellore
        • Contact:
        • Contact:
        • Principal Investigator:
          • Suceena Alexander, DM, PhD.
        • Principal Investigator:
          • Selvin Sundar Raj, MD, DM
    • Telangana
      • Hyderabad, Telangana, India, 500082
        • Not yet recruiting
        • Nizams Institute of Medical Sciences
        • Contact:
        • Principal Investigator:
          • Sree Bushan Raju
      • Hyderabad, Telangana, India, 500095
        • Not yet recruiting
        • Osmania Medical College
        • Principal Investigator:
          • Manisha Sahay
        • Contact:
    • Union Territory of Puducherry
      • Puducherry, Union Territory of Puducherry, India, 605006
        • Not yet recruiting
        • JIPMER, JIPMER Campus
        • Contact:
        • Principal Investigator:
          • Priyamvada P S
    • Uttar Pradesh
      • Lucknow, Uttar Pradesh, India, 226014
        • Not yet recruiting
        • Sanjay Gandhi Post Graduate Institute of Medical Sciences
        • Contact:
        • Principal Investigator:
          • Narayan Prasad

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Must be able to provide a written informed consent form, which must be obtained before the initiation of study assessments.
  2. Adults between 18-65 years of age.
  3. Males or Females.
  4. 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.
  5. eGFR ≥20 mL/min/1.73 m2 at screening, as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
  6. 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.
  7. 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.
  8. 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.
  9. A female is eligible if she is not pregnant and consents to avoid pregnancy during the study duration.

Exclusion Criteria:

  1. 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.
  2. Evidence of nephrotic syndrome at screening (serum albumin <3g/dL AND UPCR >3.5 g/g).
  3. Evidence of rapidly progressive glomerulonephritis defined as loss of ≥ 50% of eGFR in three months before screening.
  4. Concomitant kidney disease in addition to IgAN in kidney biopsy (e.g., diabetic nephropathy, primary focal segmental glomerulosclerosis, membranous nephropathy, C3 glomerulopathy, lupus nephritis).
  5. Female patients planning pregnancy.
  6. 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.
  7. Renal or other organ transplantation before, or expected during, the study, except for corneal transplants.
  8. Morbid obesity defined as BMI ≥ 40 kg/m2 at screening.
  9. Uncontrolled diabetes as defined by HbA1c > 8% at screening.
  10. History or diagnosis of demyelinating diseases such as multiple sclerosis or optic neuritis.

  11. 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.
    • Use of traditional medications and/or Ayurvedic medications within 12 weeks before screening.
    • Use of endothelin receptor antagonists/ oral spironolactone or oral finerenone/ GLP-1 agonists/ hydroxychloroquine within 12 weeks before screening.
  12. Patients with a history of unstable angina, Class III and IV congestive heart failure, and clinically significant arrhythmia, as judged by the Investigator.
  13. Active clinically significant viral, bacterial, or fungal infection or any major episode of infection requiring hospitalisation or treatment with parenteral anti-infectives within four weeks before or during the Screening Visit.
  14. History of malignancy within the past five years before Screening (except for adequately treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or cervical carcinoma in situ, with no evidence of recurrence).
  15. Known hypersensitivity to any of the interventions.
  16. Major surgery within six weeks before the Screening Visit.
  17. Clinically significant history of alcohol or drug abuse in the one year before the Screening Visit as per the Investigator's opinion.
  18. Unwillingness or lack of capacity to follow all study procedures.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Standard of Care (SoC)
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)
Maximal labelled or tolerated dose of ACEi/ ARB and a steady dose of SGLT2i (10mg/d of dapagliflozin).
Other Names:
  • Dapmed® by Medgenix Pharma India Pvt. Ltd.
Experimental: SoC and Oral prednisolone
This intervention arm will start with randomisation of the first participant.
Drug: Oral prednisolone and SoC
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.
Other Names:
  • Wysolone® by Pfizer Ltd.
Experimental: SoC and Gut-directed budesonide
This intervention arm will start with the randomisation of the first participant.
Drug: Gut-directed budesonide and SoC
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.
Other Names:
  • IgANEF® by MediART Life Sciences Pvt. Ltd.
Experimental: SoC and Mycophenolate mofetil (MMF)
This intervention arm will start with the randomisation of the first participant.
Drug: Mycophenolate mofetil (MMF) and SoC
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.
Other Names:
  • Mycept® by Panacea Biotec Ltd.
Experimental: SoC and Hydroxychloroquine
This intervention arm will start with the randomisation of the first participant.
Drug: Hydroxychloroquine and SoC
Hydroxychloroquine (HCQ) 6.5 mg/kg/day (maximum 400 mg daily) for 24 months. All participants in this arm will receive SoC.
Other Names:
  • Ipca HCQ® by IPCA Laboratories Ltd.
Experimental: SoC and Non-steroidal mineralocorticoid receptor antagonist
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
Generic drug not available currently. All participants in this arm will receive SoC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To evaluate the mean change in annualized eGFR slope (ml/min/1.73m2) in the interventional and the active comparator arms.
Time Frame: Baseline, 3, 6, 9, 12, 15, 18 and 24 months
Mean change in eGFR slope in ml/min/1.73m2/year
Baseline, 3, 6, 9, 12, 15, 18 and 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To evaluate the mean change in UPCR ratio in the interventional and the active comparator arms.
Time Frame: Baseline, 6, 12, 18 and 24 months
Mean change in Urine protein creatinine ratio in g/g. The mean change in UPCR ratio at 12 months is a pre-planned interim analysis for lack-of-benefit.
Baseline, 6, 12, 18 and 24 months
To evaluate the mean change in time averaged proteinuria in the interventional and the active comparator arms.
Time Frame: Baseline, 6, 12, 18 and 24 months
Mean change in Time-averaged urine protein creatinine ratio in g/g
Baseline, 6, 12, 18 and 24 months
Proportion of participants reaching the composite endpoint
Time Frame: From enrollment to the end of treatment at 24 months
Composite end-point is defined as ≥50% decline in eGFR sustained for at least 28 days, end-stage kidney disease requiring renal replacement therapy, or death.
From enrollment to the end of treatment at 24 months
Proportion of participants having rapidly progressive kidney disease
Time Frame: From enrollment to the end of treatment at 24 months
Rapidly progressive kidney disease is defined as ≥50% decline in eGFR over three months
From enrollment to the end of treatment at 24 months
Proportion of participants reaching eGFR <15 ml/min/1.73 m2
Time Frame: From enrollment to the end of treatment at 24 months
<15ml/min/1.73m2 eGFR sustained for at least 28 days
From enrollment to the end of treatment at 24 months
Proportion of participants' using rescue medication
Time Frame: From enrollment to the end of treatment at 24 months
Using of other immunomodulatory treatments after ≥50% decline in eGFR over three months
From enrollment to the end of treatment at 24 months
Adverse Events
Time Frame: From enrollment to the end of treatment at 24 months
Percentage adverse events in clinical and laboratory tests.
From enrollment to the end of treatment at 24 months
Glucocorticoid Toxicity Index
Time Frame: Baseline, 6months, 12 months
Change in Glucocorticoid Toxicity Index (GTI) score for prednisolone and budesonide arms.
Baseline, 6months, 12 months
Medication Adherence
Time Frame: From enrollment to the end of treatment at 24 months
To evaluate the proportion of participants with Medication Adherence in the interventional and the active comparator arms.
From enrollment to the end of treatment at 24 months
To evaluate participant related outcome measure (PROM) by EQ-5D-5L
Time Frame: Baseline, 12 and 24 months
EQ-5D-5L study instrument
Baseline, 12 and 24 months
To evaluate PROM by KDQOL-36
Time Frame: Baseline, 12 and 24 months
KDQOL-36 study instrument
Baseline, 12 and 24 months
To evaluate PROM py FACIT-F
Time Frame: Baseline, 12 and 24 months
FACIT-F study instrument
Baseline, 12 and 24 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum biomarker profile
Time Frame: Baseline, 12, 24 months
To evaluate the longitudinal change in serum biomarker profile from baseline to two years. This is an exploratory objective and the bio samples will be stored and the evaluation done later with supplemental funds.
Baseline, 12, 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Christian Medical College, Vellore, India

Collaborators

Medical Research Council
India Alliance

Investigators

  • Study Chair: Jonathan Barratt, PhD, FRCP, University of Leicester
  • Study Chair: George T John, DM, FRCP, FRACP, Royal Brisbane and Women's Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 15, 2025

Primary Completion (Estimated)

August 1, 2029

Study Completion (Estimated)

August 1, 2029

Study Registration Dates

First Submitted

October 26, 2024

First Submitted That Met QC Criteria

November 4, 2024

First Posted (Actual)

November 6, 2024

Study Record Updates

Last Update Posted (Actual)

July 14, 2025

Last Update Submitted That Met QC Criteria

July 10, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IA/CPHS/22/1/506541 (Other Grant/Funding Number: DBT/WELLCOME TRUST INDIA ALLIANCE)
  • 15811[INTERVEN] dated 25.10.23 (Other Identifier: CMC SILVER IRB & ETHICS COMMITTEE)
  • CTRI/2024/11/076794 (Other Identifier: ICMR)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All de-identified individual-level data, as permitted by the local law, will be made available on Mendeley Data. Access to data will be possible by writing to gracetrials@cmcvellore.ac.in or suceena@cmcvellore.ac.in on or after 31 Dec 2030.

IPD Sharing Time Frame

Within 6 months of data lock at the end of the trial and for a period of five years thereafter.

IPD Sharing Access Criteria

Upon providing a draft hypothesis and analysis plan.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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