Does GLP-1RA Prevent Deterioration of Metabolic State in Prediabetic and Diabetic Patients Treated With Antipsychotic Medication?

Does the Glucagon-like Peptide-1 Receptor Agonist Semaglutide Prevent Deterioration of Metabolic State in Prediabetic or Diabetic Patients With Schizophrenia Treated With the Antipsychotic Compounds Clozapine or Olanzapine?

Background and objective:

Clozapine and olanzapine are some of the most effective antipsychotic drugs, but unfortunately, both drugs induce weight gain and conveys a high degree of metabolic disturbances. The antipsychotic-induced side-effects cause a major clinical problem among patients diagnosed with schizophrenia receiving antipsychotic treatment. Limited effects have been demonstrated for counteracting the side-effects by the switch of antipsychotic therapy, non-pharmacological/behavioural interventions or adjunct pharmacological treatments. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA,) is approved for the treatment of type 2 diabetes worldwide. The objective of the study is to investigate effects of semaglutide once-weekly vs. semaglutide placebo once-weekly on the metabolic state in prediabetic or diabetic patients with schizophrenia, who have initiated treatment with clozapine or olanzapine.

Methods and analysis:

Trial design, intervention and participants: The study is a 26-week, double-blinded, randomized, parallel-group, placebo-controlled, good clinical practice (GCP)-monitored, clinical trial. 104 prediabetic or diabetic patients diagnosed with a schizophrenia, age 18 years and 65 years, who have initiated of clozapine- or olanzapine-treatment within 5 years will be included in the study. The patients will be randomized to receive blinded treatment in one of the two study arms; semaglutide once-weekly vs. semaglutide placebo.

The primary endpoint is the change from baseline in glycated haemoglobin A1c (HbA1c). Secondary endpoints include change in body weight, hip and waist circumference, vitals, and plasma levels of insulin, glucose, C-peptid, insulin sensitivity, beta cell function, glucagon, liver function, lipid profile, incretin hormones, lipid profile, bone makers, body composition, bone density and proteomic analyses. Additional endpoints include alcohol, tobacco and drug use, food preferences, psychopathology, activity and quality of life.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Type 2 Diabetes; Metabolic Disturbance; Clozapine; Olanzapine; GLP-1
• Intervention / Treatment: Drug: Semaglutide, 1.34 mg/mL; Drug: Semaglutide-placebo

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anders Fink-Jensen, MD; Phone Number: +45 22755843; Email: anders.fink-jensen@regionh.dk
• Study Contact Backup: Name: Marie Reeberg Sass, MD; Phone Number: +45 40217486; Email: marie.reeberg.sass@regionh.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Not yet recruiting
    • Psychosis Research Unit, Aarhus University Hospital, Psychiatry,
    • Contact: Andreas Aalkjaer Danielsen, MD
    • Contact: Marie Reeberg Sass, MD; Email: marie.reeberg.sass@regionh.dk
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Psychiatric Centre Copenhagen, Rigshospitalet
    • Contact: Marie Reeberg Sass, MD; Email: marie.reeberg.sass@regionh.dk
    • Contact: Anders Fink-Jensen, Professor, Dmsc,; Phone Number: +4538647072; Email: anders.fink-jensen@regionh.dk
  • Hillerød, Denmark, 3400
    • Recruiting
    • Psychiatric Centre Nordsjaelland, Hillerød
    • Contact: Marie Reeberg Sass, MD; Email: marie.reeberg.sass@regionh.dk
    • Contact: Maj Vinberg, MD; Email: maj.vinberg@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Informed oral and written consent
2. Diagnosed with schizophrenia according to the criteria of ICD-10 (International Classification of Diseases, World Health Organization (WHO)) or the DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the American Psychiatric Association)
3. Initiating current treatment with clozapine or olanzapine within 60 months (not PRN ordinations)
4. Age 18 years to 65 years (both included)
5. Body mass index (BMI) ≥25 kg/m2
6. Diagnosed with prediabetes or type 2 diabetes, after initiation of current treatment with clozapine- or olanzapine, with the following plasma levels: Prediabetes: HbA1c 35-47 mmol/mol or fasting plasma glucose (FPG) 5.6-6.9 mM or 2-h during 75 mg OGGT 7.8-11.0 mM. The test result has to be confirmed on a different day. Type 2 diabetes: HbA1c 48-57 mmol/mol or fasting plasma glucose (FPG) 6.9-9.9 mM or 2h OGTT > 11 mM (although FPG and HbA1c might still be under the diagnostic range). The test result has to be confirmed on a different day.

Exclusion Criteria:

1. Acute worsening of psychosis based on a clinical evaluation (score of 6 or 7 on the CGI-S scale)
2. Coercive measures
3. Females of child-bearing potential who are pregnant, breast-feeding or have intention of becoming pregnant.
4. Women who are not willing to use adequate contraceptive during the full length of the study
5. Patients treated with corticosteroids or other hormone therapy (except oestrogens)
6. Any active substance abuse or dependence for the past six months (except for nicotine)
7. Impaired hepatic function (plasma liver transaminases >3 times upper normal limit)
8. Impaired renal function (serum creatinine >150 μmol/l and/or macroalbuminuria)
9. Impaired pancreatic function (acute or chronic pancreatitis and/or plasma amylase >2 times upper normal limit)
10. Cardiac problems defined as decompensated heart failure (NYHA class III/IV), unstable angina pectoris and/or myocardial infarction within the last 12 months
11. Hypertension with systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg
12. Any condition that the investigator feels would interfere with trial participation
13. Receiving any experimental or pre-marketing drug within the last 3 months
14. Use of weight-lowering pharmacotherapy within the preceding 3 month
15. Known type 1 diabetes
16. Suicidal behavior as judged by the investigator and based on clinical evaluation. At all contact with patient attendance possible suicidality will be evaluated according to the guidelines. If the patient is evaluated as suicidal, the person will be excluded from the study and evaluated by a senior consultant in psychiatry, who will take further action.
17. Plasma HbA1c > 57 mmol/mol (tested twice) in which case the patient will be excluded from the study and transferred to general practitioner or hospital for diabetic treatment. No diabetic medication is allowed except for the trial medicin.
18. Any known contraindication towards the treatment with semaglutide.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Semaglutide injection once-weekly	Drug: Semaglutide, 1.34 mg/mL; Semaglutide 1.34 mg/ml, 1.5 ml pre-filled pen-injector is supplied in pens for injection containing 2.0 mg of the GLP-1RA semaglutide in 1.5 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Direction for use will be given together with trial products.The possible doses of semaglutide are 0.25 mg, 0.50 mg and 1.0 mg. The initial weekly dose will be 0.25 mg for four weeks, then 0.5 mg for four weeks and then 1.0 mg for the remaining treatment period. Patients who, due to adverse events, do not tolerate up-titration to 1.0 mg semaglutide will remain on 0.5 mg once-weekly. The injection is administered subcutaneously once-weekly.
Placebo Comparator: Semaglutide-Placebo injection once-weekly	Drug: Semaglutide-placebo; The semaglutide placebo pens contain "XX-vehicle" (no active drug) and are administered in the same way and volume as semaglutide. The semaglutide placebo is specially packed for this study and will be used in the study only. The initial weekly dose will be 0.25 mg for four weeks, then 0.5 mg for four weeks and then 1.0 mg for the remaining treatment period. Patients who, due to adverse events, do not tolerate up-titration to 1.0 mg semaglutide placebo will remain on 0.5 mg once-weekly. The injection is administered once-weekly. If the lowest tolerated dose is less than 0.5 mg of semaglutide placebo once-weekly, the patient will be excluded from the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary endpoint is the change from baseline in glycated haemoglobin A1c (HbA1c).	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight (Kg)		26 weeks
Hip and Waist circumference (Cm)		26 weeks
Incretin hormones (Blood sampling)	GLP-1, GLP-2 and GIP	26 weeks
Bone Markers (Blood sampling)	Calcitonin, Vit-D, Ca, Phosphate, Mg, PTH, PINP, CTX, OC	26 weeks
Lipid Profile (Blood sampling)	LDL, HDL, triglycerider, total kolesterol,	26 weeks
Hormones (blood sampling)	Insulin, glucagon and C-peptide	26 weeks
Visceral fat	DXA scanning	26 weeks
Android to Gynoid fat ratio	DXA scanning	26 weeks
Total body fat	DXA scanning	26 weeks
Bone density	DXA scanning	26 weeks
Psychopathology	PANSS-6 interview	26 weeks
Registration of body movements/level of activity with a sensor	Activity measurements (approximate for sleep, inactivity, energy expenditure and steps taken by the patient) will be collected continuously by the use of a wearable activity device worn by the patient for 1 week from inclusion day and 1 week at the end of the study	26 weeks
Reward value of sweet and fatty candy	Clicker test	26 weeks
Alcohol use	Questionnaires: AUDIT	26 weeks
Tobacco use	Questionnaires: FNTD	26 weeks
Drug use	Questionnaires: DUDIT	26 weeks
Schizophrenia quality of life scale	Questionnaire: SQLS	26 weeks
Psychosocial disability	Rating GAPD	26 weeks
Liver function (blood sampling)	ALT, ALP, AST, trombocytes and bilirubin	26 weeks
Proteomic analyses (Blood sampling)	Inflammatory biomarkers and cytokines: IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, MDA, plasma antioxidants uric acid and, vitaminC	26 weeks
Proteomic analyses (Urine sampling)	biomarkers for measurement of systemic oxidative stress on DNA and RNA: 8-oxo-7,8-dihydro2´-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo	26 weeks
FIB-4 score	A non-invasive scoring system for Liver Fibrosis is a non-invasive scoring system based on several laboratory tests (ALT, AST, trombocytes) and age	26 weeks
Vitals	Blood pressure and pulse	26 weeks
Insulin sensitivity and beta cell function	evaluated by homeostatic model assessment	26 weeks

Collaborators and Investigators

• Sponsor: Anders Fink-Jensen, MD, DMSci
• Investigators: Principal Investigator: Anders Fink-Jensen, MD, Psychiatric Centre Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: March 1, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 19, 2021

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 6, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: SemaPsychiatry

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification.
• IPD Sharing Time Frame: Immediately following publication. No end date.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No