Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)
- Conditions
- Autosomal Dominant Polycystic Kidney Disease
- Interventions
- Other: Control
- Registration Number
- NCT04939935
- Lead Sponsor
- The University of Queensland
- 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 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1174
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.
-
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Intervention Metformin XR 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 500-2000mg/day. Control Control Participants randomised to the control group receive placebo plus standard of care for 104 weeks.
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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).
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
Health-related quality of life Over 24 months This will measured using the EuroQual 5 Domain 5 Level (EQ-5D-5L) questionnaire
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 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.
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.
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.
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.
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.
Mortality Over 24 months The proportion of participants who die during the observation period, irrespective of the cause.
Changes in the urine albumin:creatinine ratio Over 24 months The percentage change in the urine albumin:creatinine ratio for each participant
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
Trial Locations
- Locations (40)
Renal Research
🇦🇺Gosford, New South Wales, Australia
Royal Prince Alfred Hospital
🇦🇺Sydney, New South Wales, Australia
Royal North Shore Hospital
🇦🇺Sydney, New South Wales, Australia
Westmead Hospital - Western Sydney Local Health District
🇦🇺Sydney, New South Wales, Australia
Bundaberg Hospital
🇦🇺Bundaberg, Queensland, Australia
Townsville University Hospital
🇦🇺Douglas, Queensland, Australia
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Royal Melbourne Hospital
🇦🇺Melbourne, Victoria, Australia
Austin Health
🇦🇺Melbourne, Victoria, Australia
Monash Medical Centre
🇦🇺Melbourne, Victoria, Australia
Sir Charles Gairdner Hospital
🇦🇺Perth, Western Australia, Australia
Te Whatu Ora - Hauora a Toi Bay of Plenty
🇳🇿Tauranga, Bay Of Plenty, New Zealand
Te Whatu Ora - Te Tai Tokerau
🇳🇿Whangārei, Northland, New Zealand
Te Whatu Ora - Southern
🇳🇿Dunedin, Otago, New Zealand
Te Whatu Ora - Taranaki
🇳🇿New Plymouth, Taranaki, New Zealand
Royal Devon & Exeter Hospital
🇬🇧Exeter, Devon, United Kingdom
Nottingham Renal Unit, Nottingham City Hospital
🇬🇧Nottingham, East Midlands, United Kingdom
Raigmore Hospital
🇬🇧Inverness, Inverness Shire, United Kingdom
Royal Preston Hospital
🇬🇧Preston, Lancashire, United Kingdom
Salford Royal Hospital
🇬🇧Salford, Lancashire, United Kingdom
Leicester General Hospital
🇬🇧Leicester, Leicestershire, United Kingdom
St Helier Hospital
🇬🇧Carshalton, London, United Kingdom
Aintree University Hospital
🇬🇧Liverpool, Merseyside, United Kingdom
Norfolk and Norwich University Hospital
🇬🇧Norwich, Norfolk, United Kingdom
Antrim Area Hospital
🇬🇧Antrim, Northern Ireland, United Kingdom
Ulster Hospital
🇬🇧Belfast, Northern Ireland, United Kingdom
Altnagelvin Hospital
🇬🇧Londonderry, Northern Ireland, United Kingdom
Daisy Hill Hospital
🇬🇧Newry, Northern Ireland, United Kingdom
Oxford Kidney Unit, Churchill Hospital,
🇬🇧Oxford, Oxfordshire, United Kingdom
Doncaster Royal Infirmary
🇬🇧Doncaster, South Yorkshire, United Kingdom
Sheffield Kidney Institute
🇬🇧Sheffield, South Yorkshire, United Kingdom
Royal Stoke University Hospital
🇬🇧Stoke-on-Trent, Staffordshire, United Kingdom
Freeman Hospital
🇬🇧Newcastle upon Tyne, Tyne And Wear, United Kingdom
Queen Elizabeth Hospital Birmingham
🇬🇧Birmingham, West Midlands, United Kingdom
Bradford Renal Unit, St Luke's Hospital
🇬🇧Bradford, West Yorkshire, United Kingdom
The Royal London Hospital
🇬🇧London, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
King's College Hospital
🇬🇧London, United Kingdom