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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    2013-002945-12
    Trial protocol
    DE   HU   ES   PL  
    Global end of trial date
    01 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Jul 2017
    First version publication date
    14 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC12619
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02273180
    WHO universal trial number (UTN)
    U1111-1131-5038
    Other trial identifiers
    Study Name: SORELLA 1
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority of SAR342434 versus Humalog in terms of change in glycated hemoglobin (HbA1c) from baseline to Week 26 in subjects with Type 1 diabetes mellitus (T1DM) also using insulin glargine (Lantus®).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    Insulin glargine 100 U/mL (Lantus) was given as the mandatory background basal insulin therapy and was injected once daily (QD) subcutaneously consistent with the local label. Doses of Lantus were adjusted to achieve glycemic target for fasting, pre-prandial plasma glucose (self measured plasma glucose [SMPG]) between 4.4 to 7.2 mmol/L (80 to 130 mg/dL) without hypoglycemia.
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 61
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    United States: 218
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Hungary: 52
    Worldwide total number of subjects
    507
    EEA total number of subjects
    178
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    463
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 89 centers in 8 countries. A total of 668 subjects were screened between 28 October 2014 and 04 June 2015, of which 161 subjects were screen failures. Screen failures were mainly due to HbA1c <7.0% or >10% at the screening visit.

    Pre-assignment
    Screening details
    A total of 506 subjects were randomized and treated 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).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SAR342434
    Arm description
    SAR342434 before each meal intake on top of QD Insulin Glargine, up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    SAR342434
    Investigational medicinal product code
    Other name
    Insulin Lispro
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SAR342434 100 U/mL (dose range of 1 Unit to 80 Units) self-administered by deep SC injection, immediately (within 5-10 minutes) before any 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.

    Arm title
    Humalog
    Arm description
    Humalog before each meal intake on top of QD Insulin Glargine, up to Week 52.
    Arm type
    Active comparator

    Investigational medicinal product name
    Humalog®
    Investigational medicinal product code
    Other name
    Insulin Lispro
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Humalog 100 U/mL (dose range of 1 unit to 60 units) self-administered by deep SC injection, immediately (within 5-10 minutes) before any 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 hypoglycemia.

    Number of subjects in period 1
    SAR342434 Humalog
    Started
    253
    254
    Treated
    252
    254
    Completed
    226
    235
    Not completed
    27
    19
         Randomized but not treated
             1
             -
         Other than specified
             21
             10
         Adverse event
             2
             2
         Lack of efficacy
             1
             -
         Poor compliance to protocol
             1
             7
         Hypoglycemia not reported as serious adverse event
             1
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SAR342434
    Reporting group description
    SAR342434 before each meal intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group title
    Humalog
    Reporting group description
    Humalog before each meal intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group values
    SAR342434 Humalog Total
    Number of subjects
    253 254 507
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.3 ± 14.5 42.6 ± 13.9 -
    Gender categorical
    Units: Subjects
        Female
    104 101 205
        Male
    149 153 302
    Previous mealtime insulin type
    Units: Subjects
        Humalog/Liprolog
    155 152 307
        NovoLog/NovoRapid
    95 95 190
        Both Humalog/Liprolog and NovoLog/NovoRapid
    3 7 10
    Randomization Strata of Screening HbA1c
    Units: Subjects
        <8 %
    99 99 198
        >=8%
    154 155 309
    Randomization strata of geographical region
    Units: Subjects
        Japan
    31 30 61
        Non-Japan
    222 224 446
    Body mass index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    26.2 ± 4 25.8 ± 4.1 -
    Duration of T1DM
    Units: years
        arithmetic mean (standard deviation)
    19.53 ± 12.63 18.57 ± 11.99 -
    Average Daily Basal Insulin Dose
    Data for average daily basal insulin dose is reported for a total of 490 subjects (SAR342434: 245 and Humalog: 245).
    Units: Units (U)/kg
        arithmetic mean (standard deviation)
    0.339 ± 0.195 0.33 ± 0.141 -
    Average Daily Mealtime Insulin Dose
    Data for average daily mealtime insulin dose is reported for a total of 485 subjects (SAR342434: 241 and Humalog: 244).
    Units: U/kg
        arithmetic mean (standard deviation)
    0.364 ± 0.175 0.355 ± 0.168 -
    Average Daily Total Insulin Dose
    Data for average daily total insulin dose is reported for a total of 480 subjects (SAR342434: 239 and Humalog: 241).
    Units: U/kg
        arithmetic mean (standard deviation)
    0.704 ± 0.309 0.685 ± 0.242 -
    Glycated Haemoglobin (HbA1c %)
    Units: percentage of hemoglobin
        arithmetic mean (standard deviation)
    8.07 ± 0.79 7.99 ± 0.64 -

    End points

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    End points reporting groups
    Reporting group title
    SAR342434
    Reporting group description
    SAR342434 before each meal intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group title
    Humalog
    Reporting group description
    Humalog before each meal intake on top of QD Insulin Glargine, up to Week 52.

    Primary: Change in HbA1c From Baseline to Week 26

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    End point title
    Change in HbA1c From Baseline to Week 26
    End point 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. Analysis was performed on intent-to-treat (ITT) population that included all randomized subjects, irrespective of compliance with the study protocol and procedures. Here, number of subjects analyzed = subjects with at least one post-baseline HbA1c assessment during the main 6-month period.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    247
    249
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.42 ± 0.051
    -0.47 ± 0.05
    Statistical analysis title
    SAR342434 vs. Humalog
    Statistical analysis description
    Analysis was performed using a MMRM approach with treatment groups, randomization strata, visits (Week 12, Week 26) 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-subject errors.
    Comparison groups
    SAR342434 v Humalog
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Least square (LS) mean difference
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.084
         upper limit
    0.197
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.071
    Notes
    [1] - 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%.

    Secondary: Percentage of Subjects with HbA1c <7.0% at Week 26

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    End point title
    Percentage of Subjects with HbA1c <7.0% at Week 26
    End point description
    Subjects who had no available assessment for HbA1c at Week 26 were considered as non-responders. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    253
    254
    Units: percentage of subjects
        number (not applicable)
    22.5
    21.7
    No statistical analyses for this end point

    Secondary: Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26

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    End point title
    Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26
    End point 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. Analysis was performed on ITT population. Here, number of subjects analyzed = subjects with at least one post-baseline FPG assessment during the main 6-month period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    240
    242
    Units: mmol/L
        least squares mean (standard error)
    -0.46 ± 0.248
    -0.62 ± 0.248
    No statistical analyses for this end point

    Secondary: Change in Mean 24-Hour Plasma Glucose Concentration from Baseline to Week 26

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    End point title
    Change in Mean 24-Hour Plasma Glucose Concentration from Baseline to Week 26
    End point 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. 7-point SMPGs were performed at least two times in a week before baseline, before visit Week 12 and before visit Week 26. 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. Analysis was performed on ITT population. Here, number of subjects analyzed=subjects with at least one post-baseline mean 24-hour plasma glucose concentration assessment during the main 6-month period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    216
    207
    Units: mmol/L
        least squares mean (standard error)
    -0.23 ± 0.145
    -0.49 ± 0.148
    No statistical analyses for this end point

    Secondary: Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26

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    End point title
    Change in Post Prandial Plasma Glucose (PPG) Excursion From Baseline to Week 26
    End point 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. Analysis was performed on ITT population. Here, 'n' signifies number of subjects with at least one post-baseline data during the main 6-month period for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    253
    254
    Units: mmol/L
    least squares mean (standard error)
        At breakfast (n=205, 198)
    -0.46 ± 0.297
    0.19 ± 0.297
        At lunch (n=207, 193)
    0.14 ± 0.298
    -0.26 ± 0.309
        At dinner (n=208, 190)
    0.48 ± 0.308
    0.56 ± 0.324
    No statistical analyses for this end point

    Secondary: Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Subject-Year

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    End point title
    Number of Hypoglycemia Events (Any Hypoglycemia, Documented Symptomatic Hypoglycemia and Severe Hypoglycemia) Per Subject-Year
    End point description
    Number of treatment-emergent hypoglycemia per subject-year of exposure were reported. Severe hypoglycemia was an event in which the subject 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. Analysis was performed on safety population that included all subjects randomized and exposed to at least 1 dose of investigational medicinal product (IMP) (SAR342434 or Humalog), regardless of the amount of treatment administered.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    252
    254
    Units: events per subject-year
    number (not applicable)
        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
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Hypersensitivity Reactions and Injection Site Reactions

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    End point title
    Percentage of Subjects with Hypersensitivity Reactions and Injection Site Reactions
    End point description
    Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    252
    254
    Units: percentage of subjects
    number (not applicable)
        Any hypersensitivity reactions
    6
    6.3
        Any injection site reactions
    1.2
    1.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Emergent Anti-insulin Antibodies (AIAs)

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    End point title
    Percentage of Subjects with Treatment Emergent Anti-insulin Antibodies (AIAs)
    End point description
    Subjects with treatment-emergent AIA (incidence) were reported (as subjects with treatment-boosted or treatment-induced AIAs). Subjects with treatment-induced AIAs were those who developed AIA following IMP administration (subjects with at least one positive AIA sample at any time during on-treatment period, in those subjects without pre-existing AIA or with missing baseline sample). Subjects with treatment-boosted AIAs were those with pre-existing AIAs that were boosted to a significant higher titer following IMP administration (subjects 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 subjects with pre-existing AIA). Analysis was performed on anti-insulin antibody population that included all subjects 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.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 1 day after the last dose administration (maximum treatment exposure: 400 days)
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    248
    252
    Units: percentage of subjects
        number (not applicable)
    22.6
    24.2
    No statistical analyses for this end point

    Other pre-specified: Change in Daily Insulin Dose from Baseline to Week 26 and Week 52

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    End point title
    Change in Daily Insulin Dose from Baseline to Week 26 and Week 52
    End point description
    Change in daily insulin dose (basal, mealtime and total) was calculated by subtracting baseline value from Week 26 and Week 52 values respectively. Analysis was performed on safety population. Here, 'n' signifies number of subjects with available data for specified categories.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 26, Week 52
    End point values
    SAR342434 Humalog
    Number of subjects analysed
    252
    254
    Units: U/kg
    arithmetic mean (standard deviation)
        Basal insulin dose at Week 26 (n=223,229)
    0.03 ± 0.236
    0.014 ± 0.006
        Mealtime insulin dose at Week 26 (n=217,222)
    0.005 ± 0.112
    -0.005 ± 0.089
        Total insulin dose at Week 26 (n=215,220)
    0.019 ± 0.134
    0.01 ± 0.111
        Basal insulin dose at Week 52 (n=199,209)
    0.046 ± 0.364
    0.013 ± 0.066
        Mealtime insulin dose at Week 52 (n=192, 203)
    0.018 ± 0.117
    0.007 ± 0.104
        Total insulin dose at Week 52 (n=191, 200)
    0.039 ± 0.135
    0.019 ± 0.127
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    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 additional 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.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    SAR342434
    Reporting group description
    SAR342434 before each meal intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group title
    Humalog
    Reporting group description
    Humalog before each meal intake on top of QD Insulin Glargine, up to Week 52.

    Serious adverse events
    SAR342434 Humalog
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 252 (7.94%)
    19 / 254 (7.48%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Gastrectomy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy Of Partner
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Threatened
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac Death
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Ovarian Cyst
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    3 / 252 (1.19%)
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Injury
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrong Drug Administered
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Ventricle Dilatation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Coma
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Seizure
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    6 / 252 (2.38%)
    6 / 254 (2.36%)
         occurrences causally related to treatment / all
    4 / 6
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis Haemorrhagic
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 254 (1.18%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Viral Infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SAR342434 Humalog
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 252 (18.25%)
    41 / 254 (16.14%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    33 / 252 (13.10%)
    28 / 254 (11.02%)
         occurrences all number
    45
    33
    Upper Respiratory Tract Infection
         subjects affected / exposed
    15 / 252 (5.95%)
    14 / 254 (5.51%)
         occurrences all number
    15
    14

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2014
    Following changes were made: • Clarification of Inclusion criteria (frequency of injections with meal time insulin therapy) were added; • Determination of AIA at Week 4 was added; • Monitoring of elevated AIA titers until return to baseline were added in subjects in whom the Allergic Reaction Assessment Committee (ARAC) assessed AIA-mediated hypersensitivity reactions or insulin resistance; • Clarification of procedure related to premature discontinuation of treatment; • Clarification of electronic transfer of patient reported outcome (PRO) (7 point and 3 point SMPG profiles, insulin doses and hypoglycemia); • Option of supplying IMP and non-investigational medicinal product (NIMP) by direct mail was removed; •Changes were done to statistical analysis: if non-inferiority of SAR342434 over Humalog was demonstrated, the inverse non-inferiority of Humalog over SAR342434 was to be tested. Analyses for the description of missing data was added; • Changes to statistical analysis: additional information on treatment group presented in the descriptive analyses: overall (pooling Humalog US and Humalog EU groups) and then by subgroup of Humalog-US (corresponding to US and Japan subjects)/Humalog EU (outside US/Japan); • Changes were done to statistical analysis: addition of an on-treatment sensitivity analysis.
    05 Feb 2016
    Following changes were made: •Clarification on ARAC procedure with elevated AIA titers: follow-up by the sponsor of elevated AIA titers until return to baseline value or until ARAC decided that no further follow-up deemed necessary in subjects whom the ARAC assessed an AIA-mediated hypersensitivity reaction or insulin resistance; •Clarification on inclusion criteria and exclusion criteria for use of Liprolog was added; •Clarification of procedure related to premature treatment discontinuation; •Editorial changes; •Change of reporting of asymptomatic overdose: not considered anymore as an adverse event of special interest (AESI).

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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