Metformin therapy in Polycystic Kidney Disease: A randomized, controlled trial
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 292
- 试验地点
- 9
- 主要终点
- Estimated GFR (CKD-EPICr 2021) at 104 weeks (24 months) from randomization
研究概览
简要总结
Summary
Rationale
Autosomal Dominant Polycystic Kidney Disease (ADPKD) accounts 3.4% of patients with CKD in India. Though relatively rare, the absolute numbers make it the most common inherited cause of CKD. There is an urgent need to identify therapies that will effectively and safely slow kidney function decline in patients affected by ADPKD.
Novelty
Metformin is a biguanide that has long been approved for use in Type 2 Diabetes Mellitus. It has well-established pharmacokinetic, pharmacodynamic and safety profiles. It is known to upregulate and activate the master cellular energy homeostasis regulator AMPK, which is decreased in the kidney cells of ADPKD patients. Multiple cell culture and animal ADPKD models have shown that metformin slows progression of ADPKD-related kidney cyst formation. Small studies have established its safety in humans with ADPKD. However, the long-term clinical effects are unknown.
Objectives
The primary objective of the study is to assess whether use of metformin in patients with ADPKD slows decline in kidney function at 24 months or not.
Methods
The study will be a multi-centric, double-blind, randomized controlled trial (RCT) designed to determine whether metformin will slow kidney function decline compared to placebo in adults with ADPKD. Patients with ADPKD, eGFR ≥38 ml/min/1.73m2 and high risk of disease progression will be eligible. Participants will undergo 3 months active run-in followed by 24 months follow up.
Expected outcome
Demonstration of efficacy and safety of metformin in patients with ADPKD would allow rapid access to a cheap, safe, effective and broadly implementable therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 70.00 Year(s)（—）
- 性别
- All
入选标准
- •Able to provide informed consent
- •Age 18-70 years
- •Diagnosis of ADPKD based on radiological or genetic criteria
- •eGFR greater than equal to 38 and less than 90 mL/min/1.73m2
- •Presence of either i.
- •One or more risk factors of progression [bilateral kidney length greater than equal to 16.5cm, total kidney volume (TKV) greater than equal to 750mL, height censored TKV (htTKV) greater than equal to 600mL/m2, Mayo class 1C/D/E or PRO-PKD score greater than equal to 6], OR ii.
- •Active disease progression as evidenced by one or more of following factors [decline in eGFR greater than equal to 5mL/min/1.73m2 in one year, decline in eGFR greater than equal to 3mL/min/1.73m2 per year over five years or more, or increase in htTKV/TKV of greater than equal to 5% per year on at least 2 measurements in the past year, excluding any initial eGFR effect over the initial 3 months of tolvaptan commencement (if applicable)]
- •For people on tolvaptan therapy, it must have been in place for at least 6 months with stable dose for at least 3 months.
排除标准
- •Diabetes mellitus or other systemic disease affecting the kidneys (excluding hypertension)
- •Uncontrolled hypertension (Systolic BP greater than 160mmHg and/or diastolic BP greater than 100mmHg after a period of rest)
- •Clinically significant heart failure, including but not limited to New York Heart Association Class (NYHA) III or IV
- •Non-polycystic liver disease, including but not limited to liver enzymes (ALT, AST or Total Bilirubin) greater than 2 times the upper limit of normal, except when a diagnosis of Gilbert Syndrome exists, and/or, Child-Pugh classification score greater than equal to 5
- •Any contraindication to metformin including abnormal liver function tests or untreated Vitamin B12 deficiency.
- •Pregnancy or breastfeeding or planning pregnancy in the next three years.
- •Currently taking metformin
- •Comorbidities with contraindication for metformin use or potential to contaminate trial outcomes, specifically active cancer, history of other solid organ (kidney, heart, liver, lung, bowel) transplantations, active chronic obstructive pulmonary disease (COPD), active inflammatory bowel disease (IBD), and stoma.
- •History of dialysis
- •Participation in another interventional clinical trial.
结局指标
主要结局
Estimated GFR (CKD-EPICr 2021) at 104 weeks (24 months) from randomization
时间窗: 24 months
次要结局
- Major adverse kidney events, albuminuria, all-cause mortality
- A composite outcome comprising a reduction from baseline eGFR of more than equal to 30%, kidney failure (defined as an eGFR less than 15mL/min/1.73m2), and all-cause mortality.(24 months)
- Reduction from baseline eGFR of more than equal to 30%(24 months)
- Kidney failure (defined as an eGFR less than 15mL/min/1.73m2)(24 month)
- All-cause mortality(24 months)
- The proportion of participants requiring a dosage adjustment or the introduction of a new anti-hypertensive agent during the treatment period.(24 months)
- Urine albumin:creatinine ratio.(24 months)
- Albuminuria (urine albumin:creatinine ratio) category (A1 less than 30 mg/g, A2 30-300 mg/g, A3 more than 300 mg/g and as a continuous variable.(24 months)
- Health-related quality of life scores measured using EuroQual 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire.(24 months)
- ADPKD related pain scores measured using the ADPKD-PDS.(24 months)
- Gastrointestinal symptoms measures using the Gastrointestinal Symptom Rating Scale (GSRS)3.(24 months)
- Incidence of gastrointestinal symptoms, lactic acidosis, deranged liver function tests, hypoglycaemia, anaemia and vitamin B12 deficiency (rate per 100-person years).(24 months)
- Health care utilisation – hospital admissions, non-admitted episodes of primary and specialist care, and prescribed medications.(24 months)
- Incremental costs, and incremental health outcomes (quality-adjusted life year (QALY) and clinically important difference in the primary outcome) of metformin therapy compared to placebo(24 months)
研究者
Dr Vivek Kumar
Postgraduate Institute of Education and Research, Chandigarh