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Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease (TAME)

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ClinicalTrials.gov Identifier: NCT02656017
Recruitment Status : Active, not recruiting
First Posted : January 14, 2016
Last Update Posted : May 10, 2019
Sponsor:
Collaborators:
Tufts Medical Center
University of Maryland, College Park
University of Southern California
United States Department of Defense
Information provided by (Responsible Party):
Kyongtae Ty Bae, M.D., Ph.D., University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE December 23, 2015
First Posted Date  ICMJE January 14, 2016
Last Update Posted Date May 10, 2019
Actual Study Start Date  ICMJE June 27, 2016
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 12, 2016)
  • 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 Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02656017 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2016)
  • 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 Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Official Title  ICMJE 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 Description 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Polycystic Kidney, Autosomal Dominant
Intervention  ICMJE
  • Drug: Metformin
    Monitoring of tolerability and symptoms.
    Other Names:
    • Glucophage
    • Metformin hydrochloride
  • Other: Placebo
    Monitoring of tolerability and symptoms.
Study Arms  ICMJE
  • Experimental: 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
    Intervention: Drug: Metformin
  • Placebo Comparator: 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
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 19, 2018)
97
Original Estimated Enrollment  ICMJE
 (submitted: January 12, 2016)
96
Estimated Study Completion Date  ICMJE December 30, 2020
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02656017
Other Study ID Numbers  ICMJE PRO15060422
CDMRP-PR141606 ( Other Identifier: US Army Medical Research and Materiel Command )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Kyongtae Ty Bae, M.D., Ph.D., University of Pittsburgh
Study Sponsor  ICMJE Kyongtae Ty Bae, M.D., Ph.D.
Collaborators  ICMJE
  • Tufts Medical Center
  • University of Maryland, College Park
  • University of Southern California
  • United States Department of Defense
Investigators  ICMJE
Principal Investigator: Kyongtae Bae, MD, PhD University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP