Clinical trial NCT04939935: Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)
Official title: Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD): A Randomised Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Autosomal Dominant Polycystic Kidney Disease
Keywords: Placebo
Metformin
ADPKD
Lead sponsor: The University of Queensland
Sponsor class: OTHER
First posted: 2021-06-25
Enrollment: 1174
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

To be eligible to participate in this trial, patients must satisfy all of the following inclusion criteria:

1. Willing to participate and provide informed consent
2. Aged 18-70 years
3. 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
4. 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.

Exclusion Criteria:

1. Diabetes mellitus (as per American Diabetes Association definition), or other systemic conditions that may cause CKD independent of PKD (excluding hypertension)
2. Uncontrolled hypertension (Systolic BP \>160 mmHg and/or diastolic BP \>100 mmHg after a period of rest)
3. Clinically significant heart failure, including but not limited to New York Heart Association Class (NYHA) III or IV
4. Non-polycystic liver disease, including but not limited to:

   1. Liver enzymes (ALT, AST or Total Bilirubin) \>2 times the upper limit of normal, except when a diagnosis of Gilbert Syndrome exists and/or,
   2. Child-Pugh classification score equal to or greater than 5
5. Any contraindication to metformin including abnormal liver function tests or untreated Vitamin B12 deficiency
6. Currently taking metformin
7. Pregnancy or breastfeeding, or planning to get pregnant in the next three years.
8. 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.
9. History of dialysis.

Primary outcomes:
measure: The change in estimated glomerular filtration rate (eGFR)
timeFrame: Over 24 months
Secondary outcomes:
measure: Annualised slope of eGFR.
timeFrame: Over 24 months
measure: Composite outcome
timeFrame: Over 24 months
measure: Severity of change in eGFR
timeFrame: Over 24 months
measure: Kidney failure
timeFrame: Over 24 months
measure: Mortality
timeFrame: Over 24 months
measure: Change in medication dosage during the trial
timeFrame: Over 24 months
measure: Changes in the urine albumin:creatinine ratio
timeFrame: Over 24 months
measure: Presence and category change of albuminuria
timeFrame: Over 24 months
measure: Health-related quality of life
timeFrame: Over 24 months
measure: ADPKD-related pain
timeFrame: Over 24 months
measure: Gastrointestinal symptoms
timeFrame: Over 24 months
measure: Presence of study-related events
timeFrame: Over 24 months
measure: Healthcare utilisation
timeFrame: Over 24 months
Other outcomes:
Locations:
city: Gosford
country: Australia
facility: Renal Research
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital - Western Sydney Local Health District
state: New South Wales
city: Bundaberg
country: Australia
facility: Bundaberg Hospital
state: Queensland
city: Douglas
country: Australia
facility: Townsville University Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Tauranga
country: New Zealand
facility: Te Whatu Ora - Hauora a Toi Bay of Plenty
state: Bay Of Plenty
city: Whangārei
country: New Zealand
facility: Te Whatu Ora - Te Tai Tokerau
state: Northland
city: Dunedin
country: New Zealand
facility: Te Whatu Ora - Southern
state: Otago
city: New Plymouth
country: New Zealand
facility: Te Whatu Ora - Taranaki
state: Taranaki
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
state: Devon
city: Nottingham
country: United Kingdom
facility: Nottingham Renal Unit, Nottingham City Hospital
state: East Midlands
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
state: Inverness Shire
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
state: Lancashire
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
state: Lancashire
city: Leicester
country: United Kingdom
facility: Leicester General Hospital
state: Leicestershire
city: Carshalton
country: United Kingdom
facility: St Helier Hospital
state: London
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: Merseyside
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: Norfolk
city: Antrim
country: United Kingdom
facility: Antrim Area Hospital
state: Northern Ireland
city: Belfast
country: United Kingdom
facility: Ulster Hospital
state: Northern Ireland
city: Londonderry
country: United Kingdom
facility: Altnagelvin Hospital
state: Northern Ireland
city: Newry
country: United Kingdom
facility: Daisy Hill Hospital
state: Northern Ireland
city: Oxford
country: United Kingdom
facility: Oxford Kidney Unit, Churchill Hospital,
state: Oxfordshire
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
state: South Yorkshire
city: Sheffield
country: United Kingdom
facility: Sheffield Kidney Institute
state: South Yorkshire
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
state: Staffordshire
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
state: Tyne And Wear
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital Birmingham
state: West Midlands
city: Bradford
country: United Kingdom
facility: Bradford Renal Unit, St Luke's Hospital
state: West Yorkshire
city: London
country: United Kingdom
facility: The Royal London Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: Townsville University Hospital
name: Andrew Mallett, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
References: