Take Control: A randomized trial evaluating the efficacy and safety of self‐ versus physician‐managed titration of insulin glargine 300 U/mL in patients with uncontrolled type 2 diabetes

Aim To compare the efficacy and safety of self‐ versus physician‐managed titration of insulin glargine 300 U/mL (Gla‐300) in people with inadequately controlled type 2 diabetes. Methods Take Control (EudraCT number: 2015‐001626‐42) was a 24‐week, multi‐national, open‐label, controlled, two‐arm, parallel‐group study in insulin‐naïve and pre‐treated participants, randomized 1:1 to a self‐ or physician‐managed titration of Gla‐300. The fasting self‐monitored plasma glucose (SMPG) target was 4.4 to 7.2 mmol/L. The primary outcome was non‐inferiority of glycated haemoglobin (HbA1c) change from baseline to week 24. Secondary outcomes included SMPG target achievement without hypoglycaemia, hypoglycaemia incidence, adverse events and participant‐reported outcomes (PROs). Results At week 24, the least squares (LS) mean HbA1c reduction was 0.97% (10.6 mmol/mol) and 0.84% (9.2 mmol/mol) in the self‐ and physician‐managed groups, respectively, with an LS mean difference of −0.13% [95% confidence interval −0.2619 to −0.0004] (–1.4 mmol/mol [–2.863 to –0.004]), demonstrating non‐inferiority (P < 0.0001) and superiority (P = 0.0247) of self‐ versus physician‐managed titration. Significantly more of the self‐ than physician‐managed group achieved SMPG target without hypoglycaemia (67% vs 58%; P = 0.0187). Overall, hypoglycaemia incidence was similar in each group. No safety concerns were reported. In both groups, similar PRO improvements were observed for distress related to diabetes disease burden and for confidence in diabetes self‐management, with even more individuals achieving a clinically relevant reduction in emotional burden and fewer individuals with high emotional burden in the self‐managed group. Conclusions Self‐managed titration of Gla‐300 was superior to physician‐managed titration in terms of HbA1c reduction, accompanied by similar total PRO scores, with a clinically relevant reduction in emotional burden, and similar hypoglycaemia frequency.


Funding information
This work was supported by Sanofi, Paris, France.

Peer Review
The peer review history for this article is available at https://publons.com/publon/ 10.1111/dom.13697.

K E Y W O R D S
glycaemic control, hypoglycaemia, randomized trial, type 2 diabetes

| INTRODUCTION
Achieving glycated haemoglobin (HbA1c) targets reduces the risk of long-term complications of diabetes, 1 but in real-world practice many individuals with type 2 diabetes (T2DM) fail to achieve adequate glycaemic control. [2][3][4] Poor glycaemic control can be a result of clinical inertia, which may be contributed to by several physician-and patient-related barriers including fear of hypoglycaemia and/or weight gain, burdensome treatment regimens, poor persistence to injectable therapies, lack of time for healthcare professionals to teach and difficulty for patients to understand the importance and performance of appropriate titration, frustration at time taken to achieve goals, insufficient communication between healthcare professionals and patients, and anxiety. [5][6][7][8][9][10] As the disease progresses, lack of glycaemic control may also indicate the need to initiate adjunctive therapies. 11 Empowering those with T2DM to take a more active role in their own treatment may help individuals to achieve their glycaemic goals and reduce the risk of all-cause mortality, 12,13 which could reduce lifetime costs of complications and hospital admissions, 14 and might help to address the increasing burden of diabetes on healthcare systems worldwide. This concept of patient-centred care and self-management is a key focus of the current consensus report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). 15 Self-managed titration of insulin glargine 100 U/mL (Gla-100) may be more effective than physician-managed titration 16,17 without any safety concerns, 18,19 but it does appear to be associated with a higher risk of symptomatic hypoglycaemia compared with physician-managed titration. 17,18 This limitation of Gla-100 could be overcome through selftitration with insulin glargine 300 U/mL (Gla-300), a second-generation basal insulin (BI) with prolonged and more stable pharmacokinetic and pharmacodynamic profiles than Gla-100. 20,21 Phase III treat-to-target studies demonstrated a lower risk of hypoglycaemia with Gla-300 versus Gla-100 in people with T2DM, especially during the titration phase. 22 This lower risk of hypoglycaemia has also been observed from real-world evidence of people switching to Gla-300 versus other BIs. 23 The present study examined the effectiveness and safety of selfversus physician-managed titration of Gla-300, in order to evaluate whether the improved glycaemic profile and lower hypoglycaemic risk of Gla-300 over Gla-100 make it suitable for a simple, self-managed titration approach.
Outpatient participants were recruited in 10 European countries, between February and November 2016. Inclusion criteria comprised age ≥18 years, T2DM diagnosis for at least 1 year before screening and at least 6 months on treatment with at least one non-insulin antihyperglycaemic drug, with or without a BI. Insulin-pretreated participants were required to have been on a stable dose (type of insulin and time/frequency of injection) within 3 months prior to screening.
Background non-insulin antihyperglycaemic drug(s), including sulphonylureas (SUs), administered at a stable dose for ≥12 weeks prior to screening were permitted according to local labelling guidelines. The type and dose remained unchanged during the study, unless safety concerns necessitated a dose reduction or discontinuation.
Non-study drug BIs were stopped by the time of randomization.
All participants provided informed, written consent. The clinical trial protocol was approved by the relevant health authorities and the appropriate local institutional review board/independent ethics committees. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice.

| Interventions
After randomization, Gla-300 was self-administered subcutaneously once daily, with doses according to the European Union label, taking into account history of insulin use (Table S2). The time of daily administration was defined at the randomization visit by the participant and investigator, and maintained for the duration of the study, with occasional variation of ±3 h in injection time if necessary.
Paper diaries were dispensed to participants at each on-site visit, and collected for review at each subsequent on-site visit. Diaries contained instructions for managing glycaemic values according to each participant's allocated titration arm. Participants were trained at visits 1 and 2 (and re-trained as necessary during the study) in how to complete these diaries to record information related to hypoglycaemic events, self-monitored plasma glucose (SMPG) and insulin doses. Insulin dose was to be adjusted to a fasting SMPG target of 4.4 to 7.2 mmol/L as per 2015 ADA recommendations, while avoiding hypoglycaemia. 11 During telephone call "visits", participants were also asked about their last fasting SMPG values, insulin dose and any adverse event (including hypoglycaemic events) they had experienced.
In both arms, the Gla-300 dose was to be adjusted based on the median of the last three consecutive fasting SMPG values from the past 3 to 4 days and including the day of adjustment, according to the titration algorithm presented in Table S3. In the physician-managed titration algorithm, doses were titrated at each visit according to study design (weekly for the first 8 weeks, bi-weekly until week 12, and then monthly until week 24). In the self-managed titration algorithm, the dose was titrated every 3 to 4 days. Participants in the selfmanaged group were instructed on the use of the algorithm but made decisions regarding titration on their own. All participants received the same training on use of the injection device and titration algorithm prior to randomization, at the first and second site visit, and training was repeated as often as necessary until participants could demonstrate competent unaided use. It was expected that most titrations to reach the target fasting SMPG would occur during the first 12 weeks of treatment with Gla-300, but titration to achieve target could continue until week 24.
The study consisted of a prespecified schedule of six on-site and 10 telephone call visits. During visits, physician-managed participants were instructed to self-inject at a dose prescribed by the investigator.
Self-managed participants were instructed to continue the same titration approach, unless participant safety was at risk. Additional contacts (telephone, on-site visit) between scheduled visits were available at the discretion of the investigator.

| Rescue medication
Addition of a new anti-hyperglycaemic drug or a dose increase of an existing anti-hyperglycaemic non-study drug, was performed based on the investigator's decision and local requirements. It was expected that the initiation of any rescue medication would be deferred until week 12 of treatment. Short-term use (ie, 10 consecutive days) of short-acting insulin (eg, due to acute illness or surgery) was not considered as rescue therapy.

| Outcome measures
The primary outcome was non-inferiority of glycaemic control, as assessed by the change from baseline to week 24 in HbA1c, achieved using the self-versus physician-managed titration algorithm for Gla-300. Key secondary outcomes included the percentage of participants reaching fasting SMPG target without experiencing hypoglycaemia that was severe and/or confirmed by a glucose measurement of <3.0 mmol/L (see below for a full definition); safety and tolerability, including hypoglycaemic events; and change in PROs according to total and subscale scores using the Diabetes Distress Scale (DDS) 24 and the Diabetes Empowerment Scale (DES). 25 The DDS evaluates patient distress attributable to diabetes burden; scores range from 1 (no problem) to 6 (serious problem), with scores of 2.0 to 2.9 indicating "moderate distress" and scores ≥3 indicating "high distress". The DES evaluates patient confidence in self-management of diabetes treatment; scores range from 1 to 5, with higher scores indicating greater confidence in self-management. The minimum clinically important difference from baseline for each PRO score was defined as half the standard deviation of baseline scores, pooled across the titration groups. A full list of outcomes is presented in Table S5. Hypoglycaemia was assessed according to ADA definitions 26 ; "confirmed and/or severe" hypoglycaemia was defined as any event that was documented symptomatic or asymptomatic with a plasma glucose measurement of ≤3.9 mmol/L or <3.0 mmol/L, and/or was severe (requiring third-party assistance).

| Statistical methods
A sample size of 592 was required to ensure that the two-sided 95% confidence interval (CI) for the mean difference between the two titration approaches would not exceed 0.3% HbA1c, with 80% power assuming the SD is 1.3%, with a one-sided test at the 2.5% significance level and that the true difference between the two dosing regimens of Gla-300 is zero.
The primary efficacy analysis was performed in the intention-totreat (ITT) population, comprising all randomized participants, irrespective of the titration arm at the time of the analysis. PROs were also analysed in the ITT population. The safety population was defined as all randomized participants who received at least one dose of Gla-300, regardless of the amount of treatment administered.
The primary endpoint was analysed using a mixed-effect model with a repeated measures approach, including fixed categorical effects of titration approach, visit, titration approach-by-visit interaction, randomization strata as well as continuous fixed covariates of baseline HbA1c and baseline HbA1c value-by-visit interaction. A stepwise closed testing approach was used for the primary efficacy variable to assess non-inferiority and superiority. Non-inferiority was demonstrated if the upper bound of the two-sided 95% CI for the difference in the mean HbA1c change from baseline to week 24 between titration approaches was <0.3% HbA1c. If non-inferiority was demon-

| Study population
Overall, 631 participants were randomized (ITT population) to selfmanaged (314; 49.8%) or physician-managed (317; 50.2%) titration ( Figure S2). A similar proportion of participants in both groups completed the study; 307 (97.8%) and 311 (98.1%) in the self-and physician-managed groups, respectively. One participant, in the physician-managed group, discontinued the study because of poor treatment adherence. During the 24-week study period, rescue medication was initiated in four (1.3%) and three (0.9%) participants from the patient-and physician-managed groups, respectively. Demographic and baseline characteristics were similar in the selfversus physician-managed groups (Table 1). Across both groups, 50.6% of participants had received SUs as a non-insulin anti-hyperglycaemic T A B L E 1 Demographic characteristics

| Adverse events
Treatment-emergent adverse events (TEAEs) were reported by 33.7% of participants in the self-managed titration group, and 34.5% in the physician-managed titration group during the 24-week on-treatment period (Table S5). Rates of serious TEAEs were similar in the selfmanaged (3.2%) and the physician-managed titration group (3.8%). No deaths occurred during the study. Only one participant in the physician-managed titration group experienced a TEAE leading to permanent treatment discontinuation. The serious TEAE was acute heart failure, assessed as unrelated to treatment.

| Insulin dose and body weight
There was a numerically higher mean daily insulin dose increase in the overall self-managed versus physician-managed group as well as in the insulin-naïve and insulin pre-treated subgroups of these titration approaches (   The mean (SD) DES total scores at baseline were 4.00 (0.50) and 4.02 (0.51) in the self-and physician-managed groups, indicating that both groups were reasonably confident in their diabetes self-management.

| Participant-reported outcomes
There was a mean increase in total DES scores from baseline to week 12 by 0.14 (0.43) and 0.06 (0.47) in the self-and physician-managed groups, respectively. These increases in DES total score were maintained at week 24, with mean increases of 0.19 (0.45) and 0.12 (0.49) from baseline, and an LS mean difference (95% CI) of 0.07 (0.00 to 0.14) for selfversus physician-managed titration, indicating that participants in both groups felt more confident in managing their diabetes ( Figure S3). Similar improvements in all DES subscales were seen in both titration groups at week 24 (data not shown).

| DISCUSSION
In the present study, self-managed titration of Gla-300 was both noninferior and superior to physician-managed titration in terms of mean reduction in HbA1c from baseline to week 24. Slightly greater HbA1c reductions were observed in self-versus physician-managed titration, regardless of previous insulin use, with more participants in the selfmanaged group achieving the HbA1c target of <7.0% (<53 mmol/mol).
Furthermore, a significantly higher proportion of participants in the selfversus physician-managed groups achieved the fasting SMPG target without experiencing confirmed (<3.0 mmol/L) or severe hypoglycaemia.
The results from the present study are generally consistent with those from two previous studies. ATLAS 18 and AT.LANTUS 16,17 were both 24-week, multicentre, randomized, open-label studies that demonstrated significant improvements in glycaemic control with selfmanaged over physician-managed titration of Gla-100, in uncontrolled T2DM. [16][17][18] There was no significant difference in the proportion of participants with self-versus physician-managed titration achieving HbA1c <7.0% (<53 mmol/mol) without severe hypoglycaemia in ATLAS, or with severe hypoglycaemia in AT.LANTUS. 17 study, although it should be noted that SMPG was used as the glycaemic target, rather than HbA1c, as in ATLAS and AT.LANTUS.
In AT.LANTUS and ATLAS, there was a higher risk of symptomatic hypoglycaemia with self -vs physician-managed titration. 17,18 Such results may cause physicians to be reluctant to encourage their patients to self-titrate, in order to avoid hypoglycaemia. By contrast, the similar incidences of all definitions of hypoglycaemia reported in Take Control may reflect the improved pharmacokinetic properties of Gla-300 versus Gla-100, 20,21 which translated to lower incidence and rate of hypoglycaemia with Gla-300 in previous randomized controlled trials and real-world studies. Importantly, in Take Control there were very few hypoglycaemic events overall, with low and similar rates of TEAEs and serious TEAEs in both titration groups, suggesting that Gla-300 would be better suited for self-managed titration than Gla-100.
At week 24, Gla-300 doses were numerically higher with self-versus physician-managed titration, consistent with the results with Gla-100 in ATLAS and AT.LANTUS. 17,18 These higher doses may reflect the more frequent titration that is possible in the self-managed algorithm. In Take Control, 1.8 times more dose adjustments were made in the self-versus physician-managed group, which may explain the better glycaemic results, although the time taken to reach fasting SMPG target was similar in both groups. Nevertheless, as described above, the proportion of participants achieving HbA1c target was less than one-third in both groups. While slightly higher proportions of participants achieve HbA1c targets in treat-to-target studies such as the EDITION programme, 22 it appears that treatment intensification may be required in many patients. Given that >60% of participants achieved fasting SMPG targets but only 20% to 30% achieved HbA1c The study benefitted from the randomized trial design with a sufficiently large sample size to detect differences in the primary endpoint.

DATA SHARING
Qualified researchers may request access to patient-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com.