Back to resultsMetformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease (TAME)
Primary Purpose
Polycystic Kidney, Autosomal Dominant
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Metformin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Polycystic Kidney, Autosomal Dominant focused on measuring kidney disease, polycystic kidney disease, autosomal dominant kidney disease, kidney cysts, PKD
Eligibility 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)
Sites / Locations
- University of Maryland Medical Center
- Tufts Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Metformin
Placebo
Arm Description
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
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
Outcomes
Primary Outcome Measures
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.
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.
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.
Secondary Outcome Measures
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.
Quality of Life Mental Component
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.
Back Pain Frequency Over the Past 3 Months Since Last Visit
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.
Estimated Glomerular Filtration Rate (eGFR)
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.
Total Kidney Volume From Magnetic Resonance Imaging
Annual percent change of height adjusted and natural log transformed total kidney volume [ln(htTKV)] was estimated with a linear mixed model.
Total Kidney Cyst Volume From Magnetic Resonance Imaging
Annual percent change of height adjusted and natural log transformed total kidney cyst volume [ln(htTKCV)] was estimated with a linear mixed model.
Liver Volume From Magnetic Resonance Imaging
Annual percent change of height adjusted and natural log transformed liver volume [ln(htLV)] was estimated with a linear mixed model.
Liver Cyst Volume From Magnetic Resonance Imaging
Annual percent change of height adjusted and natural log transformed liver cyst volume [ln(htLCV)] was estimated with a linear mixed model.
Frequency Abdominal Fullness Interfered With Ability to Perform Usual Physical Activity Over the Past 3 Months Since Last Visit.
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.
Interference of Pain With Sleep Over the Past 3 Months Since Last Visit
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.
Interference of Pain With Strenuous Physical Activity Over the Past 3 Months Since Last Visit
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.
Full Information
NCT ID
NCT02656017
First Posted
December 23, 2015
Last Updated
August 6, 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
1. Study Identification
Unique Protocol Identification Number
NCT02656017
Brief Title
Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Acronym
TAME
Official Title
Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Study Type
Interventional
2. Study Status
Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
June 27, 2016 (Actual)
Primary Completion Date
December 7, 2020 (Actual)
Study Completion Date
December 7, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the 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
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycystic Kidney, Autosomal Dominant
Keywords
kidney disease, polycystic kidney disease, autosomal dominant kidney disease, kidney cysts, PKD
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
97 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Metformin
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage, Metformin hydrochloride
Intervention Description
Monitoring of tolerability and symptoms.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Monitoring of tolerability and symptoms.
Primary Outcome Measure Information:
Title
Change in the Gastrointestinal Symptoms Rating Scale (GSRS) to 24 Months
Description
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
Title
Drug Tolerability
Description
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
Title
Rate of Serious Adverse Events (SAE)
Description
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 Outcome Measure Information:
Title
Quality of Life Physical Component
Description
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
Title
Quality of Life Mental Component
Description
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.
Time Frame
Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
Title
Back Pain Frequency Over the Past 3 Months Since Last Visit
Description
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.
Time Frame
Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
Title
Estimated Glomerular Filtration Rate (eGFR)
Description
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, and 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months
Title
Total Kidney Volume From Magnetic Resonance Imaging
Description
Annual percent change of height adjusted and natural log transformed total kidney volume [ln(htTKV)] was estimated with a linear mixed model.
Time Frame
Baseline, 6 months, 12 months, 18 months, 24 months
Title
Total Kidney Cyst Volume From Magnetic Resonance Imaging
Description
Annual percent change of height adjusted and natural log transformed total kidney cyst volume [ln(htTKCV)] was estimated with a linear mixed model.
Time Frame
Baseline, 6 months, 12 months, 18 months, 24 months
Title
Liver Volume From Magnetic Resonance Imaging
Description
Annual percent change of height adjusted and natural log transformed liver volume [ln(htLV)] was estimated with a linear mixed model.
Time Frame
Baseline, 6 months, 12 months, 18 months, 24 months
Title
Liver Cyst Volume From Magnetic Resonance Imaging
Description
Annual percent change of height adjusted and natural log transformed liver cyst volume [ln(htLCV)] was estimated with a linear mixed model.
Time Frame
Baseline, 6 months, 12 months, 18 months, 24 months
Title
Frequency Abdominal Fullness Interfered With Ability to Perform Usual Physical Activity Over the Past 3 Months Since Last Visit.
Description
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.
Time Frame
Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
Title
Interference of Pain With Sleep Over the Past 3 Months Since Last Visit
Description
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.
Time Frame
Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
Title
Interference of Pain With Strenuous Physical Activity Over the Past 3 Months Since Last Visit
Description
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.
Time Frame
Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kyongtae Bae, MD, PhD
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Maryland Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Tufts Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33768205
Citation
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.
Results Reference
derived
Learn more about this trial
Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
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