Clinical Trials Logo

Clinical Trial Summary

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder occurring in 1:400-1:1.000 live births and affects 4 to 6 million persons worldwide and about 205.000 people in Europe (EU). This figure is equivalent to 4 in 10.000 people and thus below the prevalence threshold of 5 in 10.000 used to designate a disease as rare in EU.

Renal cyst development and expansion in ADPKD involves both fluid secretion and abnormal proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK). Metformin, a drug widely used, is a pharmacological activator of AMPK. The investigators found that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis. In addition, metformin administration produces a significant decrease in the cystic index in two mouse models of ADPKD. These results suggest a possible role for AMPK activation in slowing renal cystogenesis as well as the potential for therapeutic application of metformin in the context of ADPKD.

Thus this study aims to evaluate metformin efficacy in slowing renal cystogenesis in ADPKD as compared to the actual gold standard (Tolvaptan).


Clinical Trial Description

Objective of the study is to assess if a two-year course of 1500 mg oral metformin is effective and safe in treatment of ADPKD, as compared to the actual gold-standard therapy, tolvaptan (Jinarc®) This is a phase 3a, independent, multi-centre, parallel arms, randomized controlled trial comparing efficacy and safety of metformin and tolvaptan in ADPKD.

This trial will enroll approximately 150 tolvaptan and metformin naïve subjects affected by Type I-truncating ADPKD, as these subjects have grater probability of progression.

The trial contemplates a 2 weeks screening period (included in a 9 months total recruitment period) during which 3 visits have to be collected (the 1st and the 2nd in three days, and the 3rd after biochemical analyses performed during the first two visits have been reviewed). The subject's eligibility for the trial will be confirmed by the mean of eGFR calculated from the 2 pre-treatment, central-lab, serum creatinine assessments. Longer screening periods (up to 4 additional weeks) are acceptable for subjects needing stabilization after changing or discontinuing other treatments, especially anti-hypertensives and diuretics.

Once eligibility is assessed, patients will undergo non-contrast enhanced CT-scan of kidneys (if not performed within six months prior to randomization).

Randomization visit will occur on Day -29. During this visit patients will be randomized (in a ratio 1:1 tolvaptan:metformin) to each arm of treatment and will start an IMP titration period (3 weeks from -28 to -8). Subjects not tolerating the minimum IMP dose will be considered "Titration failures" and will complete End of Treatment (EoTx) visit assessments and will be followed up after 7 days by phone call to assess any ongoing AEs. Subjects tolerating the minimum IMP dose enter the unblind run-in period (1 week from Day -7 to -1). During the "Run-in" phase, subjects will continue on a stable IMP dose to confirm tolerability over a longer period. At the end of the run-in period (Day -1), subjects not tolerating the minimum IMP dose will be considered "Run-in failures" and will complete EoTx visit assessments and will be followed up after 7 days by phone call to assess any ongoing AEs. Subjects completing the run-in will start the open-label 24 months treatment period, during which visits will be collected three-monthly. At the end of the 24th month, and in case of early treatment cessation, follow-up period (3 weeks from +8 to +21) will start, during which 2 visits have to be collected. No IMP will be administered during this period.

This trial will enroll approximately 150 tolvaptan and metformin naïve subjects and will be conducted in about 11 Italian Hospital Nephrology Departments The investigators plan to recruit a total of 150 patients which are currently within the reach of the network coordinated by the proponent and composed by 11 Nephrology Centres. This network treats a total of 1500 (already genetically studied) patients of which the investigators expect (based on standard response rates recognized in the population) acceptance to participate in the study to a value of approximately 40% of patients that will be then allocated to the experimental and control intervention.

The selected sample is adequate to evaluate a significant reduction in the slope of eGFR at 2 years by 10%, which is a clinically relevant piece of information at the current state of knowledge, as well as a complete assessment of the benefits-harms trade-off of the two interventions.

The trial has a 36 months overall duration, that include a 9 months recruitment period; has a 2 weeks duration, it is included in the 9 months recruitment period. The treatment period has a 25 months duration. Each month lasts 28 days. It includes the 3 weeks titration period and the 1 week run-in period.

The post-treatment follow-up: lasts 21 days. The total Study Duration is of about 3 years. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT03764605
Study type Interventional
Source Azienda Ospedaliero-Universitaria Consorziale
Contact Loreto Gesualdo
Phone +390805594040
Email loretoge60@gmail.com
Status Not yet recruiting
Phase Phase 3
Start date January 30, 2019
Completion date January 30, 2022

See also
  Status Clinical Trial Phase
Recruiting NCT04310319 - Wishing to Decrease Aquaresis in ADPKD Patients Treated With a V2Ra; the Effect of Regulating Protein and Salt N/A
Completed NCT02776241 - Effect of Water Intake and Water Restriction on Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease N/A
Terminated NCT04152837 - Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease Phase 3
Completed NCT03717883 - ADPKD Alterations in Hepatic Transporter Function
Recruiting NCT05014178 - Kidney Sodium Functional Imaging
Recruiting NCT05521191 - A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease Phase 1
Terminated NCT04064346 - Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease Phase 3
Completed NCT03203642 - Study of the Efficacy and Safety of Tesevatinib in Subjects With ADPKD Phase 2
Recruiting NCT04338048 - Autosomal Dominant Polycystic Kidney Disease (ADPKD) Study
Not yet recruiting NCT06100133 - Treat Autosomal Dominant Polycystic Kidney Disease With Oral Ketone Ester? Phase 2
Completed NCT01632605 - The Vienna RAP Pilot Study N/A
Terminated NCT03918447 - A Trial of Bardoxolone Methyl in Patients With ADPKD - FALCON Phase 3
Recruiting NCT06416761 - Genetics in the Progression of Nephropathies
Not yet recruiting NCT05373264 - HYDROchlorothiazide to PROTECT Polycystic Kidney Disease Patients and Improve Their Quality of Life Phase 3
Recruiting NCT06085807 - Genetic Testing in Autosomal Dominant Polycystic Kidney Disease
Completed NCT01853553 - Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney Disease (ADPKD) Phase 3
Completed NCT04472624 - Short Term Induction of Ketosis in PKD N/A
Completed NCT04680780 - Ketogenic Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease (ADPKD) N/A
Completed NCT02161068 - Clinical Care of Autosomal Polycystic Kidney Disease: Retrospective Analysis and Prospective PKD Genotyping
Active, not recruiting NCT03273413 - Statin Therapy in Patients With Early Stage ADPKD Phase 4