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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
585
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.
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.
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.
Hydroxychloroquine (HCQ) 6.5 mg/kg/day (maximum 400 mg daily) for 24 months. All participants in this arm will receive SoC.
Generic drug not available currently. All participants in this arm will receive SoC.
Maximal labelled or tolerated dose of ACEi/ ARB and a steady dose of SGLT2i (10mg/d of dapagliflozin).
Muljibhai Patel Urological Hospital
Nadiād, Gujarat, India
NOT_YET_RECRUITINGJSS Medical College
Mysuru, Karnataka, India
NOT_YET_RECRUITINGKasturba Medical College, Manipal
Udupi, Karnataka, India
NOT_YET_RECRUITINGKEM Hospital
Mumbai, Maharashtra, India
NOT_YET_RECRUITINGSafdarjung Hospital, Ansari Nagar East
Delhi, New Delhi, India
NOT_YET_RECRUITINGAIIMS Bhubaneswar
Bhubaneswar, Odisha, India
NOT_YET_RECRUITINGJIPMER, JIPMER Campus
Puducherry, Puducherry, India
NOT_YET_RECRUITINGMadras Medical College
Chennai, Tamil Nadu, India
NOT_YET_RECRUITINGChristian Medical College Vellore
Vellore, Tamil Nadu, India
RECRUITINGNizams Institute of Medical Sciences
Hyderabad, Telangana, India
NOT_YET_RECRUITING...and 2 more locations
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
Time frame: Baseline, 3, 6, 9, 12, 15, 18 and 24 months
To evaluate the mean change in UPCR ratio in the interventional and the active comparator arms.
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.
Time frame: Baseline, 6, 12, 18 and 24 months
To evaluate the mean change in time averaged proteinuria in the interventional and the active comparator arms.
Mean change in Time-averaged urine protein creatinine ratio in g/g
Time frame: Baseline, 6, 12, 18 and 24 months
Proportion of participants reaching the composite endpoint
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.
Time frame: From enrollment to the end of treatment at 24 months
Proportion of participants having rapidly progressive kidney disease
Rapidly progressive kidney disease is defined as ≥50% decline in eGFR over three months
Time frame: From enrollment to the end of treatment at 24 months
Proportion of participants reaching eGFR <15 ml/min/1.73 m2
\<15ml/min/1.73m2 eGFR sustained for at least 28 days
Time frame: From enrollment to the end of treatment at 24 months
Proportion of participants' using rescue medication
Using of other immunomodulatory treatments after ≥50% decline in eGFR over three months
Time frame: From enrollment to the end of treatment at 24 months
Adverse Events
Percentage adverse events in clinical and laboratory tests.
Time frame: From enrollment to the end of treatment at 24 months
Glucocorticoid Toxicity Index
Change in Glucocorticoid Toxicity Index (GTI) score for prednisolone and budesonide arms.
Time frame: Baseline, 6months, 12 months
Medication Adherence
To evaluate the proportion of participants with Medication Adherence in the interventional and the active comparator arms.
Time frame: From enrollment to the end of treatment at 24 months
To evaluate participant related outcome measure (PROM) by EQ-5D-5L
EQ-5D-5L study instrument
Time frame: Baseline, 12 and 24 months
To evaluate PROM by KDQOL-36
KDQOL-36 study instrument
Time frame: Baseline, 12 and 24 months
To evaluate PROM py FACIT-F
FACIT-F study instrument
Time frame: Baseline, 12 and 24 months
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