Impaired Glucose Tolerance Associated With Drugs Clinical Trial
Official title:
Does a GLP-1 Receptor Agonist Change Glucose Tolerance in Antipsychotic-treated Patients? A Randomized, Double-blinded, Placebo-controlled Clinical Trial
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.
Statistical analyses:
Power calculation:
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unpublished data in individuals with and without Impaired Glucose Tolerance (IGT) following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)
Procedure:
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).
Primary endpoint:
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.
Secondary endpoints:
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:
- Gender
- Smoking
- Antipsychotics (clozapine vs olanzapine; monopharmacy vs polypharmacy with other
antipsychotic medications)
- Lipid profile
- Liver function
- Different groups of dysglycaemia:
1. HbA1c: 43 mmol/mol ≤ HbA1c ≤ 47 mmol/mol, vs
2. Impaired fasting glucose (IFG): Fasting plasma glucose (FPG): 6.1 mmol/l ≤ FPG ≤
6.9 mmol/l and HbA1c < 48 mmol/mol, vs
3. Impaired glucose tolerance (IGT): two-hour plasma glucose after 75-g oral glucose
tolerance test >7.8 mmol/l with a FPG < 7.0 mmol/l and HbA1c < 48 mmol/mol
- IGT < 11 mmol/l vs IGT >11 mmol/l
- Liraglutide treatment (1.2 mg vs 1.8 mg liraglutide)
- Weight
- Add-on psychotropic drugs/classes (antidepressants, anxiolytics etc. vs no add-on)
- Antihypertensive treatment vs no antihypertensive treatment
- Lipid lowering treatment vs no lipid lowering treatment
- Changes in antipsychotic medication (> 20 % change in dose vs < 20 % change in dose vs
no changes in dose for clozapine or olanzapine, respectively)
- Inhalation steroid vs no inhalation steroid
- Body composition
- Insulin resistance
- Beta-cell function
- Incretin hormones
- Psychopathologic rating scales
- Alcohol consumption
- Length of disease
- Diagnosis (schizophrenia vs schizotypal disorder vs paranoid psychosis)
- Side effects
- Serious adverse events
Reference List
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment