The POWERED Study: Prophylaxis With Metformin to Prevent PTDM (POWERED)

A Single Site, Placebo Controlled, Double Blind Randomised Clinical Trial Evaluating the Effectiveness of Metformin to Prevent Post-transplant Diabetes in a Cohort of Patients Undergoing Renal Transplantation

PrOphylaxis With mEtformin to pREvent PTDM: a single site, placebo controlled, double blind randomised clinical trial evaluating the effectiveness of metformin to prevent post-transplant diabetes in a cohort of patients undergoing renal transplantation.

Study Overview

• Status: Completed
• Conditions: End Stage Renal Disease; Renal Transplantation; Kidney Transplant; Complications; Metformin; New Onset Diabetes After Transplant; Post-transplant Diabetes Mellitus; New Onset Diabetes After Transplantation
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

Renal transplantation is the optimal form of renal-replacement therapy in end-stage kidney disease. However, up to 30% of new renal transplants develop post-transplant diabetes mellitus (PTDM). The development of PTDM is associated with adverse graft and patient survival outcomes and represents an increased financial burden. There is an urgent clinical need to discover therapies which could decrease the risk of developing PTDM. Metformin offers a safe and cheap therapeutic option which has been demonstrated to reduce the incidence of type 2 diabetes in a high-risk non-transplant patient group. The investigators propose to study its safety and efficacy in preventing the development of PTDM.

POWERED is a single site, placebo-controlled, double- blind randomised clinical trial of metformin in patients without pre-existing diabetes mellitus who have received a new renal transplant. Eligible, consented patients are randomised to a 3 month course of either active drug or placebo within 10 days post-transplant. All patients will receive the usual standard of care for transplant patients. Clinical and laboratory data will be collected and assessed at baseline and throughout their participation in the study. The primary endpoint is the development of PTDM as defined by a positive oral glucose tolerance test (OGTT). Secondary endpoints include graft outcomes, pancreatic b-cell function and safety endpoints. The study began recruitment in January 2019 and plans to enrol 60 patients. There are no interim analyses planned.

Ethical approval was obtained from the London - Brighton and Sussex Ethics Committee (REC 18/LO/0958) prior to commencing the study. All study-related data will be used by the Sponsor in accordance with local data protection law. Results of the trial will be submitted for publication in a peer-reviewed journal.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, E1 1BB
    • Royal London Hospital, Barts Health NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients (male or female) undergoing renal transplantation under the care of the Barts Health NHS Trust Renal Department
2. Aged 18-75 inclusively
3. Willing to comply with study schedule

Exclusion Criteria:

1. History of Type 1 or type 2 diabetes
2. Clinically significant history of abnormal physical and/or mental health as judged by the investigator other than conditions related to chronic kidney disease
3. Participation in an investigational drug trial in the 3 months prior to administration of the initial dose of study drug
4. Subject with a known hypersensitivity or contraindication to Tacrolimus
5. Subject with a known hypersensitivity or contraindication to Metformin
6. Pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Metformin; metformin 500mg OD	Drug: Metformin; metformin 500mg OD for 3 months to start within 10 days post-renal transplant
PLACEBO_COMPARATOR: Placebo; placebo 500mg OD	Drug: Placebo; placebo 500mg OD for 3 months to start within 10 days post-renal transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis of post-transplant diabetes	Positive 2 hour oral glucose tolerance test (i.e. 2 hour sugar >11.1 mol/L)	12 months post-renal transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pancreatic beta cell function	change in calculated HOMA-IR using C-peptide measurement between baseline and month 3 using	12 months
HbA1c	HbA1c	12 months
impaired glucose tolerance	impaired glucose tolerance as per 2 hour oral glucose tolerance test (i.e. 2 hour glucose 7.9-11.1 mmol/L)	12 months
patient and graft survival	patient survival, kidney transplant (graft) survival	12 months
incidence of treatment emergent adverse events	patient safety: adverse events, serious adverse events	12 months
rejection	episodes of acute transplant rejection	12 months
eGFR	renal transplant function	12 months
diagnosis of PTDM in OGTT screen fails	incidence of PTDM in patients not randomised to study due to positive OGTT at screening: defined by appearance of PTDM on problem list or prescription of an anti-diabetic drug	12 months

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 25, 2019
• Primary Completion (ACTUAL): May 30, 2022
• Study Completion (ACTUAL): August 30, 2022

Study Registration Dates

• First Submitted: January 17, 2022
• First Submitted That Met QC Criteria: February 4, 2022
• First Posted (ACTUAL): February 15, 2022

Study Record Updates

• Last Update Posted (ACTUAL): October 18, 2022
• Last Update Submitted That Met QC Criteria: October 17, 2022
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: metformin; kidney transplant; renal transplant; PTDM; NODAT; end-stage kidney disease; post-transplant diabetes mellitus; new onset diabetes after transplant
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Kidney Diseases; Urologic Diseases; Endocrine System Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Diabetes Mellitus; Kidney Failure, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 203080

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in any published article, after de-identification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.

IPD Sharing Access Criteria

Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

The data may be used for individual participant data meta-analysis.

Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found by emailing the corresponding author.

Drug and device information, study documents

• 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