Trial Outcomes & Findings for Comparison of SAR342434 to Humalog as the Rapid Acting Insulin in Adult Patients With Type 1 Diabetes Mellitus Also Using Insulin Glargine (NCT NCT02273180)

Last Updated: 2018-01-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

507 participants

Primary outcome timeframe

Baseline, Week 26

Results posted on

2018-01-18

Participant Flow

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.

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).

Participant milestones

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

Reasons for withdrawal

Reasons for withdrawal
Measure	SAR342434 SAR342434 100 Units(U)/mL subcutaneous (SC) injection, before meals intake on top of once daily (QD) Insulin Glargine, up to Week 52.	Humalog Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Overall Study Adverse Event	2	2
Overall Study Lack of Efficacy	1	0
Overall Study Protocol Violation	1	7
Overall Study Randomized but not treated	1	0
Overall Study Hypoglycemia(not reported as serious AE)	1	0
Overall Study Other than specified above	21	10

Baseline Characteristics

Number of participants analyzed = participants with available data for specified measure.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SAR342434 n=253 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=254 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Total n=507 Participants Total of all reporting groups
Age, Continuous	43.3 years STANDARD_DEVIATION 14.5 • n=253 Participants	42.6 years STANDARD_DEVIATION 13.9 • n=254 Participants	43.0 years STANDARD_DEVIATION 14.2 • n=507 Participants
Sex: Female, Male Female	104 Participants n=253 Participants	101 Participants n=254 Participants	205 Participants n=507 Participants
Sex: Female, Male Male	149 Participants n=253 Participants	153 Participants n=254 Participants	302 Participants n=507 Participants
Previous mealtime insulin type Humalog/Liprolog	155 Participants n=253 Participants	152 Participants n=254 Participants	307 Participants n=507 Participants
Previous mealtime insulin type NovoLog/NovoRapid	95 Participants n=253 Participants	95 Participants n=254 Participants	190 Participants n=507 Participants
Previous mealtime insulin type Both Humalog/Liprolog and NovoLog/NovoRapid	3 Participants n=253 Participants	7 Participants n=254 Participants	10 Participants n=507 Participants
Randomization Strata of Screening HbA1c <8 %	99 Participants n=253 Participants	99 Participants n=254 Participants	198 Participants n=507 Participants
Randomization Strata of Screening HbA1c >=8%	154 Participants n=253 Participants	155 Participants n=254 Participants	309 Participants n=507 Participants
Randomization strata of geographical region Japan	31 Participants n=253 Participants	30 Participants n=254 Participants	61 Participants n=507 Participants
Randomization strata of geographical region Non-Japan	222 Participants n=253 Participants	224 Participants n=254 Participants	446 Participants n=507 Participants
Body mass index (BMI)	26.2 kg/m^2 STANDARD_DEVIATION 4 • n=253 Participants	25.8 kg/m^2 STANDARD_DEVIATION 4.1 • n=254 Participants	26.0 kg/m^2 STANDARD_DEVIATION 4.1 • n=507 Participants
Duration of Diabetes Type 1(T1DM)	19.53 years STANDARD_DEVIATION 12.63 • n=253 Participants	18.57 years STANDARD_DEVIATION 11.99 • n=254 Participants	19.05 years STANDARD_DEVIATION 12.31 • n=507 Participants
Average Daily Basal Insulin Dose	0.339 Units (U)/kg STANDARD_DEVIATION 0.195 • n=245 Participants • Number of participants analyzed = participants with available data for specified measure.	0.33 Units (U)/kg STANDARD_DEVIATION 0.141 • n=245 Participants • Number of participants analyzed = participants with available data for specified measure.	0.335 Units (U)/kg STANDARD_DEVIATION 0.170 • n=490 Participants • Number of participants analyzed = participants with available data for specified measure.
Average Daily Mealtime Insulin Dose	0.364 U/kg STANDARD_DEVIATION 0.175 • n=241 Participants • Number of participants analyzed = participants with available data for specified measure.	0.355 U/kg STANDARD_DEVIATION 0.168 • n=244 Participants • Number of participants analyzed = participants with available data for specified measure.	0.360 U/kg STANDARD_DEVIATION 0.172 • n=485 Participants • Number of participants analyzed = participants with available data for specified measure.
Average Daily Total Insulin Dose	0.704 U/kg STANDARD_DEVIATION 0.309 • n=239 Participants • Number of participants analyzed = participants with available data for specified measure.	0.685 U/kg STANDARD_DEVIATION 0.242 • n=241 Participants • Number of participants analyzed = participants with available data for specified measure.	0.695 U/kg STANDARD_DEVIATION 0.278 • n=480 Participants • Number of participants analyzed = participants with available data for specified measure.
Glycated Haemoglobin (HbA1c %)	8.07 percentage of hemoglobin STANDARD_DEVIATION 0.79 • n=253 Participants	7.99 percentage of hemoglobin STANDARD_DEVIATION 0.64 • n=254 Participants	8.03 percentage of hemoglobin STANDARD_DEVIATION 0.72 • n=507 Participants

PRIMARY outcome

Timeframe: Baseline, Week 26

Population: 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.

Outcome measures

Outcome measures
Measure	SAR342434 n=247 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=249 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Change in HbA1c From Baseline to Week 26	-0.42 percentage of HbA1c Standard Error 0.051	-0.47 percentage of HbA1c Standard Error 0.05

SECONDARY outcome

Timeframe: Week 26

Population: Analysis was performed on ITT population.

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

Outcome measures

Outcome measures
Measure	SAR342434 n=253 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=254 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Percentage of Participants With HbA1c <7.0% at Week 26	22.5 percentage of participants	21.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: 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.

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.

Outcome measures

Outcome measures
Measure	SAR342434 n=240 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=242 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26	-0.46 mmol/L Standard Error 0.248	-0.62 mmol/L Standard Error 0.248

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: 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.

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.

Outcome measures

Outcome measures
Measure	SAR342434 n=216 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=207 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Change in Mean 24-Hour Plasma Glucose Concentration From Baseline to Week 26	-0.23 mmol/L Standard Error 0.145	-0.49 mmol/L Standard Error 0.148

SECONDARY outcome

Timeframe: Baseline, Week 26

Population: 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.

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.

Outcome measures

Outcome measures
Measure	SAR342434 n=253 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=254 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 At breakfast	-0.46 mmol/L Standard Error 0.297	0.19 mmol/L Standard Error 0.297
Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 At lunch	0.14 mmol/L Standard Error 0.298	-0.26 mmol/L Standard Error 0.309
Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 At dinner	0.48 mmol/L Standard Error 0.308	0.56 mmol/L Standard Error 0.324

SECONDARY outcome

Timeframe: First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	SAR342434 n=252 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=254 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Participant-Year Any hypoglycemia	90.71 events per participant-year	92.7 events per participant-year
Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Participant-Year Severe hypoglycemia	0.73 events per participant-year	0.28 events per participant-year
Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Participant-Year Documented Symptomatic Hypoglycemia (<=3.9 mmol/L)	29.36 events per participant-year	31.37 events per participant-year
Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Participant-Year Documented Symptomatic Hypoglycemia (<3.0 mmol/L)	6.29 events per participant-year	6.85 events per participant-year

SECONDARY outcome

Timeframe: First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)

Population: Analysis was performed on safety population.

Percentage of participants with hypersensitivity reactions and injection site reactions were reported.

Outcome measures

Outcome measures
Measure	SAR342434 n=252 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=254 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Percentage of Participants With Hypersensitivity Reactions and Injection Site Reactions Any hypersensitivity reactions	6 percentage of participants	6.3 percentage of participants
Percentage of Participants With Hypersensitivity Reactions and Injection Site Reactions Any injection site reactions	1.2 percentage of participants	1.2 percentage of participants

SECONDARY outcome

Timeframe: First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)

Population: 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.

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).

Outcome measures

Outcome measures
Measure	SAR342434 n=248 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=252 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Percentage of Participants With Treatment Emergent Anti-insulin Antibodies (AIAs)	22.6 percentage of participants	24.2 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Week 26, Week 52

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

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

Outcome measures

Outcome measures
Measure	SAR342434 n=252 Participants SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=254 Participants Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Change in Daily Insulin Dose From Baseline to Week 26 and Week 52 Basal insulin dose at Week 26	0.03 U/kg Standard Deviation 0.236	0.014 U/kg Standard Deviation 0.06
Change in Daily Insulin Dose From Baseline to Week 26 and Week 52 Mealtime insulin dose at Week 26	0.005 U/kg Standard Deviation 0.112	-0.005 U/kg Standard Deviation 0.089
Change in Daily Insulin Dose From Baseline to Week 26 and Week 52 Total insulin dose at Week 26	0.019 U/kg Standard Deviation 0.134	0.01 U/kg Standard Deviation 0.111
Change in Daily Insulin Dose From Baseline to Week 26 and Week 52 Basal insulin dose at Week 52	0.046 U/kg Standard Deviation 0.364	0.013 U/kg Standard Deviation 0.066
Change in Daily Insulin Dose From Baseline to Week 26 and Week 52 Mealtime insulin dose at Week 52	0.018 U/kg Standard Deviation 0.117	0.007 U/kg Standard Deviation 0.104
Change in Daily Insulin Dose From Baseline to Week 26 and Week 52 Total insulin dose at Week 52	0.039 U/kg Standard Deviation 0.135	0.019 U/kg Standard Deviation 0.127

Adverse Events

SAR342434

Serious events: 20 serious events

Other events: 46 other events

Deaths: 1 deaths

Humalog

Serious events: 19 serious events

Other events: 41 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	SAR342434 n=252 participants at risk SAR342434 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.	Humalog n=254 participants at risk Humalog 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
Infections and infestations Nasopharyngitis	13.1% 33/252 • 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. 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.	11.0% 28/254 • 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. 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.
Infections and infestations Upper respiratory tract infection	6.0% 15/252 • 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. 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.	5.5% 14/254 • 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. 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.

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER