Prevention of Metabolic Complications of Glucocorticoid Excess

• Sponsor: Barts & The London NHS Trust (Other)
• Overall Status: Completed
• CT.gov ID: NCT01319994
• Collaborator: Barts and the London School of Medicine and Dentistry (Other)
• Enrollment: 57
• Location: 1
• Arms: 2
• Duration (Months): 30
• Patients Per Site Per Month: 1.9

Study Details

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.

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.

Study Design

• Study Type: Interventional
• 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: Jul 1, 2012
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin Metformin 850mg TDS (12 weeks)	Drug: Metformin; Metformin 850mg TDS (12 weeks); Other Names: metformin tablet containing 850mg metformin
Placebo Comparator: Placebo Placebo 850mg TDS (12 weeks)	Drug: Placebo; Placebo 850mg TDS (12 weeks); Other Names: Placebo tablet matching the active drug tablet

Outcome Measures

Primary Outcome Measures

1. CT Abdomen [3 months minus baseline]

   change in visceral/subcutaneous fat

Secondary Outcome Measures

1. HOMA2-IR [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/

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barts and the London	London		United Kingdom

Sponsors and Collaborators

• Barts & The London NHS Trust
• Barts and the London School of Medicine and Dentistry

Investigators

• Principal Investigator: Marta Korbonits, MD, PhD, Barts and The London

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Marta Korbonits, Professor, Barts & The London NHS Trust
• ClinicalTrials.gov Identifier: NCT01319994
• Other Study ID Numbers: 09/H1102/82
• First Posted: Mar 22, 2011
• Last Update Posted: Apr 12, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Marta Korbonits, Professor, Barts & The London NHS Trust: glucocorticoid
• Additional relevant MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Metformin

Study Results

Participant Flow

Pre-assignment Detail	Patients were recruited into "Prevention" and "Treatment" algorithms initially. However, only the "Treatment" algorithm proved feasible for logistic reasons. Below are the results relating to patients randomized into the Treatment algorithm.

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 850mg TDS for 12 weeks	Placebo 850mg TDS for 12 weeks
Period Title: Overall Study
STARTED	26	27
Abto Keep Appoinment Shedule	23	24
Tolerated at Least 1.7g/Day Dose	19	24
Glucocorticoid Dose as Inc Cri	19	22
Did Not Develop Overt Diabetes	19	21
COMPLETED	19	21
NOT COMPLETED	7	6

Baseline Characteristics

Arm/Group Title	Metformin	Placebo	Total
Arm/Group Description	Metformin 850mg TDS	Placebo 850mg TDS	Total of all reporting groups
Overall Participants	26	27	53
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47 (15)	45 (15)	46 (15)
Sex: Female, Male (Count of Participants)
Female	14 53.8%	15 55.6%	29 54.7%
Male	12 46.2%	12 44.4%	24 45.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	26 100%	27 100%	53 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
visceral to subcutanous fat ratio (ratio) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ratio]	0.44	0.58	0.50
HOMA2-IR (HOMA score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [HOMA score]	4.7	4.2	4.4

Outcome Measures

1. Primary Outcome

Title	CT Abdomen
Description	change in visceral/subcutaneous fat
Time Frame	3 months minus baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 850mg TDS	Placebo 850mg TDS
Measure Participants	19	21
Mean (Standard Deviation) [ratio]	0.08 (0.19)	-0.03 (0.22)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metformin	Placebo
Arm/Group Description	Metformin 850mg TDS	Placebo 850mg TDS
Measure Participants	19	21
Mean (Standard Deviation) [HOMA score]	0.22 (3.26)	2.35 (3.23)

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	adverse event definition is matching the definition of clinicaltrials.org
Arm/Group Title	Metformin		Placebo
Arm/Group Description	Metformin 850mg TDS for 12 weeks		Placebo 850mg TDS for 12 weeks
All Cause Mortality
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		9/27 (33.3%)
Cardiac disorders
Ischaemic heart disease	1/26 (3.8%)		0/27 (0%)
Atypical chest pain	0/26 (0%)		1/27 (3.7%)
Endocrine disorders
Severe osmotic symptoms	0/26 (0%)		2/27 (7.4%)
Gastrointestinal disorders
Diverticulitis	0/26 (0%)		1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/26 (0%)		1/27 (3.7%)
Exacerbation of asthma	0/26 (0%)		3/27 (11.1%)
Vascular disorders
Raynaud's	0/26 (0%)		1/27 (3.7%)
Other (Not Including Serious) Adverse Events
	Metformin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/26 (100%)		22/27 (81.5%)
Gastrointestinal disorders
Gastrointestinal side-effects	16/26 (61.5%)		9/27 (33.3%)
General disorders
Other	10/26 (38.5%)		18/27 (66.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.