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

• ClinicalTrials.gov Identifier: NCT02656017
• Recruitment Status: Completed
• First Posted: January 14, 2016
• Results First Posted: August 9, 2022
• Last Update Posted: August 9, 2022
• Sponsor: Kyongtae Ty Bae, M.D., Ph.D.
• Collaborators: Tufts Medical Center; University of Maryland, Baltimore; University of Southern California; United States Department of Defense
• Information provided by (Responsible Party): Kyongtae Ty Bae, M.D., Ph.D., University of Pittsburgh

Study Description

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.

Study Design

• Study Type: Interventional
• 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
• Actual Primary Completion Date: December 7, 2020
• Actual Study Completion Date: December 7, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Change in the Gastrointestinal Symptoms Rating Scale (GSRS) to 24 Months [ Time Frame: 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.

2. Drug Tolerability [ Time Frame: 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.
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. 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 (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.

2. 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 (SF-36 MCS) 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.

3. Back Pain Frequency Over the Past 3 Months Since Last Visit [ Time Frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months ]
   Odds ratio (OR) per month of back pain Often, Usually, or Always (vs. Never, Rarely, Sometimes) estimated with a repeated measures analysis (baseline, 1 month, 3 months and every 3 months thereafter to 24 months) using a generalized linear mixed model.
4. Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: Baseline, 2 weeks, and 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months ]
   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.
5. Total Kidney Volume From Magnetic Resonance Imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
   Annual percent change of height adjusted and natural log transformed total kidney volume [ln(htTKV)] was estimated with a linear mixed model.
6. Total Kidney Cyst Volume From Magnetic Resonance Imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
   Annual percent change of height adjusted and natural log transformed total kidney cyst volume [ln(htTKCV)] was estimated with a linear mixed model.
7. Liver Volume From Magnetic Resonance Imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
   Annual percent change of height adjusted and natural log transformed liver volume [ln(htLV)] was estimated with a linear mixed model.
8. Liver Cyst Volume From Magnetic Resonance Imaging [ Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months ]
   Annual percent change of height adjusted and natural log transformed liver cyst volume [ln(htLCV)] was estimated with a linear mixed model.
9. Frequency Abdominal Fullness Interfered With Ability to Perform Usual Physical Activity Over the Past 3 Months Since Last Visit. [ Time Frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months ]
   Odds ratio (OR) per month of abdominal fullness interfered Often, Usually, or Always (vs. Never, Rarely, Sometimes) estimated with a repeated measures analysis (baseline, 1 month, 3 months and every 3 months thereafter to 24 months) using a generalized linear mixed model.
10. Interference of Pain With Sleep Over the Past 3 Months Since Last Visit [ Time Frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months ]
    Odds ratio (OR) per month of pain interfered with sleep Quite a bit or Extremely (vs. Not at all, A little bit, Moderately) estimated with a repeated measures analysis (baseline, 1 month, 3 months and every 3 months thereafter to 24 months) using a generalized linear mixed model.
11. Interference of Pain With Strenuous Physical Activity Over the Past 3 Months Since Last Visit [ Time Frame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months ]
    Odds ratio (OR) per month of pain interfered with strenuous physical activity Quite a bit or Extremely (vs. Not at all, A little bit, Moderately) estimated with a repeated measures analysis (baseline, 1 month, 3 months and every 3 months thereafter to 24 months) using a generalized linear mixed model.

Eligibility Criteria

• 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)

Contacts and Locations

Locations

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, Baltimore

University of Southern California

United States Department of Defense

Investigators

• 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:

Study Protocol and Statistical Analysis Plan  [PDF] June 1, 2018

Informed Consent Form  [PDF] September 24, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Seliger SL, Watnick T, Althouse AD, Perrone RD, Abebe KZ, Hallows KR, Miskulin DC, Bae KT. Baseline Characteristics and Patient-Reported Outcomes of ADPKD Patients in the Multicenter TAME-PKD Clinical Trial. Kidney360. 2020 Dec 31;1(12):1363-1372. doi: 10.34067/KID.0004002020.

• Responsible Party: Kyongtae Ty Bae, M.D., Ph.D., Principal Investigator, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02656017
• Other Study ID Numbers: PRO15060422; CDMRP-PR141606 ( Other Identifier: US Army Medical Research and Materiel Command )
• First Posted: January 14, 2016
• Results First Posted: August 9, 2022
• Last Update Posted: August 9, 2022
• Last Verified: August 2022

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:

Arthrogryposis; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Congenital Abnormalities; Kidney Diseases, Cystic; Abnormalities, Multiple; Ciliopathies; Genetic Diseases, Inborn; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs