Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)
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 details:
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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
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
- 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 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.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE3
Study ID
NCT04939935
Intervention or treatment
DRUG: Metformin XR
OTHER: Control
Conditions
- Autosomal Dominant Polycystic Kidney Disease
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Research sites nearby
Closest Location:
Renal Research
Select from list below to view details:
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
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Who is running the clinical trial?
The University of Queensland
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Intervention
| Drug: Metformin XR |
PLACEBO_COMPARATOR: Control
| Other: Control |
What is the study measuring?
Primary Outcome
| 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
| 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 |
References
Clinical Trials Gov: Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)Other trials to consider
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