SORELLA1: Comparison of SAR342434 to Humalog as the Rapid Acting Insulin in Adult Patients With Type 1 Diabetes Mellitus Also Using Insulin Glargine

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02273180
• Collaborator: (none)
• Enrollment: 507
• Locations: 89
• Arms: 2
• Duration (Months): 21
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: SAR342434; Drug: Humalog; Drug: Insulin glargine HOE901	Phase 3

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 507 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SAR342434 SAR342434 before meals intake on top of once daily (QD) Insulin Glargine, up to Week 52.	Drug: SAR342434; 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.; Drug: Insulin glargine HOE901; 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.; Other Names: Lantus
Active Comparator: Humalog Humalog before meals intake on top of QD Insulin Glargine, up to Week 52.	Drug: Humalog; 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.; Other Names: Insulin Lispro ; Drug: Insulin glargine HOE901; 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.; Other Names: Lantus

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c From Baseline to Week 26 [Baseline, 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.

Secondary Outcome Measures

1. Percentage of Participants With HbA1c <7.0% at Week 26 [Week 26]

   Participants who had no available assessment for HbA1c at Week 26 were considered as non-responders.

2. Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 [Baseline, 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.

3. Change in Mean 24-Hour Plasma Glucose Concentration From Baseline to Week 26 [Baseline, 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.

4. Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 [Baseline, 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.

5. Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Participant-Year [First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)]

   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.

6. Percentage of Participants With Hypersensitivity Reactions and Injection Site Reactions [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 were reported.

7. Percentage of Participants With Treatment Emergent Anti-insulin Antibodies (AIAs) [First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)]

   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).

Other Outcome Measures

1. Change in Daily Insulin Dose From Baseline to Week 26 and Week 52 [Baseline, Week 26, Week 52]

   Change in daily insulin dose (basal, mealtime and total) was calculated by subtracting baseline value from Week 26 and Week 52 values respectively.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 840049	Tucson	Arizona	United States	85714
2	Investigational Site Number 840016	Bell Gardens	California	United States	90201
3	Investigational Site Number 840048	Chula Vista	California	United States	91910
4	Investigational Site Number 840046	Concord	California	United States	94520
5	Investigational Site Number 840039	Fresno	California	United States	93720
6	Investigational Site Number 840028	La Jolla	California	United States	92037
7	Investigational Site Number 840022	Ventura	California	United States	93003
8	Investigational Site Number 840003	Denver	Colorado	United States	80209
9	Investigational Site Number 840037	Denver	Colorado	United States	80262
10	Investigational Site Number 840005	Bradenton	Florida	United States	34208
11	Investigational Site Number 840061	Miami Lakes	Florida	United States	33014
12	Investigational Site Number 840057	Miami Lakes	Florida	United States	33016
13	Investigational Site Number 840050	Miami	Florida	United States	33155
14	Investigational Site Number 840042	Miami	Florida	United States	33176
15	Investigational Site Number 840006	New Port Richey	Florida	United States	34652
16	Investigational Site Number 840013	North Miami Beach	Florida	United States	33162
17	Investigational Site Number 840031	Port Charlotte	Florida	United States	33952
18	Investigational Site Number 840036	Atlanta	Georgia	United States	30318
19	Investigational Site Number 840045	Roswell	Georgia	United States	30076
20	Investigational Site Number 840020	Idaho Falls	Idaho	United States	83404
21	Investigational Site Number 840019	Chicago	Illinois	United States	60607
22	Investigational Site Number 840033	Chicago	Illinois	United States	60612
23	Investigational Site Number 840012	McHenry	Illinois	United States	60050
24	Investigational Site Number 840004	Des Moines	Iowa	United States	50314
25	Investigational Site Number 840043	Marrero	Louisiana	United States	70072
26	Investigational Site Number 840021	Metairie	Louisiana	United States	70006
27	Investigational Site Number 840038	Baltimore	Maryland	United States	21237
28	Investigational Site Number 840014	Rockville	Maryland	United States	20852
29	Investigational Site Number 840060	Great Falls	Montana	United States	59405
30	Investigational Site Number 840026	Omaha	Nebraska	United States	68114
31	Investigational Site Number 840040	Omaha	Nebraska	United States	68131
32	Investigational Site Number 840015	Albuquerque	New Mexico	United States	87106
33	Investigational Site Number 840054	Albuquerque	New Mexico	United States	87109
34	Investigational Site Number 840059	Mineola	New York	United States	11501
35	Investigational Site Number 840030	Burlington	North Carolina	United States	27215
36	Investigational Site Number 840051	Greenville	North Carolina	United States	27834
37	Investigational Site Number 840062	Wilmington	North Carolina	United States	28401
38	Investigational Site Number 840018	Gallipolis	Ohio	United States	45631
39	Investigational Site Number 840007	Dakota Dunes	South Dakota	United States	57049
40	Investigational Site Number 840027	Rapid City	South Dakota	United States	57701
41	Investigational Site Number 840041	Dallas	Texas	United States	75230
42	Investigational Site Number 840029	Dallas	Texas	United States	75231
43	Investigational Site Number 840034	Dallas	Texas	United States	75246
44	Investigational Site Number 840002	Houston	Texas	United States	77090
45	Investigational Site Number 840011	Chesapeake	Virginia	United States	23321
46	Investigational Site Number 840023	Tacoma	Washington	United States	98415-0299
47	Investigational Site Number 840009	Milwaukee	Wisconsin	United States	53209-0996
48	Investigational Site Number 250002	Corbeil Essonnes		France	91100
49	Investigational Site Number 250005	Mantes La Jolie		France	78200
50	Investigational Site Number 250003	Montpellier Cedex 5		France	34295
51	Investigational Site Number 250001	Vandoeuvre Les Nancy		France	54511
52	Investigational Site Number 276001	Berlin		Germany	10115
53	Investigational Site Number 276004	Dortmund		Germany	44137
54	Investigational Site Number 276006	Hannover		Germany	30159
55	Investigational Site Number 276002	Heidelberg		Germany	69115
56	Investigational Site Number 276003	Neumünster		Germany	24534
57	Investigational Site Number 276008	Pirna		Germany	01796
58	Investigational Site Number 276007	Potsdam		Germany	14469
59	Investigational Site Number 276005	Sulzbach-Rosenberg		Germany	92237
60	Investigational Site Number 348002	Budapest		Hungary	1023
61	Investigational Site Number 348005	Budapest		Hungary	1033
62	Investigational Site Number 348003	Budapest		Hungary	1062
63	Investigational Site Number 348011	Budapest		Hungary	1062
64	Investigational Site Number 348010	Budapest		Hungary	1139
65	Investigational Site Number 348001	Budapest		Hungary	1213
66	Investigational Site Number 348007	Debrecen		Hungary	4031
67	Investigational Site Number 392006	Chuo-Ku		Japan
68	Investigational Site Number 392003	Higashiosaka-Shi		Japan
69	Investigational Site Number 392004	Izumisano-Shi		Japan
70	Investigational Site Number 392005	Kamakura-Shi		Japan
71	Investigational Site Number 392001	Shinjuku-Ku		Japan
72	Investigational Site Number 392002	Yamato-Shi		Japan
73	Investigational Site Number 616005	Krakow		Poland	31-501
74	Investigational Site Number 616001	Poznan		Poland	60-834
75	Investigational Site Number 616003	Szczecin		Poland	70-506
76	Investigational Site Number 616002	Warszawa		Poland	02-507
77	Investigational Site Number 616004	Zabrze		Poland	41-800
78	Investigational Site Number 643003	Moscow		Russian Federation	117036
79	Investigational Site Number 643006	Samara		Russian Federation	443041
80	Investigational Site Number 643002	Saratov		Russian Federation	410030
81	Investigational Site Number 643004	St-Petersburg		Russian Federation	190068
82	Investigational Site Number 643001	St-Petersburg		Russian Federation	194354
83	Investigational Site Number 643005	St-Petersburg		Russian Federation	195257
84	Investigational Site Number 643007	Tomsk		Russian Federation	634050
85	Investigational Site Number 724002	A Coruña		Spain	15006
86	Investigational Site Number 724001	Cáceres		Spain	10003
87	Investigational Site Number 724004	Lérida		Spain	25198
88	Investigational Site Number 724005	Málaga		Spain	29010
89	Investigational Site Number 724003	Sabadell		Spain	08208

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

• Garg SK, Wernicke-Panten K, Rojeski M, Pierre S, Kirchhein Y, Jedynasty K. Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 1 Diabetes Also Using Insulin Glargine-SORELLA 1 Study. Diabetes Technol Ther. 2017 Sep;19(9):516-526. doi: 10.1089/dia.2017.0117. Epub 2017 Aug 30. Erratum in: Diabetes Technol Ther. 2017 Dec;19(12):753.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT02273180
• Other Study ID Numbers: EFC12619; 2013-002945-12; U1111-1131-5038
• First Posted: Oct 23, 2014
• Last Update Posted: Jan 18, 2018
• Last Verified: Dec 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro

Study Results

Participant Flow

Recruitment Details	The study was conducted at 89 centres in 8 countries. A total of 668 participants were screened between 28 October 2014 and 04 June 2015, of which 161 participants were screen failures. Screen failures were mainly due to glycated hemoglobin A1c (HbA1c) level <7.0% or >10% at the screening visit.
Pre-assignment Detail	A total of 507 participants were randomized in the study. Randomization was stratified by HbA1c at the screening visit (<8%, >=8%), prior use of Humalog/Liprolog (Yes, No) and geographical region (Non-Japan, Japan). Assignment to arms was done centrally using interactive voice/web response system in 1:1 ratio (SAR342434: Humalog).

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 Units(U)/mL subcutaneous (SC) injection, before meals intake on top of once daily (QD) Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Period Title: Overall Study
STARTED	253	254
Treated	252	254
COMPLETED	226	235
NOT COMPLETED	27	19

Baseline Characteristics

Arm/Group Title	SAR342434	Humalog	Total
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Total of all reporting groups
Overall Participants	253	254	507
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.3 (14.5)	42.6 (13.9)	43.0 (14.2)
Sex: Female, Male (Count of Participants)
Female	104 41.1%	101 39.8%	205 40.4%
Male	149 58.9%	153 60.2%	302 59.6%
Previous mealtime insulin type (Count of Participants)
Humalog/Liprolog	155 61.3%	152 59.8%	307 60.6%
NovoLog/NovoRapid	95 37.5%	95 37.4%	190 37.5%
Both Humalog/Liprolog and NovoLog/NovoRapid	3 1.2%	7 2.8%	10 2%
Randomization Strata of Screening HbA1c (Count of Participants)
<8 %	99 39.1%	99 39%	198 39.1%
>=8%	154 60.9%	155 61%	309 60.9%
Randomization strata of geographical region (Count of Participants)
Japan	31 12.3%	30 11.8%	61 12%
Non-Japan	222 87.7%	224 88.2%	446 88%
Body mass index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.2 (4)	25.8 (4.1)	26.0 (4.1)
Duration of Diabetes Type 1(T1DM) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19.53 (12.63)	18.57 (11.99)	19.05 (12.31)
Average Daily Basal Insulin Dose (Units (U)/kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units (U)/kg]	0.339 (0.195)	0.33 (0.141)	0.335 (0.170)
Average Daily Mealtime Insulin Dose (U/kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/kg]	0.364 (0.175)	0.355 (0.168)	0.360 (0.172)
Average Daily Total Insulin Dose (U/kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/kg]	0.704 (0.309)	0.685 (0.242)	0.695 (0.278)
Glycated Haemoglobin (HbA1c %) (percentage of hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of hemoglobin]	8.07 (0.79)	7.99 (0.64)	8.03 (0.72)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline to Week 26
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on intent-to-treat (ITT) population that included all randomized participants, irrespective of compliance with the study protocol and procedures. Here, number of participants analyzed = participants with at least one post-baseline HbA1c assessment during the main 6-month period.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	247	249
Least Squares Mean (Standard Error) [percentage of HbA1c]	-0.42 (0.051)	-0.47 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SAR342434, Humalog
	Comments	Analysis was performed using a MMRM approach with treatment groups, randomization strata, visits and treatment-by-visit interaction as fixed categorical effects, and baseline HbA1c value and baseline HbA1c value-by-visit interaction as continuous fixed covariates. An unstructured correlation matrix was used to model within-participant errors.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of SAR342434 over Humalog was demonstrated if upper bound of 2-sided 95% confidence interval(CI) of difference between SAR342434 & Humalog was <0.3%.Inverse non-inferiority of Humalog over SAR342434 was tested using hierarchical step-down testing procedure:if non-inferiority of SAR342434 over Humalog was demonstrated,then inverse non-inferiority of Humalog over SAR342434 was tested, demonstrated if lower bound of 2-sided 95%CI of difference between SAR342434 & Humalog was >-0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.084 to 0.197
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.071
	Estimation Comments	SAR342434 vs. Humalog

2. Secondary Outcome

Title	Percentage of Participants With HbA1c <7.0% at Week 26
Description	Participants who had no available assessment for HbA1c at Week 26 were considered as non-responders.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	253	254
Number [percentage of participants]	22.5 8.9%	21.7 8.5%

3. Secondary Outcome

Title	Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, number of participants analyzed = participants with at least one post-baseline FPG assessment during the main 6-month period.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	240	242
Least Squares Mean (Standard Error) [mmol/L]	-0.46 (0.248)	-0.62 (0.248)

4. Secondary Outcome

Title	Change in Mean 24-Hour Plasma Glucose Concentration From Baseline to Week 26
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, number of participants analyzed = participants with at least one post-baseline mean 24-hour plasma glucose concentration assessment during the main 6-month period.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	216	207
Least Squares Mean (Standard Error) [mmol/L]	-0.23 (0.145)	-0.49 (0.148)

5. Secondary Outcome

Title	Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, number analyzed in each row = participants with at least one post-baseline data during the main 6-month period for specified categories.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	253	254
At breakfast	-0.46 (0.297)	0.19 (0.297)
At lunch	0.14 (0.298)	-0.26 (0.309)
At dinner	0.48 (0.308)	0.56 (0.324)

6. Secondary Outcome

Title	Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Participant-Year
Description	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.
Time Frame	First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population that included all participants randomized and exposed to at least 1 dose of investigational medicinal product (IMP) (SAR342434 or Humalog), regardless of the amount of treatment administered.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	252	254
Any hypoglycemia	90.71	92.7
Severe hypoglycemia	0.73	0.28
Documented Symptomatic Hypoglycemia (<=3.9 mmol/L)	29.36	31.37
Documented Symptomatic Hypoglycemia (<3.0 mmol/L)	6.29	6.85

7. Secondary Outcome

Title	Percentage of Participants With Hypersensitivity Reactions and Injection Site Reactions
Description	Percentage of participants with hypersensitivity reactions and injection site reactions were reported.
Time Frame	First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	252	254
Any hypersensitivity reactions	6 2.4%	6.3 2.5%
Any injection site reactions	1.2 0.5%	1.2 0.5%

8. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent Anti-insulin Antibodies (AIAs)
Description	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).
Time Frame	First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)

Outcome Measure Data

Analysis Population Description

Analysis was performed on anti-insulin antibody population that included all participants randomized and exposed to at least 1 dose of IMP (SAR342434 or Humalog) with at least one AIA sample available for analysis during the 12-month on-treatment period.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	248	252
Number [percentage of participants]	22.6 8.9%	24.2 9.5%

9. Other Pre-specified Outcome

Title	Change in Daily Insulin Dose From Baseline to Week 26 and Week 52
Description	Change in daily insulin dose (basal, mealtime and total) was calculated by subtracting baseline value from Week 26 and Week 52 values respectively.
Time Frame	Baseline, Week 26, Week 52

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population. Here, number analyzed in each row = participants with available data for specified categories.

Arm/Group Title	SAR342434	Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Measure Participants	252	254
Basal insulin dose at Week 26	0.03 (0.236)	0.014 (0.06)
Mealtime insulin dose at Week 26	0.005 (0.112)	-0.005 (0.089)
Total insulin dose at Week 26	0.019 (0.134)	0.01 (0.111)
Basal insulin dose at Week 52	0.046 (0.364)	0.013 (0.066)
Mealtime insulin dose at Week 52	0.018 (0.117)	0.007 (0.104)
Total insulin dose at Week 52	0.039 (0.135)	0.019 (0.127)

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (maximum treatment exposure: 400 days) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported AEs and deaths are treatment emergent AEs that is AEs that developed/worsened or became serious and deaths that occurred during the 'on treatment period' (time from first injection of IMP up to 1 day after the last injection of IMP). Analysis was performed on safety population.
Arm/Group Title	SAR342434		Humalog
Arm/Group Description	SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.		Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
All Cause Mortality
	SAR342434		Humalog
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/252 (0.4%)		0/254 (0%)
Serious Adverse Events
	SAR342434		Humalog
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/252 (7.9%)		19/254 (7.5%)
Cardiac disorders
Acute myocardial infarction	1/252 (0.4%)		0/254 (0%)
Atrial fibrillation	0/252 (0%)		1/254 (0.4%)
Gastrointestinal disorders
Abdominal pain	0/252 (0%)		1/254 (0.4%)
Enterocolitis haemorrhagic	1/252 (0.4%)		0/254 (0%)
Vomiting	1/252 (0.4%)		0/254 (0%)
General disorders
Cardiac death	1/252 (0.4%)		0/254 (0%)
Hepatobiliary disorders
Cholangitis	1/252 (0.4%)		0/254 (0%)
Infections and infestations
Cellulitis	1/252 (0.4%)		1/254 (0.4%)
Gastroenteritis viral	0/252 (0%)		1/254 (0.4%)
Gastrointestinal viral infection	0/252 (0%)		1/254 (0.4%)
Injury, poisoning and procedural complications
Accidental overdose	3/252 (1.2%)		2/254 (0.8%)
Clavicle fracture	0/252 (0%)		1/254 (0.4%)
Joint injury	1/252 (0.4%)		0/254 (0%)
Radius fracture	0/252 (0%)		1/254 (0.4%)
Rib fracture	0/252 (0%)		2/254 (0.8%)
Spinal compression fracture	0/252 (0%)		1/254 (0.4%)
Wrong drug administered	0/252 (0%)		1/254 (0.4%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/252 (0%)		1/254 (0.4%)
Diabetic ketoacidosis	1/252 (0.4%)		2/254 (0.8%)
Hyperkalaemia	0/252 (0%)		1/254 (0.4%)
Hypoglycaemia	3/252 (1.2%)		3/254 (1.2%)
Hypokalaemia	0/252 (0%)		1/254 (0.4%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/252 (0.4%)		0/254 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	1/252 (0.4%)		0/254 (0%)
Nervous system disorders
Cerebral infarction	1/252 (0.4%)		0/254 (0%)
Cerebral ventricle dilatation	0/252 (0%)		1/254 (0.4%)
Cerebrovascular accident	1/252 (0.4%)		0/254 (0%)
Dizziness	1/252 (0.4%)		0/254 (0%)
Hypoglycaemic coma	0/252 (0%)		1/254 (0.4%)
Hypoglycaemic seizure	0/252 (0%)		1/254 (0.4%)
Hypoglycaemic unconsciousness	6/252 (2.4%)		6/254 (2.4%)
Migraine	1/252 (0.4%)		0/254 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion threatened	0/252 (0%)		1/254 (0.4%)
Renal and urinary disorders
Acute kidney injury	0/252 (0%)		1/254 (0.4%)
Reproductive system and breast disorders
Ovarian cyst	0/252 (0%)		1/254 (0.4%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/252 (0%)		1/254 (0.4%)
Social circumstances
Pregnancy of partner	0/252 (0%)		1/254 (0.4%)
Surgical and medical procedures
Gastrectomy	0/252 (0%)		1/254 (0.4%)
Other (Not Including Serious) Adverse Events
	SAR342434		Humalog
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/252 (18.3%)		41/254 (16.1%)
Infections and infestations
Nasopharyngitis	33/252 (13.1%)		28/254 (11%)
Upper respiratory tract infection	15/252 (6%)		14/254 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.