The sample was recruited from 68 male and female patients (≥18 years with a body mass index [BMI] ≤40 kg/m2) who had failed to achieve glycemic control following 26 weeks of treatment with IDegAsp BID .
Key exclusion criteria were the presence of cardiovascular (CV) events (e.g., stroke) between the start of the preceding trial and consenting to the present trial, uncontrolled hypertension (i.e., systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥100 mmHg) and the presence of recurrent severe hypoglycemia (more than one event within the previous 12 months), or hypoglycemic unawareness, as evaluated by the investigator. Dipeptidyl peptidase 4 inhibitors (DPP-4) and/or metformin was allowed only if continued from the preceding trial; commencement of new oral antidiabetic agents (OADs) during the trial was prohibited.
Of the 68 patients eligible for screening, 47 consented to enter into the current trial, of which seven failed screening (six patients failed because their HbA1c was less than 7% and one patient failed because of impaired renal function). Forty patients were randomized and 10 patients withdrew during the trial, which resulted in 30 completers (15 completers in each treatment group). The proportion of subjects withdrawn from the trial was the same between the two treatment groups. One subject (in the IDeg OD + IAsp TID group) was withdrawn because of an adverse event (AE). There was no apparent pattern in the withdrawals and no apparent clustering of withdrawals at any specific time point during the trial.
This was a 26-week, randomized, open-label, phase 3b, treat-to-target, exploratory trial in which patients were randomized 1:1 to either IDegAsp BID + IAsp OD ± OADs or IDeg OD + IAsp TID ± OADs. Participating countries were the USA (n = 26), Malaysia (n = 11), Germany (n = 2), and Turkey (n = 1).
Compliance with Ethics Guidelines
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki 1975, as revised in 2013, and Good Clinical Practice (International Conference on Harmonisation). Informed consent was obtained from all patients for being included in the trial.
The primary endpoint was change from baseline in HbA1c after 26 weeks. The secondary endpoints were FPG, mean 8-point self-measured plasma glucose (SMPG), post-prandial glucose (PPG) increment, insulin dose, and body weight.
Safety endpoints included the total number of AEs in each treatment group, the number of serious adverse events (SAEs), the AE rate per 100 patient-years of exposure (PYE), and the number of patients withdrawn due to AEs. Confirmed hypoglycemic episodes included episodes with a measured plasma glucose (PG) value of less than 3.1 mmol/L or severe episodes (severe defined as requiring assistance from another person to treat). Confirmed hypoglycemic events that occurred during 0001–0559 hours (both inclusive) were classified as nocturnal.
Insulin Dose and Titration
In the IDegAsp BID + IAsp OD treatment arm, IDegAsp was administered with breakfast and the evening meal and IAsp was administered with lunch. Patients restarted their end of trial (EOT) IDegAsp BID dose used in the preceding trial  and the lunchtime IAsp starting dose was 4 units (U).
In the IDeg OD + IAsp TID treatment arm, IDeg was administered at any time of the day. IAsp was administered with breakfast, lunch, and the evening meal. The starting IDeg dose was 70% of the EOT total daily dose from the preceding trial . The starting IAsp dose was 30% of the total EOT dose from the preceding trial divided into three doses per day.
IDeg and IDegAsp were titrated as per the stepwise algorithm in the preceding trial . IDegAsp was dosed according to weekly adjustments based on the lowest of 3 days’ pre-breakfast and pre-evening meal SMPG measurements. IDeg was dosed according to the lowest of three consecutive days’ pre-breakfast SMPG measurements prior to titration. IAsp was dosed according to the lowest of three consecutive days’ SMPG measurements at the following timepoints: breakfast dose was titrated according to the lowest of the pre-lunch SMPG measurements; lunch dose was titrated according to the lowest of the pre-dinner SMPG measurements; evening meal dose was titrated according to the lowest of the bedtime SMPG measurements. The dose of IAsp could be reduced at the discretion of the investigator.
Endpoints derived at 26 weeks were analyzed statistically using the analysis of covariance method (ANCOVA) to estimate mean treatment effects (i.e., least-square means) with 95% confidence intervals (CIs). The primary endpoint was analyzed with an ANCOVA with treatment, sex, and region entered as fixed factors. Age and baseline HbA1c were entered as covariates. Region had three levels: North America, Europe, and Asia. The number of treatment-emergent hypoglycemic episodes was analyzed using a negative binomial regression model with a log-link function and the logarithm of the time period for which a hypoglycemic episode was considered treatment emergent as offset. The model included treatment, sex, and region as fixed factors, and age as covariates. Furthermore, insulin dose in units and units per kilogram was logarithmically transformed and analyzed separately using an ANCOVA method with treatment, sex, and region as fixed factors, and age and the relevant baseline value as covariates. Changes from baseline in FPG and body weight after 26 weeks of treatment were analyzed using an ANCOVA method with treatment, sex, and region as fixed factors, and age and baseline values as covariates. Mean 8-point SMPG and PPG increment were analyzed separately using an ANCOVA method with treatment, sex, and region as fixed factors, and age and the relevant baseline value as covariates. P values were only computed for the primary endpoint. Missing values were imputed using the last observation carried forward (LOCF) method.