Prevention of Metabolic Complications of Glucocorticoid Excess

Prevention of Metabolic Complications of Glucocorticoid Excess - a Randomised, Doubleblind,Placebo Controlled Study

Sponsors

Lead Sponsor: Barts & The London NHS Trust

Collaborator: Barts and the London School of Medicine and Dentistry

Source Barts & The London NHS Trust
Brief Summary

According to current estimates, nearly 1% of the general population is treated with long-term glucocorticoids. Chronic hypercortisolism leads to a phenotype that resembles the metabolic syndrome. The investigators have shown that inhibition of adenosine-monophosphate-activated protein kinase (AMPK) activity in adipose tissue plays a role in corticosteroid-mediated insulin resistance. Metformin, one of the mainstay therapies for type 2 diabetes, is a known activator of AMPK, which mediates its beneficial effects on glucose and lipid metabolism. The investigators have shown in an animal model that metformin - via altering AMPK activity - prevents the development of the metabolic complications of glucocorticoid excess, and the investigators wish to confirm this in a human study. The aim of this prospective, randomised, double-blind, placebo-controlled study is to investigate the effect of metformin treatment on metabolic parameters in patients on long-term high-dose glucocorticoids. The study is part of the investigators translational project and could rapidly lead to immediate patient benefit, improving quality of life and reducing health care costs for the NHS.

Detailed Description

2 Study Aims and Objectives To investigate the effect of metformin treatment on metabolic parameters in patients with long-term high dose GCs.

3 Study Design 3.1 General Design We will recruit patients (18-75y) requiring glucocorticoid treatment for various inflammatory conditions (e.g. rheumatoid arthritis, giant cell arteritis/polymyalgia rheumatic, asthma, sarcoidosis) into a pilot, randomised, double-blind, placebo-controlled trial. These patients will be treated with metformin to prevent or reverse their metabolic complications. Prevention algorithm: Patients who are about to start GC treatment predictably for ≥12w at a ≥10mg/d prednisolone (or equivalent) dose who consent to participate in this study will be randomly assigned to receive either placebo (20 patients/group, see power calculations) or metformin at the maximum tolerated dose with a minimum of 850 mg bd for 12w. Treatment algorithm: Consenting patients already on long-term GC treatment (≥4w, ≥20mg/d prednisolone or equivalent) who are expected to continue for at least 12w at ≥10mg/d prednisolone will be randomly assigned to receive either placebo or metformin for 12w. In both algorithms, metformin treatment will be started gradually (as standard practice) to avoid gastrointestinal side effects and the full dose will be reached by day 10. Patients will have a full clinical assessment before the start of the metformin treatment and at the end of the 12w treatment period. Anthropometric and biochemical parameters and questionnaires will be repeated at 4 and 8 weeks.

Overall Status Completed
Start Date July 2012
Completion Date January 2015
Primary Completion Date August 2014
Phase Phase 2/Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
CT Abdomen 3 months minus baseline
Secondary Outcome
Measure Time Frame
HOMA2-IR 3 months minus baseline
Enrollment 57
Condition
Intervention

Intervention Type: Drug

Intervention Name: Metformin

Description: Metformin 850mg TDS (12 weeks)

Arm Group Label: Metformin

Other Name: metformin tablet containing 850mg metformin

Intervention Type: Drug

Intervention Name: Placebo

Description: Placebo 850mg TDS (12 weeks)

Arm Group Label: Placebo

Other Name: Placebo tablet matching the active drug tablet

Eligibility

Criteria:

Inclusion Criteria:

- patients diagnosed with an inflammatory condition and not started yet on GC treatment or • patients with an inflammatory condition treated with GC >20mg/d of prednisolone (or its cumulative equivalent) for at least 4wks

- minimal duration of prospective therapy 12w

- dose of prednisolone ≥10mg/d (or equivalent GC)

- ambulatory patients

- patients >18 years old

- ability to understand verbal and written instructions and informed consent

Exclusion Criteria:

- prior therapy with metformin during the last 6 months

- known pre-existing diabetes

- pregnancy

- breastfeeding

- liver impairment: ALT and/or AST ≥2.5 x UNL

- renal impairment: serum creatinine levels ≥135.0 µmol/L in males and ≥110.0 µmol/L in females

- current malignancy

- patients unable to give written informed consent

- or patients not understanding English

Gender: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Marta Korbonits, MD, PhD Principal Investigator Barts and The London
Location
Facility: Barts and the London
Location Countries

United Kingdom

Verification Date

January 2019

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Barts & The London NHS Trust

Investigator Full Name: Marta Korbonits

Investigator Title: Professor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Metformin

Type: Experimental

Description: Metformin 850mg TDS (12 weeks)

Label: Placebo

Type: Placebo Comparator

Description: Placebo 850mg TDS (12 weeks)

Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Triple (Participant, Care Provider, Investigator)

Source: ClinicalTrials.gov