Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)

Official title

Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD): A Randomised Placebo-Controlled Trial

Overview

This study will investigate if a medication (metformin) widely used in the treatment of diabetes could be re-purposed for the treatment of patients with a diagnosis of early stage ADPKD to slow the rate of kidney function decline, reducing morbidity and mortality and improving the quality of life for ADPKD patients.

Detailed description

Autosomal Dominant Polycystic Kidney Disease (ADPKD) affects 12.5 million people worldwide and is the 4th leading cause of kidney failure. Cyst growth begins in childhood, and over decades leads to painful kidneys, hypertension and chronic kidney disease. ADPKD patients also have a high prevalence of anxiety, depression and poor quality of life. Despite this enormous burden, there is a lack of evidence for therapies and affordable, effective treatment options. To date, only one disease modifying therapy is licensed for use in ADPKD (tolvaptan), but it is limited by its restricted availability, side effects and high cost. Metformin, an inexpensive and familiar drug, has been shown in previous studies to target cyst-forming signals, thereby slowing the cyst growth rate. IMPEDE-PKD is an Australian-led global Phase III randomised controlled trial to investigate the effect of metformin on ADPKD disease progression. The study will recruit a total of 1,174 adult ADPKD patients from around the world (250 from Australia). The outcomes of this research will identify effective and targeted therapies for ADPKD that will slow kidney function decline, reduce the impact of the illness and likelihood of death, and improve the quality of life for ADPKD patients and families.

Interventions

• Drug Metformin XR
  Extended release metformin.
• Other Control
  Placebo is inactive tablets that is identical to the intervention Metformin tablets.

Primary outcome measures

• The change in estimated glomerular filtration rate (eGFR) [Time frame: Over 24 months]

Secondary outcome measures (12)

• Annualised slope of eGFR. [Time frame: Over 24 months]
• Composite outcome [Time frame: Over 24 months]
• Severity of change in eGFR [Time frame: Over 24 months]
• Kidney failure [Time frame: Over 24 months]
• Mortality [Time frame: Over 24 months]
• Change in medication dosage during the trial [Time frame: Over 24 months]
• Changes in the urine albumin:creatinine ratio [Time frame: Over 24 months]
• Presence and category change of albuminuria [Time frame: Over 24 months]
• Health-related quality of life [Time frame: Over 24 months]
• ADPKD-related pain [Time frame: Over 24 months]
• Gastrointestinal symptoms [Time frame: Over 24 months]
• Presence of study-related events [Time frame: Over 24 months]

Eligibility criteria

Inclusion criteria

To be eligible to participate in this trial, patients must satisfy all of the following inclusion criteria:

• Willing to participate and provide informed consent
• Aged 18-70 years
• Diagnosis of ADPKD based on radiological +/- genetic criteria as per Kidney Health Australia - Caring for Australians and New Zealanders with Kidney Impairment (KHA-CARI) Guidelines
• eGFR equal to or greater than 38 mL/min/1.73m2 and <90 mL/min/1.73m2

And have either:

5(a) One or more risk factors of progression from the following:

• Bilateral kidney length equal to or greater than16.5 cm, or
• Total Kidney Volume (TKV) equal to or greater than 750 mL or height-adjusted TKV (htTKV) equal to or greater than 600 mL/m2, or
• Mayo class IC/D/E or Pro-PKD score equal to or greater than 6 OR 5(b) Evidence of Active progression
• Decline in eGFR equal to or greater than 5 mL/min/1.73m2 in one year, or
• Decline in eGFR equal to or greater than 3 mL/min/1.73m2 per year over five years or more. or
• Increase in htTKV/TKV of equal to or greater than 5% per year on at least 2 measurements in the past year, excluding any initial eGFR effect over the initial 3 months of tolvaptan commencement (if applicable) Note: Tolvaptan therapy must have been in place for at least 6 months with stable dose for at least 3 months.

Exclusion criteria

• Diabetes mellitus (as per American Diabetes Association definition), or other systemic conditions that may cause CKD independent of PKD (excluding hypertension)
• Uncontrolled hypertension (Systolic BP >160 mmHg and/or diastolic BP >100 mmHg after a period of rest)
• Clinically significant heart failure, including but not limited to New York Heart Association Class (NYHA) III or IV
• Non-polycystic liver disease, including but not limited to:

• Liver enzymes (ALT, AST or Total Bilirubin) >2 times the upper limit of normal, except when a diagnosis of Gilbert Syndrome exists and/or,
• Child-Pugh classification score equal to or greater than 5
• Any contraindication to metformin including abnormal liver function tests or untreated Vitamin B12 deficiency
• Currently taking metformin
• Pregnancy or breastfeeding, or planning to get pregnant in the next three years.
• Comorbidities with potential to contaminate trial outcomes, specifically active cancer, history of other solid organ transplantations, active chronic obstructive pulmonary disease (COPD), active inflammatory bowel disease, and the presence of stoma.
• History of dialysis.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United Kingdom · 31 centers

• Royal Devon & Exeter Hospital — Exeter
• Nottingham Renal Unit, Nottingham City Hospital — Nottingham
• Raigmore Hospital — Inverness
• Royal Preston Hospital — Preston
• Salford Royal Hospital — Salford
• Leicester General Hospital — Leicester
• St Helier Hospital — Carshalton
• Aintree University Hospital — Liverpool
• … and 23 more centers

Australia · 13 centers

• Renal Research — Gosford
• Royal Prince Alfred Hospital — Sydney
• Royal North Shore Hospital — Sydney
• Westmead Hospital - Western Sydney Local Health District — Sydney
• Bundaberg Hospital — Bundaberg
• Townsville University Hospital — Douglas
• Royal Brisbane and Women's Hospital — Herston
• Princess Alexandra Hospital — Woolloongabba
• … and 5 more centers

New Zealand · 5 centers

• Te Whatu Ora - Hauora a Toi Bay of Plenty — Tauranga
• Te Whatu Ora - Te Tai Tokerau — Whangārei
• Te Whatu Ora - Southern — Dunedin
• Te Whatu Ora - Taranaki — New Plymouth
• Ta Pae Hauora o Ruhahine o Terarua Mid Central — Palmerston North

Publications

• Chen CY, Hadla M, Khambati I, Kashyap S, Westerfield V, Fedeles S, Besse W, Hopp K, Harris PC, Patel V, Chini E, Salih M, Barry MA, Chebib FT. Emerging Therapies in Autosomal Dominant Polycystic Kidney Disease. Kidney360. 2026 Jul 1;7(7):1662-1676. doi: 10.34067/KID.0000001109. Epub 2025 Dec 12. PMID 41385299
• Cortinovis M, Perico N, Remuzzi G. The Need for Novel Therapeutic Directions in Autosomal Dominant Polycystic Kidney Disease Patient Care. Clin J Am Soc Nephrol. 2025 Dec 5. doi: 10.2215/CJN.0000000975. Online ahead of print. PMID 41348481
• Pierre KS, El-Damanawi R, Johnson DW, Hawley CM, Viecelli AK, Jha V, Green SC, Gesualdo L, Kiriwandeniya C, Velayudham P, Vergara LA, Mihala G, Matsuyama M, Brent PP, Mallett AJ; IMPEDE-PKD Global Steering Committee (see Appendix). Implementation of Metformin Therapy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD): study protocol for a phase III, multi-centre, randomiz PMID 40855441
• St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3. PMID 39356039
• El-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2. PMID 38837240

Identifiers

NCT: NCT04939935 · AKTN16.01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗