Comparison of SAR342434 to Humalog as the Rapid Acting Insulin in Adult Patients With Type 1 Diabetes Mellitus Also Using Insulin Glargine

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To demonstrate non-inferiority of SAR342434 versus Humalog in glycated haemoglobin A1c (HbA1c) change from baseline to Week 26 in participants with type 1 diabetes mellitus (T1DM) also using insulin glargine. Secondary Objectives: To assess the immunogenicity of SAR342434 and Humalog in terms of positive/negative status and antibody titers at baseline and during the course of the study. To assess the relationship of anti-insulin antibodies with efficacy and safety including during the safety extension. To assess the efficacy of SAR342434 and Humalog in terms of proportion of participants reaching target HbA1c (<7%), Fasting plasma glucose (FPG), self-measured plasma glucose (SMPG) profiles, and insulin dose. To assess safety of SAR342434 and Humalog.

Detailed Description
-----------------
The study consisted of a: Up to 2 weeks screening period 26-week treatment period 26-week comparative safety extension period 1-day follow-up period The maximum study duration would be 54 weeks per participant and a 1-day safety follow-up

Official Title
-----------------
Six-Month, Randomized, Open-Label, Parallel-group Comparison of SAR342434 to Humalog® in Adult Patients With Type 1 Diabetes Mellitus Also Using Insulin Glargine, With a 6-month Safety Extension Period

Conditions
-----------------
Type 1 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: SAR342434
* Drug: Humalog
* Drug: Insulin glargine HOE901


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Participants with T1DM diagnosed for at least 12 months and had been treated with insulin glargine and Humalog or Novolog®/Novo Rapid® (at least 3 times daily before each meal) in the 6 months prior to the screening visit. Written informed consent. Exclusion criteria: At screening visit, age under legal age of adulthood. HbA1c <7.0% or >10% at screening. Diabetes other than T1DM. Status post pancreatectomy. Status post pancreas and/or islet cell transplantation. Pregnancy and lactation. Women of childbearing potential not protected by highly effective contraceptive method of birth control. Less than 1 year on continuous insulin treatment. Use of insulin pump in the last 6 months before screening visit. Use of glucose lowering treatments other than insulin including non-insulin injectable peptides in the last 6 months prior to screening visit. Use of insulin other than insulin glargine and Humalog or Novolog/Novo Rapid as part of a multiple injection regimen (3 to 4 injections per day) in the last 6 months before screening visit. Liprolog® is a European Union approved insulin lispro and is allowed in those countries where it is marketed. Hospitalization for diabetic ketoacidosis in the last 6 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. 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: SAR342434<br>SAR342434 before meals intake on top of once daily (QD) Insulin Glargine, up to Week 52. | Drug: SAR342434<br>* SAR342434 100 U/mL (dose range of 1 Unit to 80 Units) self-administered by deep subcutaneous (SC) injection, immediately (within 5-10 minutes) before meal intake. Dose adjusted to achieve a 2-hour post prandial plasma glucose (PPG) in range of 6.7 to 8.9 mmol/L (120 to 160 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 (SMPG) between 4.4 to 7.2 mmol/L (80 to 130 mg/dL) without hypoglycemia.<br>* Other names: Lantus;|
| Active Comparator: Humalog<br>Humalog before meals intake on top of QD Insulin Glargine, up to Week 52. | Drug: Humalog<br>* Humalog 100 U/mL (dose range of 1 unit to 60 units) self-administered by deep SC injection, immediately (within 5-10 minutes) before meal intake. Dose adjusted to achieve a 2 hour PPG in range of 6.7 to 8.9 mmol/L (120 to 160 mg/dL) while avoiding hypoglycaemia.<br>* Other names: Insulin Lispro;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 (SMPG) between 4.4 to 7.2 mmol/L (80 to 130 mg/dL) without hypoglycemia.<br>* Other names: Lantus;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 26 | Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Adjusted least square 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 main 6-month period and adequate contrasts at Week 26. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HbA1c <7.0% at Week 26 | Participants who had no available assessment for HbA1c at Week 26 were considered as non-responders. | Week 26 | 
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | Change in FPG was calculated by subtracting baseline value from Week 26 value. Adjusted least squares means and standard errors were obtained from a MMRM approach to account for missing data, using all post-baseline FPG data available during the main 6-month period and adequate contrasts at Week 26. | Baseline, Week 26 | 
| Change in Mean 24-Hour Plasma Glucose Concentration From Baseline to Week 26 | 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 week before a visit. Change in mean 24-hour plasma glucose concentration was calculated by subtracting baseline value from Week 26 value. Adjusted least squares means and standard errors were obtained from a MMRM to account for missing data, using all post-baseline data available during the main 6-month period and adequate contrasts at Week 26. | Baseline, Week 26 | 
| Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 | 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 average across the profiles performed in the week before the visit. Change in PPG excursions was calculated by subtracting baseline value from Week 26 value. Adjusted least squares means and standard errors were obtained from a MMRM to account for missing data, using all post-baseline data available during the main 6-month period and adequate contrasts at Week 26. | Baseline, Week 26 | 
| Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Participant-Year | Number of treatment-emergent hypoglycemia events 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. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=70 mg/dL (3.9 mmol/L). Hypoglycemic episodes with plasma glucose of 54 mg/dL (<3.0 mmol/L) were also analyzed. | First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days) | 
| Percentage of Participants With Hypersensitivity Reactions and Injection Site Reactions | Percentage of participants with hypersensitivity reactions and injection site reactions were reported. | First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days) | 
| Percentage of Participants With Treatment Emergent Anti-insulin Antibodies (AIAs) | Participants with treatment-emergent AIA (incidence) were reported (as participants with treatment-boosted or treatment-induced AIAs). 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). 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, in those participants with pre-existing AIA). | First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days) |