Autosomal dominant polycystic kidney disease (ADPKD)
IMPEDE-PKD is a Phase III, international, prospective, multicentre, double-blind, parallel group, placebo-controlled, randomised trial. Randomisation will be by an adaptive allocation algorithm designed to minimise imbalance across treatment groups in the following variables: use of tolvaptan (yes/no), CKD stage (stage 2/stage 3), sex, presence/absence of hypertension, study centre, and starting dosage of trial medication as determined at Week 10 of the run-in phase. Randomisation is performed via the global randomisation system through Sealed Envelope. Participation occurs over two phases: the run-in phase (12 weeks) and the treatment phase (24 months). There are 13 study reviews; some occur by phone call, and others require a hospital visit. Patients will be screened by recruiting site teams, and potentially eligible participants invited to consent to the trial following a study consultation with an authorised member of the site team. A screening visit (week 0) at site comprising: consent; medical history; concomitant medication check; eligibility check; physical examination; blood pressure; fasted safety bloods (renal function tests including glucose/liver function tests/full blood count/lactate dehydrogenase/HbA1c/vitamin B12. For women of child-bearing potential bloods will also include a pregnancy test); urine tests (specific gravity/pH/blood/protein/glucose/urine albumin:creatinine ratio/urine osmolality); questionnaires (Gastrointestinal Symptom Rating Scale [GSRS]/EQ-5D-5L/APAT (including the Autosomal Dominant Polycystic Kidney Disease Pain and Discomfort Scale [ADPKD-PDS]); and run-in IMP dispense. Eligible participants will attempt a 12-week run-in phase; metformin (as 500 mg prolonged-release oral tablets) will be taken for 10 weeks, followed by a 2-week washout. Participants will commence either 500 mg or 1000 mg once daily, depending on kidney function measured using eGFR. The metformin dose will be titrated at 4-week intervals (week 4 and week 8)
To be eligible to participate in this trial, patients must satisfy ALL of the inclusion criteria: 1. Able to provide informed consent 2. Aged 18-70 years 3. Diagnosis of ADPKD based on radiological +/- genetic criteria as per standard clinical practice in the UK 4. eGFR ≥38ml/min/1.732 and <90m/min/1.73m2. eGFR measured within the previous 6 months will be used for initial screening and run-in enrolment/dosing. The eGFR measured in the week 8 bloods will determine eligibility to proceed with treatment phase enrolment and randomisation. 5. For participants on tolvaptan therapy, they need to be on it for at least 6 months with a stable dose for at least 3 months. 6. Participants MUST have either or both of: 6.1. One or more risk factors for disease progression from the following: 6.1.1. Bilateral kidney length more than or equal to 16.5 cm or 6.1.2. Total Kidney Volume (TKV) more or equal to 750 mL or height-adjusted Total Kidney Volume (htTKV) more or equal to 600 mL/m2 or 6.1.3. Mayo class 1C/D/E or 6.1.4. Pro-PKD score more than or equal to 6 OR 6.2. Evidence of active progression defined by one of the following: 6.2.1. Decline in eGFR more than or equal to 5 ml/min/1.73 m2 in 1 year or 6.2.2. Decline in eGFR more than or equal to 3 ml/min/1.73 m2 per year over 5 years or more, or 6.2.3. Increase in TKV or htTKV of more than or equal to 5% per year on at least two measurements in the past year, excluding any initial eGFR effect over the initial 3 months of tolvaptan commencement (if applicable)
1. Diabetes mellitus (as per American Diabetes Association definition) or other systemic conditions that may cause Chronic Kidney Disease (CKD) independent of Polycystic Kidney Disease (PKD) (excluding hypertension) 2. Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >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: 4.1. Liver enzymes (ALT, AST or Total Bilirubin) >2 times the upper limit of normal 4.2. In the case of Gilbert’s Syndrome; liver enzymes (ALT, AST) >2 times the upper limit of normal and/or total bilirubin >3 times the upper limit of normal 4.3. Child-Pugh classification score ≥5 5. Any contraindication to metformin and/or placebo excipients 6. Currently taking metformin 7. Pregnancy or breastfeeding, or planning to get pregnant in the next 3 years 8. Women of childbearing potential not using a highly effective form of contraception 9. Comorbidities with contraindication for metformin use or potential to contaminate trial outcomes (specifically active cancer, and/or history of other solid organ transplantations (kidney, heart, liver, lung, bowel), and/or presence of stoma 10. Active chronic obstructive pulmonary disease (COPD), active inflammatory bowel disease (IBD), or other active disease resulting in current or expected requirement for systemic steroid therapy during the trial follow-up period 11. History of dialysis 12. Participation in the active phase of another CTIMP, or within 4 weeks or 5 half-lives of last study drug administration (whichever is longer)