Home-based Intervention With Semaglutide Treatment Of Neuroleptica-Related Prediabetes

Quality control:

Usual quality control procedures will be followed in accordance with the ICH Guideline for Good Clinical Practice (GCP). The GCP unit at OUH will be responsible for monitoring the study in accordance with GCP guidelines. This protocol will be submitted as part of the notification to the Danish Medicines Agency and the Scientific Ethical Committee for the Region of Southern Denmark. Data processing regarding the trial will be reported to the Region's list of on-going research projects via the Executive Secretariat at OUH. Furthermore, Novo Nordisk will be informed of the trial.

Randomization:

A total of 154 participants will be randomized: 77 participants will be randomized to the Semaglutide group and 77 participants will be randomized to the placebo group (randomization ratio 1:1). The participant is assigned a subject number when consent is obtained, inclusion and exclusion criteria have been reviewed and the participant otherwise meets the requirements for study participation and continues to participate in the study. A participant cannot be assigned more than one randomization number and this number cannot be used for other persons. Block randomization including blocks of either 4 or 6 randomization numbers will be used, and the randomisations list will be provided by the manufacturer of Semaglutide and placebo (Novo Nordisk). The randomization will take place via the RedCAP® module.

Treatment arm allocation will be concealed to investigators. Randomization codes will be delivered in closed envelopes, kept in Odense, Denmark, in a secure place with 24-hour access.

Novo Nordisk A/S is going to provide the randomization list. The investigators of the trial are blinded and will randomize subjects via the Novo Nordisk provided blinded randomization list. Subsequently, the investigators inform the unblinded staff not otherwise involved in the trial. The staff is then using the unblinded version of the randomization list to identify the treatment arm that this specific patient is randomized to. Then, the staff allocates the correct trial product via a unique dispensing number (DUN) on the box and on an unblinded total DUN list.

Biological material / biobank:

Biological material will be stored in a research biobank to be analysed at the end of trial.

In addition biological material will also be collected and stored in a biobank for future research projects. Biological material will be stored in pseudo-anonymised form by ID-number in a biobank for 15 years, after which it will be destroyed. In case there is a need for further studies of biomaterial, application will again be made to the local Scientific Ethical Committee.

Data management:

Data from the trial will be stored with the data controller. The study's data processing will be reported to the Region of Southern Denmark's list of on-going research projects. All data will be available to co-authors of any articles based on the study, and data will also be available to the journals or authorities that may have a legitimate interest in accessing the data. In addition, data will be available for monitoring of project as the investigator allows direct access to source data/documents (including patient medical records) for monitoring, auditing and/or inspection by the GCP units, the Danish Medicines Agency and other countries' health authorities. There will be a collaboration with OPEN (Open Patient data Explorative Network, Odense, Denmark) in order to receive help to use and manage RedCAP®. Source data will be entered into or transferred to the RedCAP® module, and scan documents will be archived as source documents. All transferred documents to RedCAP® will be archived for five years after the end of the trial, after which they will be destroyed. Source data in the form of patient medical records will be handled by Odense University Hospital.

Recruitment:

To embed the study in the community psychiatry centers teams, the investigators need help from local consultants in psychiatry. Their task is to help to identify and enroll patients.

If a potential participant is interested in obtaining more information regarding the trial, the potential participant may contact the research units involved via phone or e-mail. An investigator or another member of the research staff (e.g. research technician or nurse) will contact the potential participant to answer upfront questions and to provide written information about the clinical trial.

By signing the informed consent, the participant gives permission to the Danish Medicines Agencies, Sponsor, investigator and monitor to have direct access to obtain information from the patient record including electronical records relevant for completion, surveillance or control of the clinical trial. All trial-related visits will take place in patients home or at the OPUS clinics and community psychiatry centers clinics in Region of southern Denmark or Zealand. The participants will be encouraged to bring an assessor to clinic visits.

Plan for participation:

Participation in the study will cease if the participant wishes to exit the study. Discontinuation may also occur at the investigators' request; for example, if a severe competing disorder or adverse side effects develop in the participant (up to a maximum of six weeks after the last scheduled injection), or if the participant is not compliant of the trial medication / placebo or in attendance for the administration of trial medication and the measurement of safety markers. The investigation may be terminated if information on new side effects emerges and, for this reason, the authorities recommend that the use of the medication cease. If a trial participant exits the study early, any provided biological material and scans will be included in the final analysis. If a trial participant withdraws the informed consent or exits the clinical trial before 30 weeks of treatment, no further analyses than those at the time point already planned and accepted by the participant, will be done on the biomaterial obtained from the participant. Unless the participant, who withdraws the informed consent or exits the clinical trial before 30 weeks of treatment specifically asks for destruction of the already obtained biological material, it will be stored in the biobank in accordance with the described precautions in this protocol. If more than 15% of the participants exit within three months of the start of the trial, they will be replaced by the inclusion of other participants. Patients withdrawing from the trial should be encouraged to undergo same final evaluation as patients completing trial.

eCRF: The purpose of CRF is to report all the information required by the protocol of the individual trial participants. Electronic CRF (eCRF) will be used. Completion of CRF will begin with the recruitment of the participants and filled in continuously throughout the trial by the investigators (or persons appointed by the investigators who are either experienced in using RedCAP® (or who will receive training prior to the assignment). CRF is the source document for trial data that is written directly into the eCRF and which is not first recorded in the Medical journal.

Source data, which is recorded directly in the eCRFs, includes protocol-specific measurements that are not relevant in the patient's medical record. eCRF is managed by the Odense Patient Data Explorative Network, SDU, Odense, using the RedCAP® system.

Effect analyses:

All participants randomized in the study will be included in the assessment of endpoints. Clinical results will be presented as mean, least squares mean, least square mean change from baseline or least square difference between groups with SE, SD or two-sided 95% CI. Statistical tests will be conducted as two-sided tests with a 5% significance level.

Primary outcomes for the study will be absolute changes in HbA1c. Changes in HbA1c will be evaluable after three months and after 6 months. A mixed effects linear regression analysis is used to compare changes in glucose tolerance, HbA1c, from baseline to six months' follow-up between the intervention and the placebo groups. Missing values will be imputed, primary analysis will be intention to treat. Supplementary per protocol analysis will accompany the intention to treat analysis.

The investigators conservatively assume that 6 months of semaglutide treatment changes HbA1c by 0.2%, and that SD equals 0.35%. Based on these assumptions, calculations show that 65 subjects in each arm are required to obtain a power of 90%, using a 2-sided significance level of 5%.

All changes in secondary outcomes from baseline to various follow-up times are analyzed using mixed effects linear regression analyses for continuous outcomes and mixed effects logistic regression analyses for categorical outcomes.

All analyses on continuous outcomes are adjusted for the baseline value of the outcome, and in case of large imbalances in baseline patient characteristics between the two randomized groups, exploratory analyses including such variables are conducted. To correct for multiple testing of the secondary outcomes, Holm's sequentially rejective multiple test procedure will be applied. Statistical analyses are performed using Stata software Version 16 (Statacorp, Texas, USA). The hypothesis tests are 2 sided, and the 5% level of significance is considered.

Safety:

At all visits, vital signs will be recorded, including blood pressure, body weight and waist circumference as well as adverse reactions, including information on possible cases of low blood sugar (hypoglycaemia). The safety parameters in the study include adverse reactions, vital parameters and biochemical studies (blood sugar as well as liver and kidney function). These parameters have been selected because they partly include the issues that the participant will have experienced (side effects) and partly the possible effects on vital functions, including blood pressure and liver and kidney function. Long-term blood sugar (HbA1c) and fasting blood sugar will be measured at attendance. When indicated, blood sugar will be measured by the study nurse on the regular visits. In theory, the drug can lower blood sugar, although it is only detected by concomitant treatment with other drugs to treat diabetes. If unrecognized illness is detected in participants - unless before the start of the study, they expressed a wish to the contrary - they will be informed of this and referred to the relevant healthcare professional or department. If any side effects or changes in biochemical anomalies are observed, the trial physician or the physician responsible for the test will be informed.

After 10 weeks of injections and given, that the study staff considers it safe, participants will be given the possibility to self-administer the injections under guidance via ether telephone or video.

All safety parameters will be recorded in the medical journal as soon as they have either been measured or reported by the test participant. The following information will be reported: Study name, patient identification including subject number and initials, sex and age, diagnosis, trial drug, causality assessment, outcome, and name of the reporter.

Publication of data:

All results, negative as well as positive, will be published in scientific journals and in EudraCT results database. Data will be transferred to the public data register after publication (www.clinicaltrials.gov), cf. agreement with the grant-awarding bodies that fund the investigation. ICMJE's author guidelines for scientific articles will be followed.

Funding:

Novo Nordisk Foundation. Steno Diabetes Center Zealand. Steno Diabetes Center Odense. Slagelsepuljen.