A randomized trial of Metformin in autosomal dominant polycystic kidney disease for reducing rate of decline of kidney function
Scientific Title of Study
Metformin therapy in Polycystic Kidney Disease: A randomized, controlled trial
Trial Acronym
Nil
Secondary IDs if Any
Secondary ID
Identifier
NIL
NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Vivek Kumar
Designation
Associate Professor
Affiliation
Postgraduate Institute of Education and Research, Chandigarh
Address
Department of Nephrology, PGIMER, Sector 12, Chandigarh, India, Pin code 160012
Chandigarh CHANDIGARH 160012 India
Phone
7087429731
Fax
Email
enigma165@yahoo.co.in
Details of Contact Person Scientific Query
Name
Dr Vivek Kumar
Designation
Associate Professor
Affiliation
Postgraduate Institute of Education and Research, Chandigarh
Address
Department of Nephrology, PGIMER, Sector 12, Chandigarh, India, Pin code 160012
Chandigarh CHANDIGARH 160012 India
Phone
7087429731
Fax
Email
enigma165@yahoo.co.in
Details of Contact Person Public Query
Name
Dr Vivek Kumar
Designation
Associate Professor
Affiliation
Postgraduate Institute of Education and Research, Chandigarh
Address
Department of Nephrology, PGIMER, Sector 12, Chandigarh, India, Pin code 160012
Chandigarh CHANDIGARH 160012 India
Phone
7087429731
Fax
Email
enigma165@yahoo.co.in
Source of Monetary or Material Support
Indian Council of Medical Research. V. Ramalingaswami Bhawan, P.O. Box No. 4911. Ansari Nagar, New Delhi - 110029
Primary Sponsor
Name
Indian Council of Medical Research
Address
V. Ramalingaswami Bhawan, P.O. Box No. 4911. Ansari Nagar, New Delhi - 110029
Type of Sponsor
Government funding agency
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India
Sites of Study
No of Sites = 9
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Priti Meena
AIIMS Bhubaneswar
Department of Nephrology, AIIMS Bhubaneswar, Sijua, Patrapada, Bhubaneswar, Odisha 751019 Khordha ORISSA
9582765899
pritimn@gmail.com
Dr Asheesh Kumar
AIIMS Jammu
Department of Nephrology,
All India Institute of Medical Sciences (AIIMS) Jammu
Vijaypur, Jammu, 184120
India Jammu JAMMU & KASHMIR
9418002909
asheesh03.kapil@gmail.com
Dr Anand Chellapan
AIIMS Nagpur
Department of Nephrology,
All India Institute of Medical Sciences (AIIMS) Nagpur
Plot No.2, Sector 20, MIHAN, Nagpur
Nagpur District, Maharashtra 441108
India Nagpur MAHARASHTRA
8903613270
anandthedoc@gmail.com
Dr Vinay Rathore
AIIMS Raipur
Department of Nephrology, Gate No 1, Great Eastern Rd, opposite Gurudwara, AIIMS Campus, Tatibandh, Raipur, Chhattisgarh 492099 Raipur CHHATTISGARH
9914699651
vinayrathoredm@aiimsraipur.edu.in
Dr Sreejith Parameswaran
JIPMER, Puducherry
Department of Nephrology
Super Speciality Block, Room #5348
JIPMER Campus, Dhanvantari Nagar P.O.
Puducherry - 605006
India Pondicherry PONDICHERRY
9489148338
sreejith.p@jipmer.edu.in
Dr Dinesh Khullar
Max Saket, New Delhi
Department of Nephrology, 1 and 2, Press Enclave Marg, Saket Institutional Area, Saket, New Delhi, Delhi 110017 New Delhi DELHI
9810124066
drdineshkhullar@gmail.com
Dr Shyam Bihari Bansal
Medanta Medicity Hospital
Director of Nephrology, Kidney and Urology Institute
Medanta, The Medicity
Sector 38, Gurugram, Haryana 122001 India Gurgaon HARYANA
9810383522
drshyambansal@gmail.com
Dr Vivek Kumar
PGIMER, Chandiagrh
Department of Nephrology, AKU Ward, Nehru Hospital, PGIMER, Sector 12, Chandigarh Chandigarh CHANDIGARH
7087429731
enigma165@yahoo.co.in
Prof Vivekanand Jha
The George Institute, New Delhi
Executive Director, 308, Third Floor, Elegance Tower, District Centre, Jasola, New Delhi, Delhi 110025 New Delhi DELHI
Metformin is a widely used drug that is already approved in India. The drug will be used for 24 months after 12 weeks of run in phase.
Comparator Agent
Placebo
Placebo matched to intervention. This will be used for 24 months.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
70.00 Year(s)
Gender
Both
Details
1. Able to provide informed consent
2. Age 18-70 years
3. Diagnosis of ADPKD based on radiological or genetic criteria
4. eGFR greater than equal to 38 and less than 90 mL/min/1.73m2
5. Presence of either
i. One or more risk factors of progression [bilateral kidney length greater than equal to 16.5cm, total kidney volume (TKV) greater than equal to 750mL, height censored TKV (htTKV) greater than equal to 600mL/m2, Mayo class 1C/D/E or PRO-PKD score greater than equal to 6], OR
ii. Active disease progression as evidenced by one or more of following factors [decline in eGFR greater than equal to 5mL/min/1.73m2 in one year, decline in eGFR greater than equal to 3mL/min/1.73m2 per year over five years or more, or increase in htTKV/TKV of greater than equal to 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)]
6. For people on tolvaptan therapy, it must have been in place for at least 6 months with stable dose for at least 3 months.
ExclusionCriteria
Details
1. Diabetes mellitus or other systemic disease affecting the kidneys (excluding hypertension)
2. Uncontrolled hypertension (Systolic BP greater than 160mmHg and/or diastolic BP greater than 100mmHg 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 liver enzymes (ALT, AST or Total Bilirubin) greater than 2 times the upper limit of normal, except when a diagnosis of Gilbert Syndrome exists, and/or, Child-Pugh classification score greater than equal to 5
5. Any contraindication to metformin including abnormal liver function tests or untreated Vitamin B12 deficiency.
6. Pregnancy or breastfeeding or planning pregnancy in the next three years.
7. Currently taking metformin
8. Comorbidities with contraindication for metformin use or potential to contaminate trial outcomes, specifically active cancer, history of other solid organ (kidney, heart, liver, lung, bowel) transplantations, active chronic obstructive pulmonary disease (COPD), active inflammatory bowel disease (IBD), and stoma.
9. History of dialysis
10. Participation in another interventional clinical trial
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
Estimated GFR (CKD-EPICr 2021) at 104 weeks (24 months) from randomization
24 months
Secondary Outcome
Outcome
TimePoints
Major adverse kidney events, albuminuria, all-cause mortality
24 months
A composite outcome comprising a reduction from baseline eGFR of more than equal to 30%, kidney failure (defined as an eGFR less than 15mL/min/1.73m2), and all-cause mortality.
24 months
Reduction from baseline eGFR of more than equal to 30%
24 months
Kidney failure (defined as an eGFR less than 15mL/min/1.73m2)
24 month
All-cause mortality
24 months
The proportion of participants requiring a dosage adjustment or the introduction of a new anti-hypertensive agent during the treatment period.
24 months
Urine albumin:creatinine ratio.
24 months
Albuminuria (urine albumin:creatinine ratio) category (A1 less than 30 mg/g, A2 30-300 mg/g, A3 more than 300 mg/g and as a continuous variable.
24 months
Health-related quality of life scores measured using EuroQual 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire.
24 months
ADPKD related pain scores measured using the ADPKD-PDS.
24 months
Gastrointestinal symptoms measures using the Gastrointestinal Symptom Rating Scale (GSRS)3.
24 months
Incidence of gastrointestinal symptoms, lactic acidosis, deranged liver function tests, hypoglycaemia, anaemia and vitamin B12 deficiency (rate per 100-person years).
24 months
Health care utilisation – hospital admissions, non-admitted episodes of primary and specialist care, and prescribed medications.
24 months
Incremental costs, and incremental health outcomes (quality-adjusted life year (QALY) and clinically important difference in the primary outcome) of metformin therapy compared to placebo
24 months
Target Sample Size
Total Sample Size="292" Sample Size from India="292" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - YES
What data in particular will be shared? Response - All of the individual participant data collected during the trial, after de-identification.
What additional supporting information will be shared? Response - Study Protocol Response - Statistical Analysis Plan Response - Informed Consent Form Response - Clinical Study Report Response - Analytic Code
Who will be able to view these files? Response - Researchers whose proposed use of the data has been approved by an independent review committee identified for this purpose.
For what types of analyses will this data be available? Response - To achieve aims in the approved proposal.
By what mechanism will data be made available? Response (Others) - De-identified participant-level data will be made available on request. All such requests will be submitted to steering committee of the trial, and data will be shared after steering committee approval, ethics committee approval, and signing of the data sharing agreement.
For how long will this data be available start date provided 15-08-2028 and end date provided 14-08-2033? Response - Immediately following publication. No end date.
Any URL or additional information regarding plan/policy for sharing IPD? Additional Information - None
Brief Summary
Summary
Rationale
Autosomal Dominant Polycystic Kidney Disease (ADPKD) accounts 3.4% of patients with CKD in India. Though relatively rare, the absolute numbers make it the most common inherited cause of CKD. There is an urgent need to identify therapies that will effectively and safely slow kidney function decline in patients affected by ADPKD.
Novelty
Metformin is a biguanide that has long been approved for use in Type 2 Diabetes Mellitus. It has well-established pharmacokinetic, pharmacodynamic and safety profiles. It is known to upregulate and activate the master cellular energy homeostasis regulator AMPK, which is decreased in the kidney cells of ADPKD patients. Multiple cell culture and animal ADPKD models have shown that metformin slows progression of ADPKD-related kidney cyst formation. Small studies have established its safety in humans with ADPKD. However, the long-term clinical effects are unknown.
Objectives
The primary objective of the study is to assess whether use of metformin in patients with ADPKD slows decline in kidney function at 24 months or not.
Methods
The study will be a multi-centric, double-blind, randomized controlled trial (RCT) designed to determine whether metformin will slow kidney function decline compared to placebo in adults with ADPKD. Patients with ADPKD, eGFR ≥38 ml/min/1.73m2 and high risk of disease progression will be eligible. Participants will undergo 3 months active run-in followed by 24 months follow up.
Expectedoutcome
Demonstration of efficacy and safety of metformin in patients with ADPKD would allow rapid access to a cheap, safe, effective and broadly implementable therapy.