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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Autosomal Dominant Polycystic Kidney Disease
• Intervention / Treatment: Drug: Metformin XR; Other: Control

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.

• Study Type: Interventional
• Enrollment (Estimated): 1174
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Misa Matsuyama, PhD; Phone Number: +61 437 759 894; Email: impedepkd@uq.edu.au
• Study Contact Backup: Name: Pushparaj Velayudham; Phone Number: +61 438 077 278; Email: impedepkd@uq.edu.au

Study Locations

• Australia
  • New South Wales
    • Gosford, New South Wales, Australia, 2250
      • Recruiting
      • Renal Research
      • Contact: Simon Roger, PI; Email: sdroger@bigpond.net.au
      • Contact: Leonie Kelly, SC; Phone Number: 02 - 4323 7977; Email: leonie@renalresearch.com.au
    • Sydney, New South Wales, Australia, 2050
      • Recruiting
      • Royal Prince Alfred Hospital
    • Sydney, New South Wales, Australia, 2065
      • Not yet recruiting
      • Royal North Shore Hospital
    • Sydney, New South Wales, Australia, 2145
      • Recruiting
      • Westmead Hospital - Western Sydney Local Health District
      • Contact: Gopala Rangan; Email: g.rangan@sydney.edu.au
  • Queensland
    • Bundaberg, Queensland, Australia, 4670
      • Not yet recruiting
      • Bundaberg Hospital
    • Douglas, Queensland, Australia, 4814
      • Recruiting
      • Townsville University Hospital
      • Contact: Vikas Srivastava, MD, FRACP; Phone Number: +61744335091; Email: vikas.srivastava@health.qld.gov.au
    • Herston, Queensland, Australia, 4006
      • Recruiting
      • Royal Brisbane and Women's Hospital
      • Contact: Martin Wolley, PI; Email: Martin.Wolley@health.qld.gov.au
      • Contact: Belinda Elford, SC; Email: Belinda.Elford@health.qld.gov.au
    • Woolloongabba, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Contact: Andrea Viecelli, PI; Email: andrea.viecelli@health.qld.gov.au
      • Contact: Rachael Hale, SC; Phone Number: 07 - 3240 7466; Email: rachael.hale@health.qld.gov.au
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Royal Adelaide Hospital
      • Contact: Randall Faull, PI; Email: randall.faull@sa.gov.au
      • Contact: Bronwyn Hockley, SC; Phone Number: 08 - 7074 3077; Email: bronwyn.hockley@sa.gov.au
  • Victoria
    • Melbourne, Victoria, Australia, 3084
      • Recruiting
      • Austin Health
      • Contact: Mardiana Lee, PI; Email: Mardiana.Lee@austin.org.au
      • Contact: Marieke Veenendaal, SC; Phone Number: 03 - 9496 3069; Email: Marieke.Veenendaal@austin.org.au
    • Melbourne, Victoria, Australia, 3168
      • Recruiting
      • Monash Health
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Recruiting
      • Sir Charles Gairdner Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

1. Willing to participate and provide informed consent
2. Aged 18-70 years
3. 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
4. eGFR equal to or greater than 45 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:

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

4. Non-polycystic liver disease, including but not limited to:

   1. Liver enzymes (ALT, AST or Total Bilirubin) >2 times the upper limit of normal, except when a diagnosis of Gilbert Syndrome exists and/or,
   2. Child-Pugh classification score equal to or greater than 5
5. Any contraindication to metformin including abnormal liver function tests or untreated Vitamin B12 deficiency
6. Currently taking metformin
7. Pregnancy or breastfeeding, or planning to get pregnant in the next three years.
8. 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.
9. History of dialysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Participants randomised to the intervention group receive Metformin XR plus standard of care for 104 weeks. Dosage will depend on individual participant's level of tolerance to Metformin XR as well as their estimated glomerular filtration rate (eGFR). The dosage will be between 1000-2000mg/day.	Drug: Metformin XR; Extended release metformin.; Other Names: APO-Metformin XR (500mg)
Placebo Comparator: Control; Participants randomised to the control group receive placebo plus standard of care for 104 weeks.	Other: Control; Placebo is inactive tablets that is identical to the intervention Metformin tablets.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in estimated glomerular filtration rate (eGFR)	This will be measured using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at 104 weeks (24 months) from first dispensing date.	Over 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualised slope of eGFR.	The mean rate of change in eGFR from baseline over 2 years, estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula from the serum creatinine concentration analysed in the central laboratory.	Over 24 months
Composite outcome	A composite outcome comprising a reduction from baseline eGFR of equal to or greater than 30%, kidney failure (defined as an eGFR <15 millilitres/min/1.73m2), and all-cause mortality.	Over 24 months
Severity of change in eGFR	The proportion of participants with a reduction from baseline in their eGFR of equal to or greater than 30%.	Over 24 months
Kidney failure	The proportion of participants who experience kidney failure, defined as an eGFR <15mL/min/1.73m2.	Over 24 months
Mortality	The proportion of participants who die during the observation period, irrespective of the cause.	Over 24 months
Change in medication dosage during the trial	The proportion of participants requiring a dosage increase or the introduction of a new anti-hypertensive agent during the treatment period.	Over 24 months
Changes in the urine albumin:creatinine ratio	The percentage change in the urine albumin:creatinine ratio for each participant	Over 24 months
Presence and category change of albuminuria	The proportion of participants who experience albuminuria (excess albumin in the urine) during the trial period. Raw values will be recorded and albuminuria will be categorised as either A1 (<3.39mg/mmol), A2 (3.39-33.9mg/mmol), or A3 >33.9mh/mmol.	Over 24 months
Health-related quality of life	This will measured using the EuroQual 5 Domain 5 Level (EQ-5D-5L) questionnaire	Over 24 months
ADPKD-related pain	Mean change in the ADPKD Pain and Discomfort Scale (ADPKD-PDS) from baseline to end of study (dull kidney pain, sharp kidney pain and fullness/discomfort domain scores will be reported and analysed).	Over 24 months
Gastrointestinal symptoms	This will be measured using the Gastrointestinal Symptom Rating Scale (GSRS). A score greater than 1.33 will signal the presence of patient-significant gastrointestinal symptomatology	Over 24 months
Presence of study-related events	The proportion of participants who experience a specific event related to the study treatment (sub-categorised as incidence of gastrointestinal symptoms, presence of lactic acidosis, deranged liver function tests, hypoglycaemia, anaemia and vitamin B12 deficiency) expressed as a rate per 100 person years	Over 24 months
Healthcare utilisation	Incremental cost effectiveness ratios (ICERs) will be calculated based on the incremental costs and incremental health outcomes between intervention groups	Over 24 months

Collaborators and Investigators

• Sponsor: The University of Queensland
• Investigators: Principal Investigator: Andrew Mallett, MBBS, PhD, Townsville University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: June 16, 2021
• First Submitted That Met QC Criteria: June 16, 2021
• First Posted (Actual): June 25, 2021

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Metformin; ADPKD; Placebo
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: AKTN16.01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No