Clinical trial NCT02656017: Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Official title: Metformin as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Polycystic Kidney, Autosomal Dominant
Keywords: kidney disease
polycystic kidney disease
autosomal dominant kidney disease
kidney cysts
PKD
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Tufts Medical Center
name: University of Maryland, Baltimore
name: University of Southern California
name: United States Department of Defense
First posted: 2016-01-14
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Change in the Gastrointestinal Symptoms Rating Scale (GSRS) to 24 Months
timeFrame: Baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Drug Tolerability
timeFrame: Baseline, 2 weeks, 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Rate of Serious Adverse Events (SAE)
timeFrame: 26 months
Secondary outcomes:
measure: Quality of Life Physical Component
timeFrame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Quality of Life Mental Component
timeFrame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Back Pain Frequency Over the Past 3 Months Since Last Visit
timeFrame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline, 2 weeks, and 6 weeks, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Total Kidney Volume From Magnetic Resonance Imaging
timeFrame: Baseline, 6 months, 12 months, 18 months, 24 months
measure: Total Kidney Cyst Volume From Magnetic Resonance Imaging
timeFrame: Baseline, 6 months, 12 months, 18 months, 24 months
measure: Liver Volume From Magnetic Resonance Imaging
timeFrame: Baseline, 6 months, 12 months, 18 months, 24 months
measure: Liver Cyst Volume From Magnetic Resonance Imaging
timeFrame: Baseline, 6 months, 12 months, 18 months, 24 months
measure: Frequency Abdominal Fullness Interfered With Ability to Perform Usual Physical Activity Over the Past 3 Months Since Last Visit.
timeFrame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Interference of Pain With Sleep Over the Past 3 Months Since Last Visit
timeFrame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
measure: Interference of Pain With Strenuous Physical Activity Over the Past 3 Months Since Last Visit
timeFrame: Baseline, 1 month, 3 months and every 3 months thereafter to 24 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
Study officials:
affiliation: University of Pittsburgh
name: Kyongtae Bae, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.