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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
1,174
Extended release metformin.
Placebo is inactive tablets that is identical to the intervention Metformin tablets.
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.
Time frame: Over 24 months
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.
Time frame: 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.
Time frame: 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%.
Time frame: Over 24 months
Kidney failure
The proportion of participants who experience kidney failure, defined as an eGFR \<15mL/min/1.73m2.
Time frame: Over 24 months
Mortality
The proportion of participants who die during the observation period, irrespective of the cause.
Time frame: 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.
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Renal Research
Gosford, New South Wales, Australia
ACTIVE_NOT_RECRUITINGRoyal Prince Alfred Hospital
Sydney, New South Wales, Australia
ACTIVE_NOT_RECRUITINGRoyal North Shore Hospital
Sydney, New South Wales, Australia
ACTIVE_NOT_RECRUITINGWestmead Hospital - Western Sydney Local Health District
Sydney, New South Wales, Australia
ACTIVE_NOT_RECRUITINGBundaberg Hospital
Bundaberg, Queensland, Australia
ACTIVE_NOT_RECRUITINGTownsville University Hospital
Douglas, Queensland, Australia
ACTIVE_NOT_RECRUITINGRoyal Brisbane and Women's Hospital
Herston, Queensland, Australia
ACTIVE_NOT_RECRUITINGPrincess Alexandra Hospital
Woolloongabba, Queensland, Australia
ACTIVE_NOT_RECRUITINGRoyal Adelaide Hospital
Adelaide, South Australia, Australia
RECRUITINGRoyal Melbourne Hospital
Melbourne, Victoria, Australia
ACTIVE_NOT_RECRUITING...and 30 more locations
Time frame: Over 24 months
Changes in the urine albumin:creatinine ratio
The percentage change in the urine albumin:creatinine ratio for each participant
Time frame: 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.
Time frame: Over 24 months
Health-related quality of life
This will measured using the EuroQual 5 Domain 5 Level (EQ-5D-5L) questionnaire
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Over 24 months