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

Sponsor

The University of Queensland (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04939935

Collaborator

(none)

1,164

Enrollment

Locations

Arms

Anticipated Duration (Months)

291

Patients Per Site

5.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 growth of kidney cysts, thereby slowing the rate of kidney function decline, reducing morbidity and mortality and improving the quality of life for ADPKD patients.

Condition or Disease	Intervention/Treatment	Phase
Autosomal Dominant Polycystic Kidney Disease	Drug: Metformin XR Other: Control	Phase 3

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 1,164 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 Design

Study Type:

Interventional

Anticipated Enrollment :

1164 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Enrolled participants will be randomised to either (1) intervention group receiving metformin extended release (XR) plus standard of care, or (2) placebo plus standard of care.Enrolled participants will be randomised to either (1) intervention group receiving metformin extended release (XR) plus standard of care, or (2) placebo plus standard of care.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Study participants, treating physicians and other care providers, outcome assessors, study investigators, and study statisticians will be blinded. An unblinded statistician will regularly review treatment allocations to ensure balance across treatment arms. The unblinded statistician will also prepare unblinded statistical reports for meetings of the Data and Safety Monitoring Board.

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Annualised slope of eGFR. [Over 24 months]
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.
Composite outcome [Over 24 months]
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.
Severity of change in eGFR [Over 24 months]
The proportion of participants with a reduction from baseline in their eGFR of equal to or greater than 30%.
Kidney failure [Over 24 months]
The proportion of participants who experience kidney failure, defined as an eGFR <15mL/min/1.73m2.
Mortality [Over 24 months]
The proportion of participants who die during the observation period, irrespective of the cause.
Change in medication dosage during the trial [Over 24 months]
The proportion of participants requiring a dosage increase or the introduction of a new anti-hypertensive agent during the treatment period.
Changes in the urine albumin:creatinine ratio [Over 24 months]
The percentage change in the urine albumin:creatinine ratio for each participant
Presence and category change of albuminuria [Over 24 months]
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.
Health-related quality of life [Over 24 months]
This will measured using the EuroQual 5 Domain 5 Level (EQ-5D-5L) questionnaire
ADPKD-related pain [Over 24 months]
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).
Gastrointestinal symptoms [Over 24 months]
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
Presence of study-related events [Over 24 months]
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
Healthcare utilisation [Over 24 months]
Incremental cost effectiveness ratios (ICERs) will be calculated based on the incremental costs and incremental health outcomes between intervention groups

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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:

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, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and the presence of stoma.
History of dialysis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Western Sydney Local Health District	Sydney	New South Wales	Australia	2145
2	Townsville University Hospital	Douglas	Queensland	Australia	4814
3	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
4	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102