Randomized Embedded Adaptive Platform Clinical Trial in South Asian Kidney Biopsy Proven Primary Glomerular Diseases Multi center Multi arm and Multi stage
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 585
- 试验地点
- 12
- 主要终点
- To evaluate the mean change in annualized eGFR slope (ml per min per 1.73m2) in the interventional and the active comparator arms.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Outcome Assessor Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 65.00 Year(s)（—）
- 性别
- All
入选标准
- •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 greater than or equal to 45 mL per min per 1.73 m2 or within the last ten years if eGFR less than 45 mL per min per 1.73 m
- •If diabetic, the biopsy vintage should be less than five years.
- •eGFR greater than or equal to 20 mL/min/1.73 m2 at screening, as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
- •Total urine protein excretion greater than or equal to 1 g per 24-hour or UPCR greater than or equal to 0.75 g per 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 per day of Dapagliflozin (SGLT2i) for at least 12 weeks at screening and from screening to study Day
- •Systolic blood pressure less than or equal to 140 mmHg and diastolic blood pressure less than or equal to 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.
排除标准
- •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 less than 3g per dL AND UPCR greater than 3.5 g per g).
- •Evidence of rapidly progressive glomerulonephritis defined as loss of greater than or equal to 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 greater than or eual to 40 kg per m2 at screening.
- •Uncontrolled diabetes as defined by HbA1c greater than 8 percentage 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.
- •â€¢ Use of B-cell–directed biologic therapies, including belimumab, rituximab, and ocrelizumab, within six months before screening.
- •â€¢ 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.
- •â€¢ Use of traditional medications or Ayurvedic medications within 12 weeks before screening.
- •â€¢ Use of endothelin receptor antagonists or oral spironolactone or oral finerenone or GLP-1 agonists or hydroxychloroquine within 12 weeks before screening.
- •Patients with a history of unstable angina, Class III and IV congestive heart failure, and clinically significant arrhythmia, as judged by the Investigator.
- •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.
- •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).
- •Known hypersensitivity to any of the interventions.
- •Major surgery within six weeks before the Screening Visit.
- •Clinically significant history of alcohol or drug abuse in the one year before the Screening Visit as per the Investigator’s opinion.
- •Unwillingness or lack of capacity to follow all study procedures.
结局指标
主要结局
To evaluate the mean change in annualized eGFR slope (ml per min per 1.73m2) in the interventional and the active comparator arms.
时间窗: Baseline, 3, 6, 9, 12, 15, 18 and 24 months.
次要结局
- 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. Composite end-point is defined as greater than or equal to 50 percent 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. Rapidly progressive kidney disease is defined as greater than or equal to 50 percent decline in eGFR over three months.(From enrollment to the end of treatment at 24 months.)
- Proportion of participants reaching eGFR less than 15 ml per min per 1.73 m2 sustained for at least 28 days(From enrollment to the end of treatment at 24 months.)
- Adverse Events. Percentage adverse events in clinical and laboratory tests.(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.(Baseline, 6months, 12 months.)
- Medication Adherence. 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 study instrument.(Baseline, 12 and 24 months.)
- To evaluate PROM by KDQOL-36 study instrument.(Baseline, 12 and 24 months.)
- To evaluate PROM py FACIT-F study instrument.(Baseline, 12 and 24 months.)
- Serum biomarker profile. 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.)
研究者
Suceena Alexander
Christian Medical College Vellore