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Prevention of Metabolic Complications of Glucocorticoid Excess

Primary Purpose

Iatrogenic Cushing Disease

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Metformin
Placebo
Sponsored by
Barts & The London NHS Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Iatrogenic Cushing Disease focused on measuring glucocorticoid

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Barts and the London

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Metformin

Placebo

Arm Description

Metformin 850mg TDS (12 weeks)

Placebo 850mg TDS (12 weeks)

Outcomes

Primary Outcome Measures

CT Abdomen
change in visceral/subcutaneous fat

Secondary Outcome Measures

HOMA2-IR
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/

Full Information

First Posted
February 21, 2011
Last Updated
January 14, 2019
Sponsor
Barts & The London NHS Trust
Collaborators
Barts and the London School of Medicine and Dentistry
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1. Study Identification

Unique Protocol Identification Number
NCT01319994
Brief Title
Prevention of Metabolic Complications of Glucocorticoid Excess
Official Title
Prevention of Metabolic Complications of Glucocorticoid Excess - a Randomised, Doubleblind,Placebo Controlled Study
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
July 2012 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Barts & The London NHS Trust
Collaborators
Barts and the London School of Medicine and Dentistry

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Iatrogenic Cushing Disease
Keywords
glucocorticoid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
57 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Metformin
Arm Type
Experimental
Arm Description
Metformin 850mg TDS (12 weeks)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo 850mg TDS (12 weeks)
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
metformin tablet containing 850mg metformin
Intervention Description
Metformin 850mg TDS (12 weeks)
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo tablet matching the active drug tablet
Intervention Description
Placebo 850mg TDS (12 weeks)
Primary Outcome Measure Information:
Title
CT Abdomen
Description
change in visceral/subcutaneous fat
Time Frame
3 months minus baseline
Secondary Outcome Measure Information:
Title
HOMA2-IR
Description
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/
Time Frame
3 months minus baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marta Korbonits, MD, PhD
Organizational Affiliation
Barts and The London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Barts and the London
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32109422
Citation
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.
Results Reference
derived

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Prevention of Metabolic Complications of Glucocorticoid Excess

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