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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Autosomal Dominant Polycystic Kidney Disease

Intervention / Treatment
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* Drug: Metformin XR
* Other: Control


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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>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<br>* Extended release metformin.<br>* Other names: APO-Metformin XR (500mg);|
| Placebo Comparator: Control<br>Participants randomised to the control group receive placebo plus standard of care for 104 weeks. | Other: Control<br>* Placebo is inactive tablets that is identical to the intervention Metformin tablets.<br>* Other names: Placebo;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Placebo, Metformin, ADPKD