Clinical Trial: Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease

Brief Summary: 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.

Detailed Summary: 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.
Sponsor: University of Pittsburgh

Current Primary Outcome:

  • Change in the Gastrointestinal Symptoms Rating Scale (GSRS) [ Time Frame: Baseline, 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.
  • Rate of drug discontinuation [ Time Frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months ]
    This assessment of tolerability will be based on responses (yes or no) to the following question "Can you tolerate this dose of the study drug for the rest of your life?"
  • Rate of Serious Adverse events (SAE) [ Time Frame: 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Change in Quality of Life Physical Component [ Time Frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months ]
    Short Form-36 Quality of Life Physical Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome).
  • Change in Quality of Life Mental Component [ Time Frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months ]
    Short Form-36 Quality of Life Mental Component Summary ranges from 0 (worst possible outcome) to 100 (best possible outcome).
  • Change in frequency and/or intensity of pain [ Time Frame: Baseline, 2 weeks, 1 month, 6 weeks, 3 months and every 3 months thereafter to 24 months ]
    Patient self-reporting using the TAME pain questionnaire ( a modified version of the Wisconsin Brief Pain Questionnaire) since last visit.
  • Change in kidney function measured by eGFR [ Time Frame: Baseline, 2 weeks, 1 month, 6 weeks, 3 months and every 3 months thereafter to 24 months ]
  • Change in TKV (Total Kidney Volume) using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
  • Change in kidney cyst volume using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
  • Change in liver volume using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
  • Change in liver cyst volume using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]


Original Secondary Outcome: Same as current

Information By: University of Pittsburgh

Dates:
Date Received: December 23, 2015
Date Started: May 2016
Date Completion: September 2020
Last Updated: February 1, 2017
Last Verified: May 2016