Iatrogenic Cushing DiseasePhase 2/3NCT01319994
Prevention of Metabolic Complications of Glucocorticoid Excess
A Phase 2/3 study testing Metformin in people with Iatrogenic Cushing Disease, run by Barts & The London NHS Trust at 1 site in United Kingdom.
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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Iatrogenic Cushing Disease
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 57 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 2012to Jan 2015
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- current malignancy
- patients unable to give written informed consent
- or patients not understanding English
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Prevention of Metabolic Complications of Glucocorticoid Excess - a Randomised, Doubleblind,Placebo Controlled Study
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.
Read the 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
- Being tested
- Metformin, Placebo
- Keywords
- glucocorticoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called metformin tablet containing 850mg metformin
Metformin 850mg TDS (12 weeks)
PlaceboDrug
Also called Placebo tablet matching the active drug tablet
Placebo 850mg TDS (12 weeks)
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Metformin 850mg TDS (12 weeks) Receives: Drug: Metformin |
| Placebo | Placebo comparator | Placebo 850mg TDS (12 weeks) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
CT Abdomen
change in visceral/subcutaneous fat
Measured: 3 months minus baseline
Secondary outcomes (1)
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/
Measured: 3 months minus baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Mar 2011 (estimated)
- Study startJul 2012
- Primary completionAug 2014
- Study completionJan 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Iatrogenic Cushing DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Lead sponsor
- Barts & The London NHS Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Barts and the London School of Medicine and Dentistry
- Responsible party
- Principal investigator, Marta Korbonits, Barts & The London NHS Trust
- Investigators
- Marta Korbonits, MD, PhD, Principal investigator, Barts and The London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01319994
- Sponsor's protocol ID
- 09/H1102/82
- Status last verified
- Jan 2019
- First submitted
- 21 Feb 2011
- Last updated
- 12 Apr 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 32109422
Study at a glance
From the registry record, last updated by the sponsor on 12 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prevention of Metabolic Complications of Glucocorticoid Excess - a Randomised, Doubleblind,Placebo Controlled Study
- ClinicalTrials.gov ID
- NCT01319994
- Acronym / sponsor ID
- 09/H1102/82
- Conditions
- Iatrogenic Cushing Disease
- Keywords
- glucocorticoid
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 57 participants (actual)
- Lead sponsor
- Barts & The London NHS TrustUniversity, hospital or other
- Collaborators
- Barts and the London School of Medicine and Dentistry
- Study start
- Jul 2012
- Primary completion
- Aug 2014 (actual)
- Study completion
- Jan 2015 (actual)
- First posted
- 22 Mar 2011 (estimated)
- Results
- Posted 12 Apr 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: MetforminMetformin 850mg TDS (12 weeks) |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo 850mg TDS (12 weeks) |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: metformin tablet containing 850mg metforminMetformin 850mg TDS (12 weeks) | Drug | Metformin |
| PlaceboAlso: Placebo tablet matching the active drug tabletPlacebo 850mg TDS (12 weeks) | Drug | Placebo |
Primary outcome
CT Abdomen
Time frame: 3 months minus baseline
change in visceral/subcutaneous fat
1 secondary outcome
HOMA2-IR
Time frame: 3 months minus baseline
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Apr 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32109422Pernicova 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.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marta Korbonits, MD, PhD principal investigator
Barts and The London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Metformin in people with Iatrogenic Cushing Disease, run by Barts & The London NHS Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
CT Abdomen (time frame: 3 months minus baseline). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01319994, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Apr 2019.