Does a GLP-1 Receptor Agonist Change Glucose Tolerance in Antipsychotic-treated Patients? (GREAT)
|First Received Date ICMJE||April 14, 2013|
|Last Updated Date||May 4, 2016|
|Start Date ICMJE||April 2013|
|Primary Completion Date||March 2016 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Glucose tolerance [ Time Frame: Baseline - 16 weeks ]
Change in Glucose tolerance (measured by area under the curve (AUC) for plasma glucose (PG) excursion following a 4-hour 75 g Oral Glucose Tolerance Test (OGTT))
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01845259 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE
|Original Other Outcome Measures ICMJE
|Brief Title ICMJE||Does a GLP-1 Receptor Agonist Change Glucose Tolerance in Antipsychotic-treated Patients?|
|Official Title ICMJE||Does a GLP-1 Receptor Agonist Change Glucose Tolerance in Antipsychotic-treated Patients? A Randomized, Double-blinded, Placebo-controlled Clinical Trial|
|Brief Summary||Metabolic disturbances, obesity and life-shortening cardiovascular morbidity are major clinical problems among antipsychotic-treated patients. Especially two of the most efficacious antipsychotics, clozapine and olanzapine, cause weight gain and metabolic disturbances and can rarely be replaced by other drugs due to the effectiveness of the compounds. Glucagon-like peptide 1 (GLP-1) has improved glycemic control among patients with type 2 diabetes. The study will investigate whether the beneficial effects of GLP-1 analogues on glycemic control in type 2 diabetic patients, can be extended to a population of non-diabetic, dysglycemic psychiatric patients, receiving antipsychotic medical treatment.|
A sample size of 96 participants (48 in each group) was estimated, with two-sided t-testing, an α of 5% and a power of 90%. The power calculation was based on the primary outcome measurement: Change in glucose tolerance. The glucose tolerance was estimated by the total Area Under the Curve (AUC) following a 4-hour 75-g. Oral Glucose Tolerance Test (OGTT). The expected mean total AUC for the plasma glucose excursion following a 4-hour 75-g. OGTT was estimated as 1695 (SD 158) and 1800 (SD 158) after 16 weeks of treatment for the liraglutide and liraglutide placebo group, respectively. The difference in total AUC was based on unpublished data in individuals with and without Impaired Glucose Tolerance (IGT) following a 4-hour 75-g. OGTT at baseline from the study: "The Impact of Liraglutide on Glucose Tolerance and the Risk of Type 2 Diabetes in Women With Previous Pregnancy-induced Diabetes".(1)
All analyses will be carried out with the treatment groups still blinded and labeled as "treatment group A" and "treatment group B". Before dividing participants into group A and group B, the statistical plan was completed and uploaded on clinicaltrials.gov, and the data set was locked. The final unblinding of treatment groups (liraglutide or liraglutide placebo), will not be carried out until all statistical analyses are performed. All analyses will be performed using SAS 9.4, with α set at 0.05 and two-sided testing.
All efficacy analyses will be performed using a modified intention-to-treat principle. All participants who were randomized, received at least one dose of the trial compound (liraglutide or liraglutide placebo) and who had at least one assessment after baseline will be included in the efficacy analyses. All safety analyses will be performed in the intent-to-treat sample that includes all participants, who were randomized and received at least one dose of the trial compound (liraglutide or liraglutide placebo).
The primary endpoint is the change in glucose tolerance following a 4-hour 75-g. OGTT from week 0 to week 16. During the 4-hour 75-g. OGTT, blood was sampled at fixed time points: -15, -10, 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, and 240 minutes. An analysis of covariance (ANCOVA) will be use to analyze change in glucose tolerance from week 0 to week 16 using mixed model analyses for the plasma glucose levels for the liraglutide and the liraglutide placebo group, respectively. In case of relevant baseline differences between the two groups, demographic, illness or treatment parameters will be included in the model as fixed effects together with the baseline value of the OGTTs as a covariate.
Blood was also sampled for analyses of C-peptide, glucagon and incretin hormones in response to the glucose load at the same fixed time points during the OGTT. Change in secretion of C-peptide, glucagon and incretin hormones from week 0 to week 16 will also be evaluated using mixed model ANCOVA analyses for the liraglutide and liraglutide placebo group, respectively. In case of relevant baseline differences between the two groups, demographic, illness or treatment parameters will be included in the model as fixed effects together with the baseline value of the relevant variable as a covariate.
Most secondary endpoints were repeated every 4 weeks. Few secondary endpoints were only repeated at week 0 and 16. For all repeated measurements a mixed model ANCOVA analyses will be use to analyze mean change in continuous outcomes from week 0 to week 16 for the liraglutide and the liraglutide placebo group, respectively. In case of relevant baseline differences between the two groups, demographic, illness or treatment parameters will be included in the model as fixed effects together with the baseline value of the relevant variable as a covariate. Change in categorical outcomes from week 0 to week 16 will be analyzed using mixed model logistic regression with the same fixed effects and covariates as described for the continuous outcomes.
For secondary endpoints without repeated measurements, missing data imputations will be made using Multiple Imputation of Chained Equations (MICE).
For continuous outcomes without repeated measurements, outcomes will be analyzed using ANCOVA to detect differences between the liraglutide and the liraglutide placebo group. In the model baseline demographic, illness or treatment parameters will be included. Categorical outcomes without repeated measurements will be analyzed using a multiple mixed effect logistic regression analysis model, where baseline demographic, illness or treatment parameters will be included.
Subgroup and sensitivity analyses:
Subgroup and sensitivity analyses will be performed to assess the robustness of the primary analyses. These analyses will be performed using regression analysis for continuous outcomes and logistic regression for categorical outcomes. The analyses will consider clinically or mechanistically relevant baseline and intra-treatment variables, including:
1. Foghsgaard S, Vedtofte L, Mathiesen ER et al. The effect of a glucagon-like peptide-1 receptor agonist on glucose tolerance in women with previous gestational diabetes mellitus: protocol for an investigator-initiated, randomised, placebo-controlled, double-blinded, parallel intervention trial. BMJ Open 2013;3(10):e003834.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Condition ICMJE||Impaired Glucose Tolerance Associated With Drugs|
|Publications *||Sharma AN, Ligade SS, Sharma JN, Shukla P, Elased KM, Lucot JB. GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats. Metab Brain Dis. 2015 Apr;30(2):519-27. doi: 10.1007/s11011-014-9591-7.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Completion Date||March 2017|
|Primary Completion Date||March 2016 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Also a group of healthy controls (n=10) will have the baseline examinations done. The healthy controls will be matched to our participants in regards to gender, BMI and age. The same inclusion and exclusion criteria will apply for these controls, except these participants are not allowed to have known psychiatric illness, receive anti-psychotic medications, or have a family history of type 2 diabetes (2 generations).
|Ages||18 Years to 65 Years (Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Denmark|
|Removed Location Countries|
|NCT Number ICMJE||NCT01845259|
|Other Study ID Numbers ICMJE||GLP-1 antipsychotics, 2013-000121-31, U1111-1128-3404|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||Anders Fink-Jensen, MD, DMSci, Psychiatric Centre Rigshospitalet|
|Study Sponsor ICMJE||Psychiatric Centre Rigshospitalet|
|Information Provided By||Psychiatric Centre Rigshospitalet|
|Verification Date||May 2016|
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