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Prevention of Metabolic Complications of Glucocorticoid Excess

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ClinicalTrials.gov Identifier: NCT01319994
Recruitment Status : Completed
First Posted : March 22, 2011
Results First Posted : April 12, 2019
Last Update Posted : April 12, 2019
Barts and the London School of Medicine and Dentistry
Information provided by (Responsible Party):
Marta Korbonits, 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.

Condition or disease Intervention/treatment Phase
Iatrogenic Cushing Disease Drug: Metformin Drug: Placebo Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Prevention of Metabolic Complications of Glucocorticoid Excess - a Randomised, Doubleblind,Placebo Controlled Study
Study Start Date : July 2012
Actual Primary Completion Date : August 2014
Actual Study Completion Date : January 2015

Arm Intervention/treatment
Experimental: Metformin
Metformin 850mg TDS (12 weeks)
Drug: Metformin
Metformin 850mg TDS (12 weeks)
Other Name: metformin tablet containing 850mg metformin

Placebo Comparator: Placebo
Placebo 850mg TDS (12 weeks)
Drug: Placebo
Placebo 850mg TDS (12 weeks)
Other Name: Placebo tablet matching the active drug tablet

Primary Outcome Measures :
  1. CT Abdomen [ Time Frame: 3 months minus baseline ]
    change in visceral/subcutaneous fat

Secondary Outcome Measures :
  1. HOMA2-IR [ Time Frame: 3 months minus baseline ]
    The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-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/

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01319994

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United Kingdom
Barts and the London
London, United Kingdom
Sponsors and Collaborators
Barts & The London NHS Trust
Barts and the London School of Medicine and Dentistry
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Principal Investigator: Marta Korbonits, MD, PhD Barts and The London
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Marta Korbonits, Professor, Barts & The London NHS Trust
ClinicalTrials.gov Identifier: NCT01319994    
Other Study ID Numbers: 09/H1102/82
First Posted: March 22, 2011    Key Record Dates
Results First Posted: April 12, 2019
Last Update Posted: April 12, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Marta Korbonits, Barts & The London NHS Trust:
Additional relevant MeSH terms:
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ACTH-Secreting Pituitary Adenoma
Pituitary ACTH Hypersecretion
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Pituitary Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Hypoglycemic Agents
Physiological Effects of Drugs