Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD): A Randomised Placebo-Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,174
- 试验地点
- 40
- 主要终点
- The change in estimated glomerular filtration rate (eGFR)
研究概览
简要总结
This study will investigate if a medication (metformin) widely used in the treatment of diabetes could be re-purposed for the treatment of patients with a diagnosis of early stage ADPKD to slow the rate of kidney function decline, reducing morbidity and mortality and improving the quality of life for ADPKD patients.
详细描述
Autosomal Dominant Polycystic Kidney Disease (ADPKD) affects 12.5 million people worldwide and is the 4th leading cause of kidney failure. Cyst growth begins in childhood, and over decades leads to painful kidneys, hypertension and chronic kidney disease. ADPKD patients also have a high prevalence of anxiety, depression and poor quality of life. Despite this enormous burden, there is a lack of evidence for therapies and affordable, effective treatment options. To date, only one disease modifying therapy is licensed for use in ADPKD (tolvaptan), but it is limited by its restricted availability, side effects and high cost. Metformin, an inexpensive and familiar drug, has been shown in previous studies to target cyst-forming signals, thereby slowing the cyst growth rate. IMPEDE-PKD is an Australian-led global Phase III randomised controlled trial to investigate the effect of metformin on ADPKD disease progression. The study will recruit a total of 1,174 adult ADPKD patients from around the world (250 from Australia). The outcomes of this research will identify effective and targeted therapies for ADPKD that will slow kidney function decline, reduce the impact of the illness and likelihood of death, and improve the quality of life for ADPKD patients and families.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Study participants, treating physicians and other care providers, outcome assessors, study investigators, and study statisticians will be blinded. An unblinded statistician will regularly review treatment allocations to ensure balance across treatment arms. The unblinded statistician will also prepare unblinded statistical reports for meetings of the Data and Safety Monitoring Board.
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •To be eligible to participate in this trial, patients must satisfy all of the following inclusion criteria:
- •Willing to participate and provide informed consent
- •Aged 18-70 years
- •Diagnosis of ADPKD based on radiological +/- genetic criteria as per Kidney Health Australia - Caring for Australians and New Zealanders with Kidney Impairment (KHA-CARI) Guidelines
- •eGFR equal to or greater than 38 mL/min/1.73m2 and <90 mL/min/1.73m2
- •And have either:
- •5(a) One or more risk factors of progression from the following:
- •Bilateral kidney length equal to or greater than16.5 cm, or
- •Total Kidney Volume (TKV) equal to or greater than 750 mL or height-adjusted TKV (htTKV) equal to or greater than 600 mL/m2, or
- •Mayo class IC/D/E or Pro-PKD score equal to or greater than 6 OR 5(b) Evidence of Active progression
- •Decline in eGFR equal to or greater than 5 mL/min/1.73m2 in one year, or
- •Decline in eGFR equal to or greater than 3 mL/min/1.73m2 per year over five years or more. or
- •Increase in htTKV/TKV of equal to or greater than 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) Note: Tolvaptan therapy must have been in place for at least 6 months with stable dose for at least 3 months.
排除标准
- •Diabetes mellitus (as per American Diabetes Association definition), or other systemic conditions that may cause CKD independent of PKD (excluding hypertension)
- •Uncontrolled hypertension (Systolic BP >160 mmHg and/or diastolic BP >100 mmHg 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) >2 times the upper limit of normal, except when a diagnosis of Gilbert Syndrome exists and/or,
- •Child-Pugh classification score equal to or greater than 5
- •Any contraindication to metformin including abnormal liver function tests or untreated Vitamin B12 deficiency
- •Currently taking metformin
- •Pregnancy or breastfeeding, or planning to get pregnant in the next three years.
- •Comorbidities with potential to contaminate trial outcomes, specifically active cancer, history of other solid organ transplantations, active chronic obstructive pulmonary disease (COPD), active inflammatory bowel disease, and the presence of stoma.
- •History of dialysis.
研究组 & 干预措施
Intervention
Participants randomised to the intervention group receive Metformin XR plus standard of care for 104 weeks.
Dosage will depend on individual participant's level of tolerance to Metformin XR as well as their estimated glomerular filtration rate (eGFR). The dosage will be between 500-2000mg/day.
干预措施: Metformin XR (Drug)
Control
Participants randomised to the control group receive placebo plus standard of care for 104 weeks.
干预措施: Control (Other)
结局指标
主要结局
The change in estimated glomerular filtration rate (eGFR)
时间窗: Over 24 months
This will be measured using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at 104 weeks (24 months) from first dispensing date.
次要结局
- Presence and category change of albuminuria(Over 24 months)
- Change in medication dosage during the trial(Over 24 months)
- Annualised slope of eGFR.(Over 24 months)
- Severity of change in eGFR(Over 24 months)
- Kidney failure(Over 24 months)
- Composite outcome(Over 24 months)
- Mortality(Over 24 months)
- Changes in the urine albumin:creatinine ratio(Over 24 months)
- Healthcare utilisation(Over 24 months)
- ADPKD-related pain(Over 24 months)
- Presence of study-related events(Over 24 months)
- Health-related quality of life(Over 24 months)
- Gastrointestinal symptoms(Over 24 months)