Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 97
- 试验地点
- 2
- 主要终点
- Rate of Serious Adverse Events (SAE)
研究概览
简要总结
This study will test to see if metformin is safe and if it is tolerated compared to placebo in adult Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients with beginning stages of chronic kidney disease. We will also measure its effect on progression of kidney disease as reflected in the kidney size and the kidney function, along with its effect on kidney pain and quality of life.
详细描述
There is growing evidence that metformin, a drug widely used for the treatment of type 2 diabetes and polycystic ovary syndrome, may serve as a novel therapy for individuals in the early stages of Autosomal Dominant Polycystic Kidney Disease ADPKD by activating the metabolic sensor AMP-activated protein kinase (AMPK). AMPK is activated under conditions of metabolic and other cellular stresses. Through its actions on downstream mediators, AMPK activation during low energy states decreases cellular energy consumption while stimulating energy generating pathways. It has been shown that AMPK phosphorylates and inhibits cystic fibrosis transmembrane conductance regulator (CFTR), thus suppressing epithelial fluid and electrolyte secretion. Similarly, AMPK phosphorylates the tuberin protein, leading to indirect inhibition of the mTOR pathway. Thus, AMPK inhibits both CFTR and mTOR, suggesting that targeted activation of this kinase by metformin may provide a therapeutic benefit in ADPKD. It has been shown that metformin treatment of kidney epithelial cells leads to stimulation of AMPK and subsequent inhibition of both mTOR and CFTR activity. It has also been shown that metformin slows cystogenesis in animal models of PKD, supporting the potential of this drug in ADPKD treatment.
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)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject has Autosomal Dominant Polycystic Kidney Disease; Subject is fluent in English
排除标准
- •Subject is not on active military duty; Subject is not currently participating in another clinical trial; Subject's current GFR is not <50 cc/min/1.73m2; Subject does not have diabetes; Subject does not have a systemic disease other than hypertension and PKD; Subject does not have a solitary kidney; Subject does not have an allergy or intolerance to metformin; Subject is not pregnant or lactating or intending to become pregnant within the next three years; Subject does not have an unstable or unclipped cerebral aneurysm; Subject does not have active coronary artery disease; Subject does not have an MRI incompatible device/implant; Subject does not have severe claustrophobia; Subject has not had any solid organ transplant; Subject does not have a Vitamin B12 deficiency; Subject does not currently take any medications that interact with metformin, such as nifedipine, furosemide, cationic drugs (amiloride, ranitidine, triamterene digoxin, procainamide, quinidine, vancomycin, trimethoprim); Subject does not currently take nor has taken (within 2 weeks) the drug tolvaptan (Jynarque or Samsca)
研究组 & 干预措施
Metformin
Participants will be started on 500 mg of metformin once daily, with the following scheduled dose titrations:
-
Increase to 500mg twice daily at week 2
-
Increase to 1000mg qAM, 500mg qPM at week 4
-
Increase to 1000mg twice daily at week 6 for the duration of their participation (26 months).
-
Increased titrations based on tolerability
干预措施: Metformin (Drug)
Placebo
Participants will be started on 500 mg of placebo once daily, with the following scheduled dose titrations:
-
Increase to 500mg twice daily at week 2
-
Increase to 1000mg qAM, 500mg qPM at week 4
-
Increase to 1000mg twice daily at week 6 for the duration of their participation (26 months).
-
Increased titrations based on tolerability
干预措施: Placebo (Other)
结局指标
主要结局
Rate of Serious Adverse Events (SAE)
时间窗: 26 months
Serious adverse events (SAE) occurring from the time a participant signs the informed consent (at the screening visit) until the end of the study, meeting 1 or more of the criteria of: 1) Resulting in death, 2) Non-elective hospitalization, 3) Life threatening (if patient continued on study drug would result in death), 4) Harming or disabling persistently or permanently , 5) Exceeding the nature, severity or frequency of risk described in the protocol or 6) Resulting in congenital anomaly.
Change in the Gastrointestinal Symptoms Rating Scale (GSRS) to 24 Months
时间窗: Baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months
GSRS is a widely used, validated 15-item questionnaire used to assess GI symptom burden (minimum, maximum: 1, 7, where higher mean score is worse outcome). Mean change to 24 months, estimated with a repeated measures analysis (baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months) using a linear mixed model.
Drug Tolerability
时间窗: Baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months
Tolerability was based on the first visit a participant responded no to the following question "Can you tolerate this dose of study drug the rest of your life?", which was asked at baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months.
次要结局
- Quality of Life Physical Component(Baseline, 1 month, 3 months and every 3 months thereafter to 24 months)
- Quality of Life Mental Component(Baseline, 1 month, 3 months and every 3 months thereafter to 24 months)
- Interference of Pain With Strenuous Physical Activity Over the Past 3 Months Since Last Visit(Baseline, 1 month, 3 months and every 3 months thereafter to 24 months)
- Total Kidney Cyst Volume From Magnetic Resonance Imaging(Baseline, 6 months, 12 months, 18 months, 24 months)
- Liver Volume From Magnetic Resonance Imaging(Baseline, 6 months, 12 months, 18 months, 24 months)
- Liver Cyst Volume From Magnetic Resonance Imaging(Baseline, 6 months, 12 months, 18 months, 24 months)
- Back Pain Frequency Over the Past 3 Months Since Last Visit(Baseline, 1 month, 3 months and every 3 months thereafter to 24 months)
- Total Kidney Volume From Magnetic Resonance Imaging(Baseline, 6 months, 12 months, 18 months, 24 months)
- Frequency Abdominal Fullness Interfered With Ability to Perform Usual Physical Activity Over the Past 3 Months Since Last Visit.(Baseline, 1 month, 3 months and every 3 months thereafter to 24 months)
- Estimated Glomerular Filtration Rate (eGFR)(Baseline, 2 weeks, and 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months)
- Interference of Pain With Sleep Over the Past 3 Months Since Last Visit(Baseline, 1 month, 3 months and every 3 months thereafter to 24 months)
研究者
Kyongtae Ty Bae, M.D., Ph.D.
Principal Investigator
University of Pittsburgh