Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease

Kyongtae Ty Bae, M.D., Ph.D.97 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Polycystic Kidney, Autosomal Dominant

Interventions

MetforminDRUG

Monitoring of tolerability and symptoms.

PlaceboOTHER

Monitoring of tolerability and symptoms.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: Subject has Autosomal Dominant Polycystic Kidney Disease; Subject is fluent in English Exclusion Criteria: 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)

Locations (2)

University of Maryland Medical Center

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

Change in the Gastrointestinal Symptoms Rating Scale (GSRS) 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.

Time frame: Baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months

Drug Tolerability

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.

Time frame: Baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months

Rate of Serious Adverse Events (SAE)

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.

Time frame: 26 months

Secondary Outcomes

Quality of Life Physical Component

Short Form-36 Quality of Life Physical Component Summary (SF-36 PCS) ranges from 0 (worst possible outcome) to 100 (best possible outcome). Mean change to 24 months, estimated with a repeated measures analysis (baseline, 1 month, 3 months and every 3 months thereafter to 24 months) using a linear mixed model.

Time frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months

Data from ClinicalTrials.gov

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