Prevention of Metabolic Complications of Glucocorticoid Excess

Iatrogenic Cushing Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01319994
• Other study ID #: 09/H1102/82
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: July 2012
• Est. completion date: January 2015

Study information

• Verified date: January 2019
• Source: Barts & The London NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: January 2015
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• ACTH-Secreting Pituitary Adenoma
• Cushing Syndrome
• Iatrogenic Cushing Disease
• Pituitary ACTH Hypersecretion

Intervention

Drug:
• Metformin
Metformin 850mg TDS (12 weeks)
• Placebo
Placebo 850mg TDS (12 weeks)

Locations

Country	Name	City	State
United Kingdom	Barts and the London	London

Sponsors (2)

Lead Sponsor	Collaborator
Barts & The London NHS Trust	Barts and the London School of Medicine and Dentistry

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CT Abdomen	change in visceral/subcutaneous fat	3 months minus baseline
Secondary	HOMA2-IR	The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (ß)-cell function. HOMA2-IR is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin resistance which is the reciprocal of insulin sensitivity (%S)(100/%S) as a percentage of a normal reference population (normal young adults). HOMA2-IR is calculated using the HOMA model: www.dtu.ox.ac.uk/homacalculator/	3 months minus baseline