Back to resultsImplementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)
Primary Purpose
Autosomal Dominant Polycystic Kidney Disease
Status
Recruiting
Phase
Phase 3
Locations
Australia
Study Type
Interventional
Intervention
Metformin XR
Control
Sponsored by
About this trial
This is an interventional treatment trial for Autosomal Dominant Polycystic Kidney Disease focused on measuring Placebo, Metformin, ADPKD
Eligibility Criteria
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, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and the presence of stoma.
- History of dialysis.
Sites / Locations
- Renal ResearchRecruiting
- Royal Prince Alfred Hospital
- Royal North Shore Hospital
- Westmead Hospital - Western Sydney Local Health DistrictRecruiting
- Bundaberg Hospital
- Townsville University Hospital
- Royal Brisbane and Women's HospitalRecruiting
- Princess Alexandra HospitalRecruiting
- Royal Adelaide HospitalRecruiting
- Austin HealthRecruiting
- Monash Health
- Sir Charles Gairdner Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Intervention
Control
Arm Description
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.
Participants randomised to the control group receive placebo plus standard of care for 104 weeks.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
Severity of change in eGFR
The proportion of participants with a reduction from baseline in their eGFR of equal to or greater than 30%.
Kidney failure
The proportion of participants who experience kidney failure, defined as an eGFR <15mL/min/1.73m2.
Mortality
The proportion of participants who die during the observation period, irrespective of the cause.
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.
Changes in the urine albumin:creatinine ratio
The percentage change in the urine albumin:creatinine ratio for each participant
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.
Health-related quality of life
This will measured using the EuroQual 5 Domain 5 Level (EQ-5D-5L) questionnaire
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).
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
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
Healthcare utilisation
Incremental cost effectiveness ratios (ICERs) will be calculated based on the incremental costs and incremental health outcomes between intervention groups
Full Information
NCT ID
NCT04939935
First Posted
June 16, 2021
Last Updated
September 4, 2023
Sponsor
The University of Queensland
1. Study Identification
Unique Protocol Identification Number
NCT04939935
Brief Title
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
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 29, 2022 (Actual)
Primary Completion Date
December 2026 (Anticipated)
Study Completion Date
May 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Queensland
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autosomal Dominant Polycystic Kidney Disease
Keywords
Placebo, Metformin, ADPKD
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Study participants, treating physicians and other care providers, outcome assessors, study investigators, and study statisticians will be blinded. An unblinded statistician will regularly review treatment allocations to ensure balance across treatment arms. The unblinded statistician will also prepare unblinded statistical reports for meetings of the Data and Safety Monitoring Board.
Allocation
Randomized
Enrollment
1174 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Intervention
Arm Type
Experimental
Arm Description
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.
Arm Title
Control
Arm Type
Placebo Comparator
Arm Description
Participants randomised to the control group receive placebo plus standard of care for 104 weeks.
Intervention Type
Drug
Intervention Name(s)
Metformin XR
Other Intervention Name(s)
APO-Metformin XR (500mg)
Intervention Description
Extended release metformin.
Intervention Type
Other
Intervention Name(s)
Control
Other Intervention Name(s)
Placebo
Intervention Description
Placebo is inactive tablets that is identical to the intervention Metformin tablets.
Primary Outcome Measure Information:
Title
The change in estimated glomerular filtration rate (eGFR)
Description
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
Secondary Outcome Measure Information:
Title
Annualised slope of eGFR.
Description
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
Title
Composite outcome
Description
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
Title
Severity of change in eGFR
Description
The proportion of participants with a reduction from baseline in their eGFR of equal to or greater than 30%.
Time Frame
Over 24 months
Title
Kidney failure
Description
The proportion of participants who experience kidney failure, defined as an eGFR <15mL/min/1.73m2.
Time Frame
Over 24 months
Title
Mortality
Description
The proportion of participants who die during the observation period, irrespective of the cause.
Time Frame
Over 24 months
Title
Change in medication dosage during the trial
Description
The proportion of participants requiring a dosage increase or the introduction of a new anti-hypertensive agent during the treatment period.
Time Frame
Over 24 months
Title
Changes in the urine albumin:creatinine ratio
Description
The percentage change in the urine albumin:creatinine ratio for each participant
Time Frame
Over 24 months
Title
Presence and category change of albuminuria
Description
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
Title
Health-related quality of life
Description
This will measured using the EuroQual 5 Domain 5 Level (EQ-5D-5L) questionnaire
Time Frame
Over 24 months
Title
ADPKD-related pain
Description
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
Title
Gastrointestinal symptoms
Description
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
Title
Presence of study-related events
Description
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
Title
Healthcare utilisation
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Misa Matsuyama, PhD
Phone
+61 437 759 894
Email
impedepkd@uq.edu.au
First Name & Middle Initial & Last Name or Official Title & Degree
Pushparaj Velayudham
Phone
+61 438 077 278
Email
impedepkd@uq.edu.au
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Mallett, MBBS, PhD
Organizational Affiliation
Townsville University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Renal Research
City
Gosford
State/Province
New South Wales
ZIP/Postal Code
2250
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Simon Roger, PI
Email
sdroger@bigpond.net.au
First Name & Middle Initial & Last Name & Degree
Leonie Kelly, SC
Phone
02 - 4323 7977
Email
leonie@renalresearch.com.au
Facility Name
Royal Prince Alfred Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Individual Site Status
Not yet recruiting
Facility Name
Royal North Shore Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2065
Country
Australia
Individual Site Status
Not yet recruiting
Facility Name
Westmead Hospital - Western Sydney Local Health District
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gopala Rangan
Email
g.rangan@sydney.edu.au
Facility Name
Bundaberg Hospital
City
Bundaberg
State/Province
Queensland
ZIP/Postal Code
4670
Country
Australia
Individual Site Status
Not yet recruiting
Facility Name
Townsville University Hospital
City
Douglas
State/Province
Queensland
ZIP/Postal Code
4814
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vikas Srivastava, MD, FRACP
Phone
+61744335091
Email
vikas.srivastava@health.qld.gov.au
Facility Name
Royal Brisbane and Women's Hospital
City
Herston
State/Province
Queensland
ZIP/Postal Code
4006
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Martin Wolley, PI
Email
Martin.Wolley@health.qld.gov.au
First Name & Middle Initial & Last Name & Degree
Belinda Elford, SC
Email
Belinda.Elford@health.qld.gov.au
Facility Name
Princess Alexandra Hospital
City
Woolloongabba
State/Province
Queensland
ZIP/Postal Code
4102
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andrea Viecelli, PI
Email
andrea.viecelli@health.qld.gov.au
First Name & Middle Initial & Last Name & Degree
Rachael Hale, SC
Phone
07 - 3240 7466
Email
rachael.hale@health.qld.gov.au
Facility Name
Royal Adelaide Hospital
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Randall Faull, PI
Email
randall.faull@sa.gov.au
First Name & Middle Initial & Last Name & Degree
Bronwyn Hockley, SC
Phone
08 - 7074 3077
Email
bronwyn.hockley@sa.gov.au
Facility Name
Austin Health
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mardiana Lee, PI
Email
Mardiana.Lee@austin.org.au
First Name & Middle Initial & Last Name & Degree
Marieke Veenendaal, SC
Phone
03 - 9496 3069
Email
Marieke.Veenendaal@austin.org.au
Facility Name
Monash Health
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Individual Site Status
Not yet recruiting
Facility Name
Sir Charles Gairdner Hospital
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Individual Site Status
Not yet recruiting
12. IPD Sharing Statement
Plan to Share IPD
No
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Implementation of Metformin theraPy to Ease Decline of Kidney Function in Polycystic Kidney Disease (IMPEDE-PKD)
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