Metformin as RenoProtector of Progressive Kidney Disease (RenoMet)

• Sponsor: Universiteit Antwerpen
• Information provided by (Responsible Party): Prof Dr. Marc De Broe, Universiteit Antwerpen

Study Description

Brief Summary:

A multi-center, practice-oriented, repurposing, double-blinded, placebo-controlled, randomized clinical trial. The RenoMet trial is repurposing an already approved agent (Metformin , Glucophage SR ) in a new indication (renoprotection ) in a new class of patients (chronic kidney disease patients CKD 2, 3A, 3B)

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Diseases	Drug: Metformin Hydrochloride; Drug: Placebo Oral Tablet	Phase 3

Detailed Description:

The intervention consists in the treatment of patients with progressive kidney disease and blindly randomized to the treatment group with metformin as medication, added to their usual treatment. Metformin is a well-known and cheap medication used for many years and still used as main treatment of type 2 diabetes. In our study, this 'old' product will be used for a 'new' indication, slowing down the progression of CKD. After randomization in the participating renal care clinic, patients in the intervention group will be treated with metformin at a dose of 1000 mg/day (2x500mg) in the evening during 30 months (Metformin - Glucophage SR (Merck KGaA)). During the first month of the trial a dose of 1x500mg will be used in order to avoid as much as possible some well-known mainly gastrointestinal side effects of metformin treatment At each visit during the study period, the metformin medication will be hand over to the patient in a HDPE bottle, closed with a MEMS cap (Medication Event Monitoring System). The MEMS a cap that registers the time and date of each opening ( presumed intake of the medication in the bottle).

Patients blindly randomized to the control group will receive placebo treatment (2 tablets per day) also in a MEMS device and will continue to receive usual care. Control patients will have the same data collection.

Follow-up of patients during the entire study period will be the responsibility of the treating nephrologist in the renal care clinic. All patients will have a baseline data collection at study entry (demographics, comorbidities, concomitant medication, clinical parameters, lab results). During the study period of 30 months patients will have follow-up visits at their renal care clinic every four months with collection of follow-up data (concomitant medication, clinical parameters, routine lab results and drug related problems). Extra blood and urine samples will be collected for a centralized second determination of serum creatinine and proteinuria

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 385 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: A multi-center, practice-oriented, repurposing, double-blinded, placebo-controlled, randomized clinical trial. The RenoMet trial is repurposing an already approved agent (Metformin , Glucophage SR ) in a new indication (renoprotection ) in a new class of patients (chronic kidney disease patients CKD 2, 3A, 3B)
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Metformin as RenoProtector in Non-Diabetic Patients With Progressive Chronic Kidney Disease (CKD Stages 2, 3A and 3B): a Multi-centre, Practice-oriented, Repurposing, Double-blind, Placebo-controlled, Randomized Clinical Trial
• Estimated Study Start Date: September 1, 2019
• Estimated Primary Completion Date: October 1, 2021
• Estimated Study Completion Date: April 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Metformin treatment group	Drug: Metformin Hydrochloride; The intervention will consist in IMP treatment during 30 months with half of the patients treated with Metformin Glucophage SR. Tablets of 500mg will be used at a dose of 2x500mg preferably taken during the evening meal. During the first month of the trial a dose of 1x500mg will be used in order to avoid as much as possible some well-known mainly gastrointestinal side effects of metformin treatment .
Placebo Comparator: Placebo control group	Drug: Placebo Oral Tablet; The intervention will consist in IMP treatment during 30 months with half of the patients treated with matched placebo. Tablets of 500mg will be used at a dose of 2x500mg preferably taken during the evening meal.

Outcome Measures

Primary Outcome Measures :

1. Reaching a 30% decline of eGFR [ Time Frame: Period of 30 months ]
   Values of serum creatinine obtained from local determination will be used for the calculation of eGFR.

Secondary Outcome Measures :

1. Mortality rate during the investigation period [ Time Frame: Period of 30 months ]
   The time to the event of all-cause mortality will be compared between Metformin and placebo.
2. Evolution of the renal function [ Time Frame: Period of 30 months ]
   Expressed as the slopes of the 8 eGFR determinations during the study period
3. Percentage of patients developing end-stage renal disease [ Time Frame: Period of 30 months ]
   The time to development a doubling of serum creatinine or end-stage renal failure will be compared between Metformin and placebo.
4. Evolution of proteinuria [ Time Frame: Difference between baseline and study end ]
   This will be examined by a generalized linear mixed models using baseline measurement and study end measurement.
5. Evolution of hypertension [ Time Frame: Difference between baseline and study end ]
   This will be examined by a generalized linear mixed models using baseline measurement and study end measurement.
6. Frequency of Major Adverse Cardiovascular Events [ Time Frame: Period of 30 months ]
   This will be examined by a generalized linear mixed models using baseline measurement and study end measurement. This model will allow inclusion of correcting variables.
7. Hospitalization during the investigation period [ Time Frame: Period of 30 months ]
   Hospitalization during the investigation period will be studied using a Cox regression with multiple events.
8. Hospitalization during the investigation period [ Time Frame: Period of 30 months ]
   Total number of hospitalization days will be analyzed using a multiple regression model.
9. Adverse drug events [ Time Frame: Period of 30 months ]
   Number of lactic acidosis events, number of deaths related to lactic acidosis, other adverse events. Reported selected AEs and all SAEs will be summarized using descriptive statistics and a comparison between Metformin and placebo group will be performed.
10. Evolution of Quality of life [ Time Frame: Period of 30 months ]
    During the study period (area under the curve as well as difference between baseline and study end) of the utility Qol score of the EQ-5D-5L questionnaire. Quality of life as measured during the follow-up visits as well as the evolution of Qol during the trial will be compared between Metformin and placebo group.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Seen on a regular base in one of the participating outpatient clinics of renal care with a previous consultation within the last year

• Having a chronic kidney disease with:

  • a CKD stage 2, 3A or 3B ( i.e. with estimated glomerular filtration rate (eGFR) between 30 and 90 ml/min/1.73m2) at the time of the baseline visit
  • without proteinuria or with proteinuria below or equal to 2 g/24hrs
  • showing a decline of eGFR between 2.0 and 15.0 ml/min/year determined using at least three determinations of eGFR (CKD-Epi formula) within the last three years whereby the oldest one should be from more than 1 year ago and the most recent can be the one of the baseline visit.

Exclusion Criteria:

1. Illiteracy: patients not knowing how to read or write
2. Patients not able to communicate in Dutch or French
3. Patients with mental deterioration, incapable to give informed consent and to understand the safety instructions of the study (at the discretion of the treating nephrologist)

4. Patients with one of the following clinical problems:

   • Patients with overt proteinuria (more than 2 g/24hrs)
   • Patients showing a fast decline of renal function (more than 15 ml/min/year) during the preceding three years
   • Diabetes mellitus (any type: 1, 2, maturity onset diabetes of the young (MODY)…) confirmed by a glycemia level > 126 mg/L (7.0 mmol/L) after a fasting time of 8 hours
   • Chronic obstructive pulmonary disease ( COPD) stage Gold IV (Oxygene-dependency)
   • Congestive heart failure (NYHA stage IV)
   • Inflammatory bowel disease (IBD)
   • Stoma
   • Hepatic insufficiency or cirrhosis, acute alcohol intoxication or alcoholism (> 20 glasses of alcoholic beverages per week)
   • History of solid organ transplantation
   • History of metabolic diseases (e.g. mitochondrial encephalomyopathy (MELAS), lactic acidosis, stroke-like episodes, etc…)
   • Pregnancy and/or lactating women at the time of recruitment and during the study period

5. Patient with one of the following medication:

   • Prior use of metformin within the past 12 months (e.g. glucose intolerance, polycystic ovary syndrome, etc…)
   • Chronic use of CNI (calcineurine inhibitors) (e.g. psoriasis...)
6. Patients showing elevated serum lactate level(s) at the time of recruitment ( i.e. a serum lactate level >2.5 mmol/L at baseline visit or a confirmed serum lactate level > 2.0 mmol/L within a period of 4 weeks)
7. Hypersensitivity to metformin or to any of the excipients listed in section 6.1 of the Glucophage SR SmPC (see Attachment A5 Glucophage SR SmPC)
8. One of the following diseases during the previous 6 months: myocardial infarction, shock, acute problems of decompensated heart failure or respiratory failure.

Contacts and Locations

Contacts

Contact: Marc De Broe, Professor; 0486 84 32 82; marc.debroe@uantwerpen.be

Locations

Belgium

AZ Delta; Not yet recruiting

Roeselare, West-Vlaanderen, Belgium, 8800

Principal Investigator: Bart Maes, Dr.

Sub-Investigator: An Vanacker, Dr.

OLVZ Aalst; Not yet recruiting

Aalst, Belgium

Principal Investigator: Bruno Van Vlem, Dr.

Imelda Ziekenhuis Bonheiden; Not yet recruiting

Bonheiden, Belgium

Principal Investigator: Wim Lemahieu, Dr.

CHU Brugmann; Not yet recruiting

Brussel, Belgium

Principal Investigator: Frédéric Collart, Dr.

UZ Brussel; Not yet recruiting

Brussel, Belgium

Principal Investigator: Lissa Pipeleers, Dr.

Grand Hôpital de Charleroi; Not yet recruiting

Charleroi, Belgium

Principal Investigator: Jean-François Cambier, Dr.

Antwerp University Hospital; Not yet recruiting

Edegem, Belgium

Principal Investigator: Ester Philipse, Dr.

Ghent University Hospital; Not yet recruiting

Ghent, Belgium

Principal Investigator: Francis Verbeke, Prof. Dr.

Jessa Ziekenhuis; Not yet recruiting

Hasselt, Belgium

Principal Investigator: Johan Vanwalleghem, Dr.

Centre Hospitalier Régional de la Citadelle; Not yet recruiting

Liège, Belgium

Principal Investigator: Xavier Warling, Dr.

Centre Hospitalier Universitaire Liège (CHU Liège); Not yet recruiting

Liège, Belgium

Principal Investigator: François Jouret, Dr.

Hôpital de Marche

Marche-en-Famenne, Belgium

Centre Hospitalier Régional de Namur; Not yet recruiting

Namur, Belgium

Principal Investigator: Benoit Georges, Dr.

AZ Nikolaas; Not yet recruiting

Sint-Niklaas, Belgium

Principal Investigator: Kirstine Dyckmans, Dr.

Centre Hospitalier de Wallonie Picarde

Tournai, Belgium

AZ Turnhout; Not yet recruiting

Turnhout, Belgium

Principal Investigator: Paul Arnouts, Dr.

Sponsors and Collaborators

Universiteit Antwerpen

More Information

• Responsible Party: Prof Dr. Marc De Broe, Prof Dr., Universiteit Antwerpen
• ClinicalTrials.gov Identifier: NCT03831464 History of Changes
• Other Study ID Numbers: RenoMet
• First Posted: February 5, 2019
• Last Update Posted: May 22, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Urologic Diseases; Renal Insufficiency; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs