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    Clinical Trial Results:
    AN OPEN-LABEL, RANDOMIZED, MULTI-CENTER, PARALLEL-GROUP CLINICAL TRIAL COMPARING THE EFFICACY AND SAFETY OF MYLAN’S INSULIN GLARGINE WITH LANTUS® IN TYPE 1 DIABETES MELLITUS PATIENTS

    Summary
    EudraCT number
    		 2014-000747-32
    Trial protocol
    		 SK   CZ   DE   GB   EE   HU   LV  
    Global end of trial date
    07 Jul 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Jun 2018
    First version publication date
    21 Jul 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Following CSR Amendment, Week 52 secondary endpoint values required update; Incident rate of adverse event ‘Depression’ did not have enough occurrences to meet reporting requirements

    Trial information

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    Trial identification
    Sponsor protocol code
    MYL-GAI-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02227862
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND number: 105279
    Sponsors
    Sponsor organisation name
    Mylan GMBH
    Sponsor organisation address
    Thurgauerstrasse 40 , Zurich , Switzerland, 8050
    Public contact
    Keri Vaughan, Director Global Clinical Operations, General Medicine, Mylan, Inc, keri.vaughan@mylan.com
    Scientific contact
    Keri Vaughan, Director Global Clinical Operations, General Medicine, Mylan, Inc, keri.vaughan@mylan.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
    13 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test whether Mylan’s insulin glargine once daily is non-inferior to Lantus® once daily (based on change in HbA1c from baseline to 24 weeks) when administered in combination with mealtime insulin lispro.
    Protection of trial subjects
    All study participants signed an Informed Consent Form prior to study participation.
    Background therapy
    		 Humalog
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jun 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
    Canada: 25
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    United States: 227
    Country: Number of subjects enrolled
    Romania: 35
    Country: Number of subjects enrolled
    Slovakia: 66
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Czech Republic: 42
    Country: Number of subjects enrolled
    Estonia: 14
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Hungary: 48
    Country: Number of subjects enrolled
    Latvia: 36
    Worldwide total number of subjects
    558
    EEA total number of subjects
    290
    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)
    547
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 · Gender: male or female; · Age: 18-65 years, inclusive; · Body mass index (BMI): 18.5-35.0 kg/m2, inclusive.

    Pre-assignment
    Screening details
    		 Eight hundred eighty-three (883) patients were screened to participate in the study, six hundred and nine (609) patients entered the run-in period, and Five Hundred fifty eight (558) patients were randomized to study treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 609 [1]
    Number of subjects completed
    		 558

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 The Study Prematurely Terminated By Investigator: 1
    Reason: Number of subjects
    		 Lost to follow-up: 5
    Reason: Number of subjects
    		 Other: 2
    Reason: Number of subjects
    		 Protocol deviation: 5
    Reason: Number of subjects
    		 Failed To Meet Inclusion Or Exclusion Criteria: 13
    Reason: Number of subjects
    		 Consent withdrawn by subject: 19
    Reason: Number of subjects
    		 Reason not collected: 6
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects per country, from which the worldwide number enrolled in the trial is calculated, represent the subjects in the treatment period, which were randomized to study medication (see also Screening Details).
    Period 1
    Period 1 title
    Active Treatment Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MYL IG
    Arm description
    		 Mylan's insulin Glargine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Glargine - New Formulation
    Investigational medicinal product code
    MYL-1501D
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 IU/mL once daily

    Arm title
    		 Lantus
    Arm description
    		 Lantus
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin Glargine
    Investigational medicinal product code
    Lantus®
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100 IU/mL once daily

    Number of subjects in period 1
    		MYL IG Lantus
    Started
    280
    278
    Week24
    269
    263
    Completed
    261
    256
    Not completed
    19
    22
         Consent withdrawn by subject
    7
    6
         Adverse event, non-fatal
    4
    3
         Other
    -
    2
         Lost to follow-up
    1
    2
         Protocol deviation
    7
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MYL IG
    Reporting group description
    		 Mylan's insulin Glargine

    Reporting group title
    Lantus
    Reporting group description
    		 Lantus

    Reporting group values
    		 MYL IG Lantus Total
    Number of subjects
    		 280 278 558
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 275 272 547
        From 65-84 years
    		 5 6 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42 ± 12.03 42.2 ± 11.97 -
    Gender categorical
    Units: Subjects
        Female
    		 116 106 222
        Male
    		 164 172 336
    Race
    Units: Subjects
        Asian
    		 2 2 4
        Black
    		 2 5 7
        Caucasian
    		 263 265 528
        Hispanic
    		 6 3 9
        Other
    		 7 3 10
    Geographic Region
    Units: Subjects
        Europe
    		 145 145 290
        North America
    		 126 126 252
        South Africa
    		 9 7 16
    Insulin History
    Units: Subjects
        Yes
    		 280 277 557
        No
    		 0 1 1
    Dosing Time
    Units: Subjects
        Morning
    		 38 40 78
        Evening
    		 242 238 480
    Body Mass Index (BMI)
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 26.435 ± 3.7058 26.636 ± 4.2022 -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 18.685 ± 11.7771 19.697 ± 11.2868 -
    Baseline fasting plasma blood glucose
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 167.4 ± 68.43 163.9 ± 61.61 -
    Baseline HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 7.37 ± 0.869 7.39 ± 0.843 -
    Baseline fasting C-peptide
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 0.298 ± 0.2291 0.291 ± 0.2508 -

    End points

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    End points reporting groups
    Reporting group title
    MYL IG
    Reporting group description
    		 Mylan's insulin Glargine

    Reporting group title
    Lantus
    Reporting group description
    		 Lantus

    Subject analysis set title
    Randomized Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who were enrolled and randomized to study drug.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population included patients who were randomized and took at least 1 dose of the study drug

    Subject analysis set title
    Intent to Treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) Population included all randomized patients (including patients who received incorrect treatment, did not complete the study or did not comply with the protocol) and had ≥ 1 baseline (randomization visit) and 1 post-baseline value.

    Subject analysis set title
    Per-protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) Population included patients who completed the study at Week 24, and had HbA1c measurements as per the protocol, or had at least 12‑week HbA1c data (for patients who discontinued prematurely), and did not have protocol violations (significant protocol deviations) that impacted the primary outcome.

    Primary: Change in HbA1c from Baseline to Week 24

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    End point title
    		 Change in HbA1c from Baseline to Week 24
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [1]
    277 [2]
    Units: percent
        least squares mean (standard error)
    0.14 ± 0.054
    0.11 ± 0.054
    Notes
    [1] - Intent-to-Treat Population
    [2] - Intent-to-Treat Population
    Statistical analysis title
    		 Mixed Effect Repeated Measure model
    Comparison groups
    Lantus v MYL IG
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.066
         upper limit
    		 0.117
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.046

    Secondary: Summary of Actual and Change from Baseline in HbA1c

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    End point title
    		 Summary of Actual and Change from Baseline in HbA1c
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [3]
    277 [4]
    Units: percent
    arithmetic mean (standard deviation)
        week 24
    0.12 ± 0.599
    0.09 ± 0.526
        week 52
    0.2 ± 0.633
    0.25 ± 0.595
    Notes
    [3] - Intent-to-Treat Population
    [4] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in FPG over time

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    End point title
    		 Change from Baseline in FPG over time
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [5]
    277 [6]
    Units: mmol/L
    arithmetic mean (standard deviation)
        week 24
    -0.81 ± 4.485
    0.09 ± 4.507
        week 52
    0.23 ± 4.281
    0.43 ± 4.455
    Notes
    [5] - Intent-to-Treat-Population
    [6] - Intent-to-Treat-Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in 8-point SMBG profile over time

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    End point title
    		 Change from Baseline in 8-point SMBG profile over time
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [7]
    277 [8]
    Units: mmol/L
    arithmetic mean (standard deviation)
        week 24
    0.038 ± 2.3751
    -0.095 ± 1.5012
        week 52
    -0.082 ± 1.5032
    -0.082 ± 1.5267
    Notes
    [7] - Intent-to-Treat Population
    [8] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Change in total daily insulin dose per unit body weight from baseline over time

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    End point title
    		 Change in total daily insulin dose per unit body weight from baseline over time
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [9]
    277 [10]
    Units: U/Kg
    arithmetic mean (standard deviation)
        week 24
    0.0203 ± 0.09962
    0.0127 ± 0.10871
        week 52
    0.0278 ± 0.1044
    0.0138 ± 0.11372
    Notes
    [9] - Intent-to-Treat Population
    [10] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Rate of hypoglycemic events per 30 days over time

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    End point title
    		 Rate of hypoglycemic events per 30 days over time
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [11]
    278 [12]
    Units: Episodes/30 Days
    arithmetic mean (standard deviation)
        week 24
    -5.162 ± 9.0724
    -4.93 ± 8.3815
        week 52
    -6.241 ± 9.214
    -5.765 ± 8.3658
    Notes
    [11] - Safety Population
    [12] - Safety Population
    No statistical analyses for this end point

    Secondary: Hypoglycemia occurrence

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    End point title
    		 Hypoglycemia occurrence
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [13]
    278 [14]
    Units: Number of patients
        Any hypoglycemic event
    273
    269
        Severe Hypoglycemia
    11
    13
        Documented Symptomatic Hypoglycemia
    249
    249
        Asymptomatic Hypoglycemia
    246
    243
        Probable Symptomatic Hypoglycemia
    37
    36
        Relative Hypoglycemia
    35
    44
        Other Hypoglycemia
    19
    19
        Unknown
    77
    71
    Notes
    [13] - Safety Population
    [14] - Safety Population
    No statistical analyses for this end point

    Secondary: Occurrence of local and systemic reactions

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    End point title
    		 Occurrence of local and systemic reactions
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [15]
    278 [16]
    Units: number of patients
        Local
    3
    4
        Systemic
    2
    2
    Notes
    [15] - Safety Population
    [16] - Safety Population
    No statistical analyses for this end point

    Secondary: Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay over time

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    End point title
    		 Change in Total Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay over time
    End point description
    per cent Specific Binding (%SB)
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [17]
    278 [18]
    Units: %SB
    arithmetic mean (standard deviation)
        week 24
    -0.3063 ± 7.22075
    0.3592 ± 7.16624
        week 52
    -0.9591 ± 8.51754
    -1.0634 ± 8.42794
    Notes
    [17] - Safety Population
    [18] - Safety Population
    No statistical analyses for this end point

    Secondary: Change in Total Insulin Antibody Percent Binding for Lantus Assay over time

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    End point title
    		 Change in Total Insulin Antibody Percent Binding for Lantus Assay over time
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [19]
    278 [20]
    Units: %SB
    arithmetic mean (standard deviation)
        week 24
    -0.215 ± 7.3298
    0.157 ± 7.411
        week 52
    -0.896 ± 8.5610
    -1.233 ± 8.623
    Notes
    [19] - Safety Population
    [20] - Safety Population
    No statistical analyses for this end point

    Secondary: Change in Cross-Reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay over time

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    End point title
    		 Change in Cross-Reactive Insulin Antibody Percent Binding for Mylan's Insulin Glargine Assay over time
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [21]
    278 [22]
    Units: %SB
    arithmetic mean (standard deviation)
        week 24
    -0.363 ± 7.1081
    0.27 ± 7.1204
        week 52
    -1.132 ± 8.3911
    -1.21 ± 8.4096
    Notes
    [21] - Safety Population
    [22] - Safety Population
    No statistical analyses for this end point

    Secondary: Change in Cross-Reactive Insulin Antibody Percent Binding for Lantus Assay over time

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    End point title
    		 Change in Cross-Reactive Insulin Antibody Percent Binding for Lantus Assay over time
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [23]
    278 [24]
    Units: %SB
    arithmetic mean (standard deviation)
        week 24
    -0.265 ± 7.2543
    0.055 ± 7.3985
        week 52
    -1.060 ± 8.4414
    -1.367 ± 8.6848
    Notes
    [23] - Safety Population
    [24] - Safety Population
    No statistical analyses for this end point

    Secondary: Proportion of Patients with HbA1c <7%

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    End point title
    		 Proportion of Patients with HbA1c <7%
    End point description
    End point type
    Secondary
    End point timeframe
    52 Weeks
    End point values
    		 MYL IG Lantus
    Number of subjects analysed
    280 [25]
    277 [26]
    Units: patients
        week 24
    73
    84
        week 52
    65
    61
    Notes
    [25] - Intent-to-Treat Population
    [26] - Intent-to-Treat Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    56 Weeks
    Adverse event reporting additional description
    After Week 52, all the patients resumed treatment as per local standard of care. A safety follow up visit was done at Week 56.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Lantus
    Reporting group description
    		 -

    Reporting group title
    MYL IG
    Reporting group description
    		 -

    Serious adverse events
    		 Lantus MYL IG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 278 (7.91%)
    18 / 280 (6.43%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant oligodendroglioma
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory distress
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 278 (0.36%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 278 (0.72%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 278 (0.00%)
    2 / 280 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis minimal lesion
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    2 / 278 (0.72%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         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 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 278 (0.00%)
    1 / 280 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral rash
         subjects affected / exposed
    1 / 278 (0.36%)
    0 / 280 (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
    Hypoglycaemia
         subjects affected / exposed
    10 / 278 (3.60%)
    7 / 280 (2.50%)
         occurrences causally related to treatment / all
    3 / 16
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Lantus MYL IG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    236 / 278 (84.89%)
    222 / 280 (79.29%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 278 (2.16%)
    9 / 280 (3.21%)
         occurrences all number
    6
    9
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 278 (1.44%)
    5 / 280 (1.79%)
         occurrences all number
    4
    6
    Oedema peripheral
         subjects affected / exposed
    3 / 278 (1.08%)
    4 / 280 (1.43%)
         occurrences all number
    3
    4
    Fatigue
         subjects affected / exposed
    2 / 278 (0.72%)
    4 / 280 (1.43%)
         occurrences all number
    2
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 278 (1.08%)
    2 / 280 (0.71%)
         occurrences all number
    3
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 278 (1.80%)
    6 / 280 (2.14%)
         occurrences all number
    5
    6
    Oropharyngeal pain
         subjects affected / exposed
    3 / 278 (1.08%)
    6 / 280 (2.14%)
         occurrences all number
    3
    6
    Sinus congestion
         subjects affected / exposed
    4 / 278 (1.44%)
    4 / 280 (1.43%)
         occurrences all number
    4
    4
    Asthma
         subjects affected / exposed
    0 / 278 (0.00%)
    5 / 280 (1.79%)
         occurrences all number
    0
    6
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 278 (1.08%)
    2 / 280 (0.71%)
         occurrences all number
    3
    2
    Anxiety
         subjects affected / exposed
    1 / 278 (0.36%)
    3 / 280 (1.07%)
         occurrences all number
    1
    3
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 278 (1.44%)
    1 / 280 (0.36%)
         occurrences all number
    4
    1
    Blood pressure increased
         subjects affected / exposed
    3 / 278 (1.08%)
    0 / 280 (0.00%)
         occurrences all number
    3
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 278 (0.72%)
    3 / 280 (1.07%)
         occurrences all number
    2
    3
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 278 (1.08%)
    0 / 280 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 278 (5.04%)
    5 / 280 (1.79%)
         occurrences all number
    20
    5
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 278 (0.00%)
    4 / 280 (1.43%)
         occurrences all number
    0
    5
    Diabetic neuropathy
         subjects affected / exposed
    3 / 278 (1.08%)
    1 / 280 (0.36%)
         occurrences all number
    3
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 278 (0.00%)
    3 / 280 (1.07%)
         occurrences all number
    0
    3
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    5 / 278 (1.80%)
    2 / 280 (0.71%)
         occurrences all number
    5
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 278 (2.16%)
    10 / 280 (3.57%)
         occurrences all number
    8
    10
    Diarrhoea
         subjects affected / exposed
    4 / 278 (1.44%)
    11 / 280 (3.93%)
         occurrences all number
    4
    12
    Toothache
         subjects affected / exposed
    5 / 278 (1.80%)
    4 / 280 (1.43%)
         occurrences all number
    5
    7
    Vomiting
         subjects affected / exposed
    2 / 278 (0.72%)
    6 / 280 (2.14%)
         occurrences all number
    3
    7
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    4 / 278 (1.44%)
    0 / 280 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Microalbuminuria
         subjects affected / exposed
    0 / 278 (0.00%)
    3 / 280 (1.07%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 278 (0.72%)
    9 / 280 (3.21%)
         occurrences all number
    4
    13
    Back pain
         subjects affected / exposed
    6 / 278 (2.16%)
    5 / 280 (1.79%)
         occurrences all number
    7
    5
    Muscle spasms
         subjects affected / exposed
    0 / 278 (0.00%)
    4 / 280 (1.43%)
         occurrences all number
    0
    4
    Osteoarthritis
         subjects affected / exposed
    0 / 278 (0.00%)
    3 / 280 (1.07%)
         occurrences all number
    0
    3
    Trigger finger
         subjects affected / exposed
    3 / 278 (1.08%)
    0 / 280 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    39 / 278 (14.03%)
    25 / 280 (8.93%)
         occurrences all number
    58
    37
    Upper respiratory tract infection
         subjects affected / exposed
    33 / 278 (11.87%)
    27 / 280 (9.64%)
         occurrences all number
    44
    38
    Influenza
         subjects affected / exposed
    12 / 278 (4.32%)
    12 / 280 (4.29%)
         occurrences all number
    14
    12
    Urinary tract infection
         subjects affected / exposed
    10 / 278 (3.60%)
    9 / 280 (3.21%)
         occurrences all number
    11
    13
    Bronchitis
         subjects affected / exposed
    8 / 278 (2.88%)
    9 / 280 (3.21%)
         occurrences all number
    8
    9
    Gastroenteritis
         subjects affected / exposed
    6 / 278 (2.16%)
    10 / 280 (3.57%)
         occurrences all number
    6
    10
    Sinusitis
         subjects affected / exposed
    8 / 278 (2.88%)
    8 / 280 (2.86%)
         occurrences all number
    8
    10
    Gastroenteritis viral
         subjects affected / exposed
    7 / 278 (2.52%)
    6 / 280 (2.14%)
         occurrences all number
    7
    6
    Viral infection
         subjects affected / exposed
    6 / 278 (2.16%)
    5 / 280 (1.79%)
         occurrences all number
    6
    5
    Pharyngitis
         subjects affected / exposed
    2 / 278 (0.72%)
    5 / 280 (1.79%)
         occurrences all number
    2
    5
    Fungal infection
         subjects affected / exposed
    3 / 278 (1.08%)
    3 / 280 (1.07%)
         occurrences all number
    4
    3
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 278 (0.72%)
    4 / 280 (1.43%)
         occurrences all number
    2
    6
    Rhinitis
         subjects affected / exposed
    5 / 278 (1.80%)
    1 / 280 (0.36%)
         occurrences all number
    5
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 278 (1.08%)
    2 / 280 (0.71%)
         occurrences all number
    3
    2
    Onychomycosis
         subjects affected / exposed
    3 / 278 (1.08%)
    1 / 280 (0.36%)
         occurrences all number
    3
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 278 (1.08%)
    5 / 280 (1.79%)
         occurrences all number
    3
    5
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 278 (1.08%)
    1 / 280 (0.36%)
         occurrences all number
    4
    1
    Tonsillitis
         subjects affected / exposed
    1 / 278 (0.36%)
    3 / 280 (1.07%)
         occurrences all number
    1
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    3 / 278 (1.08%)
    1 / 280 (0.36%)
         occurrences all number
    3
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 278 (0.00%)
    3 / 280 (1.07%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    166 / 278 (59.71%)
    151 / 280 (53.93%)
         occurrences all number
    3168
    3037
    Hyperglycaemia
         subjects affected / exposed
    5 / 278 (1.80%)
    3 / 280 (1.07%)
         occurrences all number
    6
    3
    Hyperlipidaemia
         subjects affected / exposed
    3 / 278 (1.08%)
    2 / 280 (0.71%)
         occurrences all number
    3
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 278 (0.00%)
    3 / 280 (1.07%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2014
    Retinal photography added Clarification regarding recording device-related safety Immunogenicity sampling added at visit 10 and visit 12 Titration committee added Measurement and analysis of crossreacting antibody added  Treatment compliance criteria modified Clarifications and minor editorial corrections
    22 Jul 2015
    Key statistical analyses added to the synopsis, to make the synopsis more comprehensive (synopsis). Clarification made to inclusion criterion #1 that patient signature for authorization to use protected health information is part of the ICF; and will not be collected on a separate form Clarification made in inclusion criterion #10 to indicate that oral contraception alone is also acceptable; and that only women of childbearing potential need to perform pregnancy test Clarification made in exclusion criterion #9 that patients will be excluded for ECG or laboratory abnormalities only if they are considered by the investigator to be clinically significant enough to make the patient ineligible Clarification made to exclude glucocorticoids by all routes which have systemic effects; not only oral, inhaled and intravenous Clarification made that dose titration of insulin glargine/Lantus® should be kept to a minimum from 0 to 24 weeks. In the previous version, the period between 0 and 12 weeks was not covered; though implied “Serum”/“plasma” glucose corrected to “capillary” glucose where appropriate Clarification made that serious or severe hypoglycemia will be reported as an SAE (as per reporting guidelines), and recorded on the AE CRF page; while other types of hypoglycemia will be captured only on the hypoglycemia CRF page, and not on the AE page The use of basal insulin more than once daily, or at more than the prescribed dose (though this is rare) - for specified periods - have been added as non-compliance criteria Patients with glucose levels between 270 and 271 mg/dL were inadvertently not covered in the insulin dose titration guidance tables; this has been corrected; and “human insulin regular” has been removed from the table; as it is not permitted in the trial (Appendix II) The definition of per-protocol population has been modified
    04 May 2016
    In the section Contact Details For Reporting Serious Adverse Events, the sentence “Any SAE occurring in a subject from consent until 28 days after the last dose of the study drug must be reported” has been replaced with “Any SAE occurring in a subject from consent until his/her last study visit/phone visit (scheduled or unscheduled) must be reported”. • The Synopsis and section 2.1, Secondary objectives, Immunogenicity, the sentence “change from baseline in titer, incidence of ADA, anti-HCP and neutralizing antibodies” has been replaced with “incidence and change from baseline in the relative levels of ADA, incidence and change from baseline the relative levels of anti-HCP antibodies”. The Synopsis, Schedule of Activities, Section 3.1, Section 6.3 and Section 6.6 have been modified to clarify that the required number of patients who qualify for the MYL-1501D-3003 study will not go through the Follow-Up Visit of MYLGAI- 3001, but will continue in MYL- 1501D-3003 after the completion of 52 week visit (EOT). • Synopsis, Schedule of Activities, Section 3.1 and Section 6.3.The following statement has been added in the Schedule of Activities: Patients who qualify for the MYL-1501D-3003 study will be requested to sign a new ICF (for MYL- 1501D-3003) prior to enrollment or any study activity. • In the Synopsis and Section 6.6, the withdrawal criteria have been modified to remove text on use of prohibited medications and non-compliance. • Section 3.5, figure 1, was updated to include the opportunity to enroll into the MYL-1501D-3003 study. • Section 7.2.1 has been rewritten to reflect methodological changes. • In Section 7.2.2, the following sentences have been removed: “All designated samples will undergo a screening assay that allows for a 5% false positive rate, to identify the presence of anti-HCP. Samples identified as positive in the screening assay will then be tested in a confirmatory assay that employs either

    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
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