Efficacy and Safety of Toujeo® Versus Tresiba® in Insulin-Naive Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Oral Antihyperglycemic Drug(s) ± GLP-1 Receptor Agonist

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To demonstrate the noninferiority in the efficacy of Toujeo® to Tresiba® in glycated hemoglobin (HbA1c) change from Baseline to Week 24. Secondary Objectives: Change From Baseline in HbA1c to Week 12 To assess the effects of the insulin Toujeo® in comparison with insulin Tresiba® at week 12 and week 24 on: Change in Fasting plasma glucose (FPG); Change in Fasting self-monitored plasma glucose (SMPG) and 4-point SMPG and 8-point SMPG profile; Percentage of participants reaching HbA1c targets <7% or ≤6.5%; Percentage of participants reaching HbA1c targets <7% or ≤6.5% without severe and/or confirmed hypoglycemia Frequency of occurrence and diurnal distribution of hypoglycemia by American Diabetes Association (ADA) category of hypoglycemia. To assess the safety in each treatment group. To assess the treatment effects in each treatment group on Patient Reported Outcomes (PRO). Percentage of participants requiring rescue therapy.

Detailed Description
-----------------
The maximum study duration per participant was approximately 27 weeks: an up to 2-week screening period, a 24-week randomized treatment period (including 12 weeks active titration), and a 7-day posttreatment safety follow-up period.

Official Title
-----------------
A 24-week, Multicenter, Randomized, Open-Label, Parallel-group StudyComparing the Efficacy and Safety of Toujeo® and Tresiba® in Insulin-NaivePatients With Type 2 Diabetes Mellitus Not Adequately Controlled With OralAntihyperglycemic Drug(s) ± GLP-1 Receptor Agonist

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: Insulin glargine, 300U/mL
* Drug: Insulin degludec, 100 U/mL
* Drug: Non-insulin anti-diabetic treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria : Adult participants with type 2 diabetes mellitus (T2DM) inadequately controlled with OADs therapy with/without GLP-1 receptor agonist at stable dose for at least 3 months. Signed written informed consent. Exclusion criteria: Age <18 years. HbA1c <7.5% or >10.5% (at screening visit). Body mass index (BMI) <25 kg/m^2 or >40 kg/m^2. History of T2DM for less than 1 year before screening. Less than 6 months before screening on OADs treatment and GLP-1 receptor agonist (if taken). Current or previous insulin use except for a maximum of 8 consecutive days or totally 15 days (eg, acute illness, surgery) during the last year prior to screening. Initiation of new glucose-lowering medications and/or weight loss drug in the last 3 months before screening visit. Participant receiving only noninsulin antihyperglycemic drugs not approved for combination with insulin according to local labelling/local treatment guideline. History of hypoglycemia unawareness or repeated episodes of severe hypoglycemia or metabolic acidosis, including hospitalization for diabetic ketoacidosis during the last 12 months prior to screening. Unstable proliferative diabetic retinopathy or any other rapidly progressive diabetic retinopathy or macular edema likely to require treatment (eg, laser, surgical treatment, or injectable drugs) during the study period. End stage renal disease. Any acute or chronic condition that in the opinion of Investigator would affect the safety of participant, compliance, or study results. Any contraindication to use of Toujeo® or Tresiba® as defined in the national product label, hypersensitivity to Toujeo® or Tresiba® active ingredients or one of the excipients. Pregnant or breast-feeding women. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Toujeo<br>Toujeo® (Insulin glargine, 300 U/mL) subcutaneous (SC) injection once daily up to Week 24 on top of non-insulin antidiabetic treatment. | Drug: Insulin glargine, 300U/mL<br>* Self-administered by subcutaneous (SC) injection in the evening using a pre-filled pen. Dose titration to achieve fasting self-monitored plasma glucose (SMPG) from 80 to 100 mg/dL (4.4 to 5.6 mmol/L).<br>* Other names: Toujeo;Drug: Non-insulin anti-diabetic treatment<br>* Background therapy: Oral Anti diabetics Drugs (OADs), Glucagon-like peptide-1 (GLP-1) receptor agonist.<br>|
| Active Comparator: Tresiba<br>Tresiba® (Insulin Degludec, 100 U/mL) SC injection once daily up to Week 24 on top of non-insulin antidiabetic treatment . | Drug: Insulin degludec, 100 U/mL<br>* Self-administered by subcutaneous (SC) injection in the evening using a pre-filled pen. Dose titration to achieve fasting self-monitored plasma glucose (SMPG) from 80 to 100 mg/dL (4.4 to 5.6 mmol/L). Route of administration: subcutaneous<br>* Other names: Tresiba;Drug: Non-insulin anti-diabetic treatment<br>* Background therapy: Oral Anti diabetics Drugs (OADs), Glucagon-like peptide-1 (GLP-1) receptor agonist.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c to Week 24 | Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Adjusted Least Square (LS) means and standard errors were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data, using all post-baseline HbA1c data available during the 24-week on-treatment period. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c to Week 12 | Change in HbA1c was calculated by subtracting baseline value from Week 12 value. Adjusted least square means and standard errors were obtained from a mixed-effect model with MMRM. | Baseline, Week 12 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) to Week 12 and Week 24 | Change in FPG was calculated by subtracting baseline value from Week 12 and Week 24 value. Adjusted LS means were obtained from MMRM including post baseline values during the 24-week on-treatment period. | Baseline, Week 12 and Week 24 | 
| Change From Baseline in Fasting Self-Monitoring Plasma Glucose (SMPG) to Week 12 and Week 24 | Fasting SMPG was measured by the participant before breakfast and before the administration of the glucose-lowering agents once a day during the study. Adjusted LS means were obtained from MMRM including post baseline values during the 24 week on treatment period. | Baseline, Week 12 and Week 24 | 
| Change From Baseline in 8 Point SMPG Profile to Week 12 and Week 24 Per Time Point | 8-point SMPG profiles were measured at the following 8 points: 03:00 at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime. | Baseline, Week 12 and Week 24 | 
| Change From Baseline in 4-point SMPG Profile to Week 12 and Week 24 Per Time Point | 4-point SMPG profiles were measured at the following 4 points: prebreakfast, prelunch, predinner and bedtime. | Baseline, Week 12 and Week 24 | 
| Change From Baseline in 24-hour Average 8-point SMPG Profile to Week 12 and Week 24 | The 8-point SMPG profile was measured at the following 8 points: 03:00 at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime. Adjusted LS means were obtained from MMRM. | Baseline, Week 12 and Week 24 | 
| Change From Baseline in Variability of Fasting SMPG to Week 12 and Week 24 | Adjusted LS means were obtained from MMRM. Variability was assessed by the mean of coefficient of variation calculated over at least 3 SMPG measured during the 7 days preceding the given visit. | Baseline, Week 12 and Week 24 | 
| Change From Baseline in Variability of 24-Hour 8-Point SMPG Profiles at Week 12 and Week 24 | Adjusted LS means were obtained from MMRM. | Baseline, Week 12 and Week 24 | 
| Percentage of Participants Reaching Target HbA1c of < 7% and =<6.5% at Week 12 and Week 24 | Only the post-baseline HbA1c measurements before rescue and during the 12 week and 24-week on-treatment period were considered in the analysis. | Week 12, and Week 24 | 
| Percentage of Participants Reaching Target HbA1c <7% and =<6.5% at Week 12 and Week 24 Without Severe and/or Confirmed Hypoglycemia (70 mg/dL) Event | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycemia event was a severe event or an event confirmed by plasma glucose =<3.9 mmol/L (=<70 mg/dL). | Week 12, and Week 24 | 
| Percentage of Participants With Sulphonylurea or Meglitinide Dose Reduction/ Discontinuation Due to Hypoglycemia During 24 Weeks Treatment Period | Percentage of participants With Sulphonylurea or Meglitinide dose reduction/ discontinuation due to Hypoglycemia during 24 Week treatment period were reported. Only participants with Sulphonylurea or meglitinides at Screening as per actual strata were taken into account in this analysis. | Baseline to Week 24 | 
| Percentage of Participants Requiring a Rescue Therapy During 24 Weeks Treatment Period | Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. Threshold values at Week 12: FPG >200 mg/dL (11 mmol/L), or HbA1c >8.5%. | Baseline to Week 24 | 
| Change From Baseline in Basal Insulin Dose (U/kg Body Weight) to Week 12 and Week 24 | Only the insulin dose measurements performed before initiation of rescue therapy and during the on-treatment period were considered in the analysis. | Baseline, Week 12 and Week 24 | 
| Percentage of Participants With At Least One Hypoglycemic Events (Any, Severe and/or Confirmed Hypoglycemia: Any Time of the Day) by Study Period | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycemia event was a severe event or an event confirmed with plasma glucose =<70 mg/dL (=<3.9 mmol/L), or < 54 mg/dL (<3.0 mmol/L). Assessment was done by treatment period (for =<12 weeks, for >12 weeks to =<24 weeks (24W)). Percentage of participants with at least one hypoglycemia (hypo) event at any time of the day were reported. | Day 1-Week 12, Week 13-Week 24, and 24 Week Period | 
| Percentage of Participants With At Least One Hypoglycemic Events (Any, Severe and/or Confirmed Hypoglycemia: Nocturnal) by Study Period | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycaemia event was a severe event or an event confirmed with plasma glucose =<70 mg/dL (=<3.9 mmol/L), or < 54 mg/dL (<3.0 mmol/L). Nocturnal hypoglycemia was hypoglycemia that occurred between 00:00 and 05:59 hours (clock time). Assessment was done by treatment period (for =<12 weeks, for >12 weeks to =<24 weeks). | Day 1-Week 12, Week 13-Week 24, and 24 Week Period | 
| Hypoglycemia (Any, Severe and/or Confirmed Hypoglycemia: Any Time of the Day) Event Rate Per Participant Year During Study Period | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycemia event was a severe event or an event confirmed with plasma glucose =<70 mg/dL (=<3.9 mmol/L), or < 54 mg/dL (<3.0 mmol/L). | Day 1-Week 12, Week 13-Week 24, and 24 Week Period | 
| Hypoglycemia (Any, Severe and/or Confirmed Hypoglycemia: Nocturnal ) Event Rate Per Participant Year During Study Period | Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycemia event was a severe event or an event confirmed with plasma glucose =<70 mg/dL (=<3.9 mmol/L), or < 54 mg/dL (<3.0 mmol/L). Nocturnal hypoglycemia was hypoglycemia that occurred between 00:00 and 05:59 hours (clock time). | Day 1-Week 12, Week 13-Week 24, and 24 Week Period |