A total of 20 participants meeting the eligibility criteria will be included in the trial. Eligible trial participants are adults ( aged ≥18 years) who for at least 1 year have had a diagnosis of T2D and have been in treatment with metformin and optionally an SGLT2i. A participant will only be eligible if a HbA1c of 53-75 mmol/mol has been recorded less than 3 months prior to trial inclusion. As the participants are not in glycemic control, the next step in the treatment is to add an antidiabetic drug to obtain glycemic control [4], which in this clinical trial is oral semaglutide.

Thus, eligible participants for this study should have an antidiabetic drug added to their current treatment regardless of participation in this study. The participants will continue their current treatment, and treatment with oral semaglutide will be initiated 3 weeks after inclusion in the trial. Furthermore, the participants must be able to understand and read Danish and be able to use a smartphone as well as the devices used in the clinical trial.

Potential participants will be excluded if they previously have received treatment with glucose-lowering medications other than metformin and SGLT2i. Potential participants who are only treated with metformin and have cardiovascular or kidney disease, which would indicate use of other second-line treatments such as SGLT2 inhibitors or subcutaneous GLP1 receptor agonists, are not eligible for inclusion. Participants will also be excluded if any of the following apply: (1) they have other types of diabetes than T2D, (2) they are participating in an interventional trial, (3) they are pregnant or breastfeeding, (4) they have known retinopathy, (5) they have a known allergy to semaglutide, (6) they have major surgery planned during the trial period, (7) they have uncontrolled cancer, (8) they have a personal or family history of medullary thyroid carcinoma, (9) they have multiple endocrine neoplasia syndrome type 2, or (10) they have other conditions that the investigators deem to render the participant unfit for inclusion in the trial, including a physical or cognitive inability to participate in the trial.

Trial participants will be recruited using the following different strategies: (1) telephone calls to a group of potential participants who have agreed to be contacted regarding the initiation of new trials at SDCN; (2) announcements in newspapers, the Danish diabetes magazine, the website of Region North Denmark, social media, and relevant patient organizations; (3) posters and leaflets placed at SDCN, Aalborg University Hospital, and other relevant health centers; and (4) digital mail sent to the official digital mailbox (e-boks) of a list of potential participants (people with T2D on metformin and optionally SGLT2i with high HbA1c obtained less than 3 months ago), which will be obtained from the Business Intelligence Unit at the North Denmark Region.

A participation information letter describing the trial will be mailed or handed to interested potential participants. An information interview will be held at Aalborg University Hospital with the interested potential participant, an optional companion, and either the investigator, subinvestigator, or a delegated project member with the required professional knowledge. In the information interview, the potential participant will be informed on the voluntary nature of participating in the trial, their right to reflect on whether to participate prior to giving informed consent to trial participation, and their right to withdraw consent at any time, without any explanation. A participant cannot be included in the trial until informed consent has been signed by both the participant and the investigator.

The trial period starts with the first visit to the trial site and ends 12 weeks later with the second visit to the trial site. A CGM baseline reading from each participant will be collected prior to oral semaglutide initiation, corresponding to the first 2 weeks of the trial period. After oral semaglutide initiation, CGM data, physical activity, time of dosing, and water volume intake at dosing time will be collected throughout the remaining trial period. The participants will be asked to report occurrences of nausea and vomiting, including time, duration, and severity (using a scale from 0-10 with 10 being the worst imaginable) in a paper diary. In addition, the participants will be asked to register the time of breakfast at 3 time periods during the trial (Figure 2).

All participants will continue their current treatment throughout the trial period. Additionally, the participants will be started on oral semaglutide 2 weeks after trial initiation, at which time a lab technician from SDCN will contact the participant by phone (Figure 2). The oral semaglutide will be handed out to the participants at the first visit to the trial site. The initiation and dosage evaluation of oral semaglutide will be in accordance with the product information on dose escalation [16,17]. Thus, the initial dosage of oral semaglutide will be one 3 mg tablet once daily (OD), which the participants will be instructed to take in the morning in a fasting state with maximum of a half glass of water, approximately 120 mL. Participants will be instructed to wait at least 30 minutes before the intake of food, liquids, or other medications. After 4 weeks, corresponding to telephone call 2 (Figure 2), the dosage of oral semaglutide will be increased to one 7 mg tablet OD [16,17]. After an additional 4 weeks, corresponding to telephone call 3 (Figure 2), the dosage of oral semaglutide will be re-evaluated and, if needed, increased to one 14 mg tablet OD to reach the glycemic target of the participant [16,17]. The dosage evaluation will be based on the collected CGM data, which the trial staff at SDCN will access remotely in connection with telephone call 3.

Demographic information on each participant will be obtained at the first visit and includes birth date, biological sex, ethnicity, height and body weight, systolic and diastolic blood pressure, duration of diabetes (defined as the time from T2D diagnosis), diabetes complications, smoking status, alcohol intake, exercise, diet, marital status, housing status, level of education, employment status, and concomitant medications and illnesses.

The participants’ view on their adherence to the treatment and perceived adherence barriers will be captured using previously published questionnaires. Data on health beliefs will be obtained by asking the participants to answer the questionnaire developed by Given et al [21] and adapted by Becker and Janz [22]. The participants will also be asked to answer a questionnaire on social support developed by Sarason et al [23].

The patient-reported adherence to and satisfaction with the diabetes treatment will be assessed using the treatment-related impact measure for diabetes (TRIM-D) questionnaire, which consists of 5 subcategories: treatment burden, daily life, diabetes management, compliance, and psychological health [24]. The participants will be asked to answer the TRIM-D questionnaire at the start and end of the trial. Figure 3 provides a schematic of the trial timeline.

Throughout the trial, data will be collected by asking the participants to use or wear several devices to collect data. These devices include an unblinded CGM sensor (Dexcom G6 CGM System, Dexcom Inc) to determine the level of glycemic control, a smartwatch (Fitbit Charge 4, Fitbit Inc) worn all hours of the day to track activity and determine time of sleep, a smart pill bottle (MEMS Cap Smart Pill Bottle, Aardex Group) to collect time of dosing, a smart bottle (HidrateSpark Pro, HidrateSpark) to collect time and volume of water intake at dosing time, and a smartphone to take a photo of their breakfast in the week before and after dosage evaluation (Figure 2) to collect time of breakfast data.

Completion of the trial is defined as attendance at the final visit regardless of the degree to which the devices of the trial have been used. The entire trial is complete after the final visit by the last participant. In case a participant wants to withdraw from the trial, a visit at the trial site will be offered. All questions the participant may have will be answered and the devices returned.

A participant will be withdrawn from the trial if the participant experiences severe hypoglycemia or hyperglycemia or ketoacidosis that the investigators attribute to the trial, or if the investigators deem the participant unfit to continue the trial. The entire trial will be stopped prematurely if serious adverse events associated with the trial, as judged by the principal investigator or subinvestigators, occur.

The disadvantages of participation are considered to be limited. These disadvantages include the inconvenience of trial participation and use of the CGM sensor, which may cause local skin irritation and elevates the risk of infection. As oral semaglutide will be initiated in the trial, side effects due to oral semaglutide may occur. The most frequently reported side effects of oral semaglutide are related to the gastrointestinal symptoms, such as nausea, vomiting, diarrhea, constipation, stomach pain, gastritis, decreased appetite, and gastroesophageal reflux disease [16,17]. Other common side effects include tiredness, hypoglycemia, and complications of retinopathy [16,17]. Uncommon side effects are gall stones, weight loss, and fast pulse [16,17]. Rare side effects include acute pancreatitis and anaphylactic reaction [16,17].

Adverse events occurring during the trial period will be reported, and the investigators will note whether the adverse event in their opinion is related to trial participation in accordance with the guidelines of the National Committee on Health Research Ethics.

The primary endpoint is the change from baseline to end-of-study time-in-range (TIR) derived from CGM data calculated in accordance with the International Consensus on Use of Continuous Glucose Monitoring [25].

Secondary endpoints include the following:

An exploratory endpoint is steps per day. Additionally, qualitative interviews will be carried out with selected participants to explore their adherence to oral semaglutide during the trial period.

Statistical analyses will be performed on the data of all included trial participants, and a statistical significance level of 5% (α=.05) will be used.

The primary endpoint (change from baseline to end-of-study in TIR) will be analyzed using a simple linear regression model with the average (in weeks 10-12) of time elapsed from dosing time to time of breakfast.

With 20 participants, there is 80% power to detect a significant correlation of 0.58 between the elapsed time from dosing to time of breakfast and the improvement in TIR.

CGM-derived metrics such as TIR are only calculated for a specific interval if data have been collected ≥80% of the time in accordance with the International Consensus on Use of Continuous Glucose Monitoring [25]. Missing data will be treated as missing at random, and multiple imputation to impute missing data will be used in the statistical analysis.

No biological material will be obtained from the trial participants.

Data storage will consist of both paper files and digital files on a computer using Research Electronic Data Capture (REDCap) [27], both of which will be accessible only by the investigator, subinvestigators, and relevant members of the project team. Data related to the trial will be kept stored for the duration reported to the Danish Data Protection Agency. Third-party data use will only occur if agreed upon by the subinvestigators and the primary investigator.

The electronic journal of potential trial participants will be accessed by health care professionals affiliated with SDCN to assess if the potential participant is suitable for trial inclusion by reviewing information including health status, medications, and comorbidities. The electronic journal will not be accessed without the participants’ consent. Furthermore, prospective inspection authorities will be given access to the patients’ electronic journal in relation to monitoring and quality control of the trial.