Comparison of SAR341402 to NovoLog/NovoRapid in Adult Patients With Diabetes Mellitus Also Using Insulin Glargine

Study Overview
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Brief Summary
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Primary Objective: To demonstrate non-inferiority of SAR341402 versus NovoLog/NovoRapid in glycated hemoglobin A1c (HbA1c) change from baseline to Week 26 in participants with type 1 or type 2 diabetes mellitus (T1DM or T2DM) also using Lantus®. Secondary Objectives: To assess the immunogenicity of SAR341402 and NovoLog/NovoRapid in terms of positive/negative status and anti-insulin antibody (AIA) titers during the course of the study. To assess the relationship of AIAs with efficacy and safety. To assess the efficacy of SAR341402 and NovoLog/NovoRapid in terms of proportion of participants reaching HbA1c lesser than (<) 7.0% and change in HbA1c, fasting plasma glucose (FPG), and self-measured plasma glucose (SMPG) profiles from baseline to Week 26 and Week 52 (only Week 52 for HbA1c). To assess safety of SAR341402 and NovoLog/NovoRapid.

Detailed Description
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The study consisted of a 2-week screening period, a 26-week treatment period, a 26-week comparative safety extension period, and a 1-day follow-up period. The maximum study duration was 54 weeks per participant and a 1 day safety follow-up.

Official Title
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Six-month, Randomized, Open-label, Parallel-group Comparison of SAR341402 to NovoLog®/NovoRapid® in Adult Patients With Diabetes Mellitus Also Using Insulin Glargine, With a 6-month Safety Extension Period

Conditions
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Type 1 Diabetes Mellitus-Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin aspart
* Drug: NovoLog/NovoRapid
* Drug: Insulin glargine (HOE901)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with T1DM or T2DM (T2DM US only) diagnosed for at least 12 months, who have been treated with a multiple daily injection regimen with NovoLog/NovoRapid or insulin lispro (100 U/mL) in the last 6 months prior to screening visit AND insulin glargine (100 U/mL) in the last 6 months prior to screening visit OR insulin detemir (Levemir®) in the last 12 months prior to screening visit. Exclusion criteria: At screening visit, age under legal age of adulthood. HbA1c <7.0% or greater than (>) 10% at screening. Less than 1 year on continuous insulin treatment. Use of insulin pump in the last 3 months before screening visit. Participants with incomplete baseline 7-point SMPG profile, defined as participants who do not have 7-point profiles with at least 5 points on at least 2 days in the week before randomization Visit 3. Participants with T1DM: Use of glucose lowering agents other than insulin including use of non-insulin injectable peptides in the last 3 months prior to screening. Participants with T2DM: Use of glucagon-like peptide-1 (GLP-1) receptor agonists in the last 3 months before screening visit. Use of oral antidiabetic drugs (OADs) not on stable dose in the last 3 months before screening visit (sulfonylureas was discontinued at baseline). At screening visit, body mass index (BMI) greater than or equal to (>=) 35 kilogram per meter square (kg/m^2) in participants with T1DM and >=40 kg/m^2 in participants with T2DM. Use of insulin other than: insulin glargine 100 U/mL and NovoLog/NovoRapid or insulin lispro 100 U/mL as part of a multiple injection regimen in the last 6 months before screening visit, OR insulin detemir 100 U/mL in the 12 months before screening visit and NovoLog/NovoRapid or insulin lispro 100 U/mL in the last 6 months before screening visit as part of a multiple injection regimen. Status post pancreatectomy. Status post pancreas and/or islet cell transplantation. Hospitalization for recurrent diabetic ketoacidosis in the last 3 months before screening visit. History of severe hypoglycemia requiring Emergency Room admission or hospitalization in the last 3 months before screening visit. 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. Pregnant or breastfeeding women. Women of childbearing potential not protected by highly effective method(s) of birth control. 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
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR341402<br>SAR341402 subcutaneous (SC), before meals intake on top of once daily (QD) Insulin Glargine, up to Week 52. | Drug: Insulin aspart<br>* SAR341402 100 units per milliliters (U/mL) (dose range of 1 unit to 80 units) self-administered by SC injection, immediately (within 5-10 minutes) before meal intake. Dose adjusted to achieve a 2-hour postprandial plasma glucose (PPG <10 millimoles/liter [mmol/L] [<180 milligram/deciliter {mg/dL}]) while avoiding hypoglycemia.<br>Drug: Insulin glargine (HOE901)<br>* Insulin glargine 100 U/mL injected QD subcutaneously consistent with the local label. Doses adjusted to achieve glycemic target for fasting, preprandial plasma glucose between 4.4 to 7.2 mmol/L (80 to 130 mg/dL) without hypoglycemia.<br>* Other names: Lantus;|
| Active Comparator: NovoLog/NovoRapid<br>NovoLog/NovoRapid SC, before meals intake on top of QD Insulin Glargine, up to Week 52. | Drug: NovoLog/NovoRapid<br>* NovoLog/NovoRapid 100 U/mL (dose range of 1 unit to 60 units) self-administered by SC injection, immediately (within 5-10 minutes) before meal intake. Dose adjusted to achieve a 2-hour postprandial plasma glucose (PPG <10 mmol/L [<180 mg/dL]) while avoiding hypoglycemia.<br>* Other names: Insulin aspart;Drug: Insulin glargine (HOE901)<br>* Insulin glargine 100 U/mL injected QD subcutaneously consistent with the local label. Doses adjusted to achieve glycemic target for fasting, preprandial plasma glucose between 4.4 to 7.2 mmol/L (80 to 130 mg/dL) without hypoglycemia.<br>* Other names: Lantus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycated Hemoglobin A1c (HbA1c) From Baseline to Week 26 | All values up to Week 26 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Missing changes at Week 26 were imputed using a retrieved dropout multiple imputation method (separately for participants who prematurely discontinued or completed treatment). Adjusted least square (LS) means and standard errors (SE) were obtained using an analysis of covariance (ANCOVA) model on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 52 | All values up to Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c was calculated by subtracting baseline value from Week 52 value. Missing changes at Week 52 were imputed using a retrieved dropout multiple imputation method (separately for participants who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA model on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 52 | 
| Percentage of Participants With HbA1c <7% at Week 26 and Week 52 | Participants who had no available assessment at Week 26 and Week 52 were considered as non-responders. | Week 26 and Week 52 | 
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 and Week 52 | All values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in FPG at Week 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a retrieved dropout multiple imputation method (separately for participants who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26, and Week 52 | 
| Change in the Mean 24-hour Plasma Glucose Concentration From Baseline to Week 26 and Week 52 | Mean 24-hour plasma glucose concentration was calculated based on 7-point self-measured plasma glucose (SMPG) profiles with plasma glucose measurements before and 2-hours after each main meal and at bedtime. Mean 24-hour plasma glucose concentration was calculated for each profile and then averaged across profiles performed in the week before a visit. All calculated values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in mean 24-hour plasma glucose concentration at Weeks 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a return-to-baseline multiple imputation method (values imputed as participant baseline plus an error). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26, and Week 52 | 
| Change in Postprandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 and Week 52 | Plasma glucose excursions were calculated at breakfast, lunch and dinner for each 7-point SMPG profile, as 2-hour PPG minus plasma glucose value obtained 30 minutes prior to start of the meal. Values of plasma glucose excursions at each visit were then calculated as the average across profiles performed in the week before the visit. All calculated values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in PPG excursions at Weeks 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a return-to-baseline multiple imputation method (values imputed as participant baseline plus an error). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin's formulae). | Baseline, Week 26, and Week 52 | 
| Change in 7-Point SMPG Profiles From Baseline to Week 26 and Week 52 Per Time Point | 7-point SMPG profiles were measured at the following 7 points at each visit (Baseline, Week 26, and Week 52): before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, and bedtime. For each time point, the value at each visit was calculated as the average of values obtained for the same time point across profiles performed in the week before the visit. | Baseline, Week 26, and Week 52 | 
| Number of Participants With at Least One Hypoglycemic 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, because the participant was not capable of helping self. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=3.9 mmol/L (<=70 mg/dL) or plasma glucose level of <3.0 mmol/L (<54 mg/dL). | From first injection of investigational medicinal product (IMP) up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | 
| Number of Hypoglycemia Events Per Participant-Year | Number of hypoglycemia events (any, severe and documented [both thresholds]) per participant-year of exposure were reported. Severe hypoglycemia was an event in which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the participant was not capable of helping self. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=3.9 mmol/L (<=70 mg/dL) or plasma glucose level of <3.0 mmol/L (<54 mg/dL). | From first injection of investigational medicinal product (IMP) up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | 
| Percentage of Participants With Hypersensitivity Reactions and Injection Site Reactions | Participants with at least one treatment-emergent adverse event linked to hypersensitivity reaction and injection site reaction regardless of relationship to IMP during the main 6-month and the 12-month on-treatment periods was assessed and reported. | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | 
| Percentage of Participants With at Least One Positive Anti-Insulin Aspart Antibodies (AIA) Sample | Participants with at least one positive AIA sample at baseline or at any time during the on-treatment period (Prevalence). | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 | 
| Percentage of Participants With Treatment-Induced, Treatment-Boosted and Treatment-Emergent Anti-insulin Aspart Antibodies (AIAs) | AIA incidence were categorized as: treatment-induced, treatment-boosted AIAs, and treatment-emergent AIA. 1) Participants with treatment-induced AIAs were those who developed AIA following IMP administration (participants with at least one positive AIA sample at any time during on-treatment period, in those participants without pre-existing AIA or with missing baseline sample). 2) Participants with treatment-boosted AIAs were those with pre-existing AIAs that were boosted to a significant higher titer following IMP administration (participants with at least one AIA sample with at least a 4-fold increase in titers compared to baseline value at any time during on-treatment period). 3) Participants with treatment-emergent AIA were defined as participants with treatment-induced, or treatment-boosted AIAs. | From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52 |