This was a 32-week, open-label, randomized, parallel-group, multicenter, multinational, phase 4 trial in patients with T2D aged at least 18 years (clinicaltrials.gov identifier, NCT02453685). The trial was conducted in nine countries: Australia, Bulgaria, Hungary, India, Republic of Korea, Serbia, Thailand, Turkey, and United Arab Emirates, between September 2015 and September 2016. The trial period consisted of a screening period (up to 2 weeks before randomization) and a 32-week treatment period divided into four periods of 8 weeks each. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study.
Eligible participants were insulin-naïve men or women aged at least 18 years and had been clinically diagnosed with T2D for at least 6 months prior to screening, were treated with a stable daily dose (for at least 90 days prior to screening) of metformin (at least 1000 mg or maximum tolerated dose in the patient medical record) and sulfonylurea (SU) and were willing to discontinue any other OADs, including insulin secretagogues (except SU), dipeptidyl peptidase-4 inhibitor (DPP-4i), sodium glucose co-transporter 2 inhibitor (SGLT2i), colesevelam, bromocriptin, and/or combination products at randomization, had an HbA1c 7.0–9.5% (both inclusive) and body mass index (BMI) less than 40.0 kg/m2. Key exclusion criteria included previous participation in the current trial or participation in another clinical trial 1 month before screening, any contraindication to BIAsp 30, IGlar, or IAsp, impaired liver function, high blood pressure, proliferative retinopathy or maculopathy requiring acute treatment, mental incapacity, psychiatric disorder, unwillingness or language barriers precluding adequate understanding or co-operation.
Eligible patients were randomized (stratified by pretrial OAD therapy) into one of two treatment arms: (1) BIAsp 30 OD with the largest meal, with the possibility of treatment intensification up to BIAsp 30 TID; (2) IGlar OD, with the possibility of treatment intensification with IAsp up to TID (basal–bolus).
Treatments, Insulin Dosing and Titration
Patients were instructed in trial product administration and the investigator documented that direction for use was given to the patient orally and in writing at the first dispensing visit. Subsequent directions for use were given at succeeding visits if deemed appropriate by the investigator. It was the investigator’s or delegated staff’s responsibility to assess if the patient was capable of following instructions during training and those in the directions for use.
Pretrial treatment with metformin and SU was continued as background treatment throughout the entire trial, in line with the treatment practice demonstrated in the A1chieve study . The stable dose levels and dosing frequencies prescribed pretrial could be changed for safety reasons only, at the discretion of the investigator. An individualized approach to insulin titration and intensification regimen was used in the current trial as opposed to using fixed insulin doses. All patients underwent a weekly insulin dose titration during the entire treatment period in order to achieve the pre-meal self-monitored plasma glucose (SMPG) target of 4.4–6.1 mmol/L (80–110 mg/dL).
At the end of each 8-week period (weeks 8, 16, and 24), insulin treatment was intensified in a stepwise manner by adding an additional injection of BIAsp 30 in the BIAsp 30 arm, and IAsp in the basal–bolus arm, on the basis of whether patients had achieved target HbA1c below 7.0%. The insulin treatment could only be stepwise intensified at the appropriate 8-week period. Patients randomized to BIAsp 30 had the possibility of receiving up to three daily injections of BIAsp 30 and patients randomized to basal–bolus had one daily injection of IGlar plus the possibility of up to three daily injections of IAsp. In the BIAsp 30 arm, patients received BIAsp 30 OD at a starting dose of 12 U administered with the largest meal. In the event of intensification to twice- or thrice-daily injections of BIAsp 30, the second or third injection was given at the second or third largest meal, respectively. Patients randomized to the basal–bolus arm received IGlar OD at a starting dose of 10 U administrated at the same point of time every day. For patients receiving IGlar OD who were intensified to once-, twice-, or thrice-daily insulin injections with IAsp, the first, second, or third injection was given at the first, second, or third largest meal, respectively, with a starting dose of 4 U.
Efficacy and Safety Endpoints
The primary endpoint was change from baseline in HbA1c after 32 weeks of treatment. Secondary endpoints included the proportion of patients achieving HbA1c below 7% after 32 weeks of treatment (total and without severe hypoglycemia during the last 12 weeks of treatment), change from baseline in fasting plasma glucose (FPG) after 32 weeks of treatment, mean 7-point SMPG profiles and prandial plasma glucose (PG) increments after 32 weeks of treatment, total daily insulin dose during the 32 weeks of treatment, and change in patient-reported diabetes treatment satisfaction from baseline to 32 weeks of treatment assessed by the diabetes treatment satisfaction questionnaire (DTSQ) . Safety endpoints included the number of treatment-emergent hypoglycemic episodes classified according to the Novo Nordisk definition of confirmed symptomatic hypoglycemia during 32 weeks of treatment, change in body weight from baseline to 32 weeks of treatment, incidence of adverse events (AEs) during 32 weeks of treatment, and change in clinical safety parameters (physical examination, vital signs, laboratory parameters) from baseline to 32 weeks of treatment.
Sample size was based on the half-width of a 95% confidence interval (CI) for the difference between the two means of change from baseline in HbA1c for the full analysis set (FAS) (i.e., all randomized patients). The sample size was determined by requiring that half the length of the 95% confidence interval was less than 0.27 with 90% probability. To ensure this, 336 patients needed to be randomized. Thus, assuming a screening failure rate of 30%, 480 patients were needed to be screened for inclusion in the trial.
Change from baseline in HbA1c after 32 weeks of randomized treatment was analyzed using a mixed model repeated measurement (MMRM) where all calculated changes in HbA1c from baseline at weeks 4, 7, 12, 15, 20, 23, 28, and 32 were included in the analysis. This model included treatment, region, and strata (two levels: pretrial metformin and SU, with/without other OAD) as fixed effects, HbA1c at baseline as covariate, and interactions between all fixed effects and visit, and between the covariate and visit. A dichotomous (responder/non-responder) endpoint was defined on the basis of whether a patient had met HbA1c below 7.0% after 32 weeks of randomized treatment (overall and without severe hypoglycemia during the last 12 weeks of treatment). As a conservative approach, patients withdrawn before 32 weeks were defined as non-responders. It was analyzed using a logistic regression model with treatment, strata, and region as factors, and baseline HbA1c as covariate. Changes from baseline in FPG after 32 weeks of randomized treatment were analyzed on the basis of all planned post-baseline measurements until or at 32 weeks using an MMRM similar to the model used for analysis of the primary endpoint, except with the respective baseline value as covariate. Prandial PG increment for each meal (breakfast, lunch, main evening meal) was derived from the 7-point SMPG profile as the difference between prandial 90-min PG values and the PG value before meal in each separate profile. Mean 90-min postprandial glucose increments over all meals were derived as the mean of all corresponding meal increments. Prandial PG increment endpoints (mean and each separate meal) were analyzed on the basis of all planned post-baseline measurements until or at 32 weeks using an MMRM similar to the model used for analysis of the primary endpoint and with the corresponding baseline value as covariate.