Prevention of Metabolic Complications of Glucocorticoid Excess

NCT ID: NCT01319994

Last Updated: 2019-04-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 57 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2015-01-31

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.

Conditions

Iatrogenic Cushing Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Metformin

Metformin 850mg TDS (12 weeks)

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Metformin 850mg TDS (12 weeks)

Placebo

Placebo 850mg TDS (12 weeks)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo 850mg TDS (12 weeks)

Interventions

Metformin

Metformin 850mg TDS (12 weeks)

Intervention Type: DRUG

Placebo

Placebo 850mg TDS (12 weeks)

Intervention Type: DRUG

Other Intervention Names

metformin tablet containing 850mg metformin; 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Barts and the London School of Medicine and Dentistry

OTHER

Sponsor Role: collaborator

Barts & The London NHS Trust

OTHER

Sponsor Role: lead

Responsible Party

Marta Korbonits

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marta Korbonits, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Barts and The London

Locations

Barts and the London

London, , United Kingdom

Countries

United Kingdom

References

Pernicova I, Kelly S, Ajodha S, Sahdev A, Bestwick JP, Gabrovska P, Akanle O, Ajjan R, Kola B, Stadler M, Fraser W, Christ-Crain M, Grossman AB, Pitzalis C, Korbonits M. Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial. Lancet Diabetes Endocrinol. 2020 Apr;8(4):278-291. doi: 10.1016/S2213-8587(20)30021-8. Epub 2020 Feb 25.

Reference Type: DERIVED

PMID: 32109422 (View on PubMed)

Other Identifiers

09/H1102/82

Identifier Type: -

Identifier Source: org_study_id