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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

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.

Condition or disease Intervention/treatment Phase
Polycystic Kidney, Autosomal Dominant Drug: Metformin Other: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 97 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Actual Study Start Date : June 27, 2016
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
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
Drug: Metformin
Monitoring of tolerability and symptoms.
Other Names:
  • Glucophage
  • Metformin hydrochloride

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
Other: Placebo
Monitoring of tolerability and symptoms.




Primary Outcome Measures :
  1. 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.

  2. 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?"

  3. 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.


Secondary Outcome Measures :
  1. 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).

  2. 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).

  3. 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.

  4. 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 ]
  5. Change in TKV (Total Kidney Volume) using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
  6. Change in kidney cyst volume using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
  7. Change in liver volume using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
  8. Change in liver cyst volume using MR imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02656017


Locations
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United States, Maryland
University of Maryland Medical Center
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
Sponsors and Collaborators
Kyongtae Ty Bae, M.D., Ph.D.
Tufts Medical Center
University of Maryland, College Park
University of Southern California
United States Department of Defense
Investigators
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Principal Investigator: Kyongtae Bae, MD, PhD University of Pittsburgh
  Study Documents (Full-Text)

Documents provided by Kyongtae Ty Bae, M.D., Ph.D., University of Pittsburgh:
Informed Consent Form  [PDF] September 24, 2018


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Responsible Party: Kyongtae Ty Bae, M.D., Ph.D., Principal Investigator, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02656017     History of Changes
Other Study ID Numbers: PRO15060422
CDMRP-PR141606 ( Other Identifier: US Army Medical Research and Materiel Command )
First Posted: January 14, 2016    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Kyongtae Ty Bae, M.D., Ph.D., University of Pittsburgh:
kidney disease
polycystic kidney disease
autosomal dominant kidney disease
kidney cysts
PKD

Additional relevant MeSH terms:
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Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic Diseases
Kidney Diseases, Cystic
Abnormalities, Multiple
Congenital Abnormalities
Ciliopathies
Genetic Diseases, Inborn
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs