COMET-T was designed as a non-interventional, multicenter prospective study with Gla-300 to document the efficacy and safety of Gla-300 in combination with any bolus insulin in PwT1D in Germany, Austria, and Switzerland from 2021 to 2022. The study was planned and conducted in accordance with Good Pharmacoepidemiology Practice guidelines [20] and local legal and ethical guidelines.

Study sites were selected according to their care for PwT1D, their familiarity with software of CGM and intermittently scanned (isCGM) systems in daily clinical practice and representative distribution across all regions of the three countries. The participating physicians were informed about the aims, background, and procedures of the observational study and had to ensure the conduct of the study according to the observation plan in accordance with local regulations and international guidelines.

The study was conducted in accordance with the Helsinki Declaration of 1964. The study received approval from the institutional review board or ethics committee at each participating center. Approval reference numbers were BASEC-Nr. 2020-01997, F-2020-106, 32-605 ex 19/2 (Supplementary Table 1). A formal written informed consent was obtained from all patients prior to their enrolment in the study.

The study included adult PwT1D (≥ 18 years old at the time of signing the informed consent form) with insufficient glycemic control who are treated with a basal insulin in combination with any bolus insulin and already using a CGM or FGM system for continuous glucose measurement. The treating physicians performed the patient screening. PwT1D for whom the treating physician had already decided to switch basal insulin to Gla-300 within the scope of the marketing authorization (according to the summary of product characteristics [SmPC]) were eligible for the documentation. The decision to treat was made independently of the decision to participate in this study and indicated by an HbA1c value between 7.5% and 10% in the last 3 months.

Additionally, participants needed to be experienced in glucose self-management using their own CGM or isCGM system for at least 3 months prior and needed to achieve at least 70% sensor activities in the last 14 days. Participants were not eligible in case of participation in other clinical trials, having type 2 diabetes (T2D), with contraindication to Gla-300, using continuous insulin substitution, e.g., via insulin pump or with planned or existing pregnancy, cancer, drug/alcohol abuse, dementia, or inability to understand the content of this non-interventional study (NIS).

The primary endpoint was the change of TIR between baseline and approximately 12 and 24 weeks after switching to Gla-300, respectively.

Secondary efficacy endpoints included the absolute change in total time [%] above range (TAR: > 180 mg/dl) or below range (TBR: < 70 mg/dl), analysis of fasting plasma glucose (FPG) measured with their own blood glucose meter, insulin dose, body weight (BW) and HbA1c.

Safety endpoints assessed the absolute change in the occurrence of nocturnal and all-day hypoglycemia with severity level classified according to ADA (level 1 hypoglycemia: measurable glucose concentration < 70 mg/dl but ≥ 54 mg/dl; level 2 hypoglycemia: blood glucose concentration < 54 mg/dl; level 3 hypoglycemia: severe event characterized by altered mental and/or physical functioning that requires assistance from another person for recovery) [2], treatment-emergent adverse events and adverse reactions, serious adverse events and reactions and adverse events leading to discontinuation.

The overall observation duration was approximately 24 weeks with an interim evaluation after approximately 12 weeks (Fig. 1). Data were collected at the start of the study at the time of patient enrollment (baseline documentation, week 0), at approximately 12 weeks after switching to Gla-300 as basal insulin and any bolus insulin in the form of interim documentation, and once at the end of the observation period approximately 24 weeks after switching to Gla-300 as basal insulin and any bolus insulin in the form of final documentation. During the observation period, patients were managed and treated according to the physician’s usual practice. The total study duration from inclusion of the first patient to follow-up of the last patients is approximately 15 months.

Study design. CGM continuous glucose monitoring, DTSQ Diabetes Treatment Satisfaction Questionnaire, FPG fasting plasma glucose, Gla-300 insulin glargine 300 U/ml, HbA1c glycated hemoglobin

All visits occurred according to routine clinical practice without additional procedures, assessments, or changes in participants’ routine management. Data collection was performed using electronic case report forms (eCRFs), isCGM or CGM systems. Diabetes Treatment Satisfaction Questionnaire (DTSQ) was used to collect data about treatment satisfaction from all patients during the initial (week 0) and final visit (week 24). CGM data from the last 14 days was collected during control visits. For appropriate evaluation of CGM data, 70% of 14 days data from isCGM or CGM systems should be available. Participating physicians were required to report all adverse events (AEs) for each patient from signing of the informed consent form until the end of the study as defined in the observation plan.

Data quality control was performed in 5% of the participating sites (which had documented at least one participant), chosen at random.

Since this was a non-confirmatory, observational study with no prior hypotheses, no formal sample size or power calculation was conducted; only an informal justification was provided.

A sample size of 266 participants was calculated to have 90% power to detect a difference in means of 4%, assuming a standard deviation of 20%, using a paired t test with a 0.05 two-sided significance level.

For safety assessments, the following presumptions were made: in 266 participants, a 95% probability of at least one “rare” adverse event occurring in this participant population was expected with a probability of 0.011. Due to the COVID-19 pandemic, recruitment was limited, reducing the participant number to 135.

All collected data were analyzed descriptively. For continuous variables, the number of participants, mean, standard deviation, median, minimum, maximum and quartiles were determined; for categorical variables, frequencies, percentage frequencies and, if necessary, adjusted percentage frequencies were determined. Appropriate 95% confidence intervals (CI) were calculated for estimated parameters.

The main evaluation variable was analyzed for the full analysis set (FAS), defined as all participants who provided written informed consent, fulfilled all eligibility criteria, took at least one dose of Gla-300 during the NIS and had sufficient data for the evaluation of at least one efficacy endpoint.

Efficacy and safety parameters were analyzed in comparison: values before treatment with Gla-300 versus after the observation period of approximately 12 and 24 weeks. The t test for the paired samples was used to check whether there was a significant difference. In addition, the interactions of the parameters were investigated by means of a variance analysis. For the change in coefficient of variation and standard deviation (SD) of glucose levels, endpoints were only analyzed in device-specific subgroups.

All statistical evaluations are purely exploratory in nature. All descriptive and inferential statistical analyses were performed using the SAS statistical software version 9.4.