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    Clinical Trial Results:
    An investigational trial comparing the efficacy and safety of once weekly NNC0148-0287 C (insulin 287) versus once daily insulin glargine, both in combination with metformin, with or without DPP-4 inhibitors, in insulin naïve subjects with type 2 diabetes mellitus

    Summary
    EudraCT number
    		 2018-000322-63
    Trial protocol
    		 SI   CZ   SK   GR  
    Global end of trial date
    17 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jan 2021
    First version publication date
    29 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1436-4383
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03751657
    WHO universal trial number (UTN)
    		 U1111-1208-4124
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, clinicaltrials@novonordisk.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
    04 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect on glycaemic control after 26 weeks treatment of once weekly insulin 287 versus once daily insulin glargine both in combination with metformin with or without dipeptidyl peptidase-4 inhibitors in insulin-naïve type 2 diabetes mellitus subjects inadequately treated with metformin with or without dipeptidyl peptidase-4 inhibitors.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (64th WMA general assembly; Oct 2013) and ICH Good Clinical Practice, including archiving of essential documents (Nov 2016, current Step 4 version) and FDA 21 CFR 312.120.
    Background therapy
    		 Subjects were to continue their pre-trial metformin alone or in combination with Dipeptidyl peptidase 4 inhibitors (DPP4i) throughout the trial.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    29 Nov 2018
    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: 34
    Country: Number of subjects enrolled
    Czechia: 43
    Country: Number of subjects enrolled
    Greece: 36
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Slovakia: 38
    Country: Number of subjects enrolled
    Slovenia: 17
    Country: Number of subjects enrolled
    United States: 37
    Worldwide total number of subjects
    247
    EEA total number of subjects
    176
    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)
    167
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 49 sites in Canada (7), Czech Republic (9), Greece (5), Poland (6), Slovakia (6),Slovenia (2) and United States (14). One site in the United States screened, but didn’t randomise any subject.

    Pre-assignment
    Screening details
    		 Insulin-naïve subjects with T2D inadequately controlled on metformin with or without DPP4i were randomized in a 1:1 manner to receive once weekly insulin 287 and once daily placebo or once weekly placebo and once daily insulin glargine subcutaneously (s.c).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Insulin 287 and Insulin glargine were visually identical in order to maintain the blinding. The trial products were packed blinded and each box was labelled with a unique dispensing unit number.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Insulin 287
    Arm description
    		 Subjects were to receive once weekly s.c. injection of insulin 287 using PDS290 prefilled pen-injector and once daily placebo for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNC0148-0287 C
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive once weekly s.c. injection of insulin 287 using PDS290 prefilled pen-injector at a starting dose of 70 units (U) and once daily placebo for 26 weeks. The insulin dose was then adjusted once weekly to reach the glycaemic target of 3.9-6.0 millimoles per liter (mmol/L) based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 3.0 mmol/L- dose reduced by 28 U, and 3.0-3.8- dose reduced by 14 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was: 3.9-6.0 mmol/L- no adjustment; 6.1-7.0 mmol/L- dose increased by 14U, and >7.0 mmol/L- dose increased by 28U.

    Arm title
    		 Insulin glargine
    Arm description
    		 Subjects were to receive once daily s.c injection of Insulin glargine using 10 ml vial and syringe and once weekly placebo for 26 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive once daily s.c injection of Insulin glargine using 10 ml vial and syringe at a starting dose of 10 U and once weekly placebo for 26 weeks. The insulin dose was then adjusted to reach the glycaemic target of 3.9-6.0 mmol/L based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the titration. If at least one pre-breakfast SMPG value was: < 3.0 mmol/L- dose reduced by 4 U, and 3.0-3.8 dose reduced by 2 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was: 3.9-6.0 mmol/L- no adjustment; 6.1-7.0 mmol/L- dose increased by 2 U, and >7.0 mmol/L- dose increased by 4 U.

    Number of subjects in period 1
    		Insulin 287 Insulin glargine
    Started
    125
    122
    Completed
    122
    119
    Not completed
    3
    3
         Consent withdrawn by subject
    1
    1
         Physician decision
    -
    1
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin 287
    Reporting group description
    		 Subjects were to receive once weekly s.c. injection of insulin 287 using PDS290 prefilled pen-injector and once daily placebo for 26 weeks.

    Reporting group title
    Insulin glargine
    Reporting group description
    		 Subjects were to receive once daily s.c injection of Insulin glargine using 10 ml vial and syringe and once weekly placebo for 26 weeks.

    Reporting group values
    		 Insulin 287 Insulin glargine Total
    Number of subjects
    		 125 122 247
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 85 82 167
        From 65-84 years
    		 40 40 80
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.7 ( 8.2 ) 59.4 ( 9.5 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 55 53 108
        Male
    		 70 69 139

    End points

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    End points reporting groups
    Reporting group title
    Insulin 287
    Reporting group description
    		 Subjects were to receive once weekly s.c. injection of insulin 287 using PDS290 prefilled pen-injector and once daily placebo for 26 weeks.

    Reporting group title
    Insulin glargine
    Reporting group description
    		 Subjects were to receive once daily s.c injection of Insulin glargine using 10 ml vial and syringe and once weekly placebo for 26 weeks.

    Primary: Change in glycated haemoglobin (HbA1c) (%-point)

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    End point title
    		 Change in glycated haemoglobin (HbA1c) (%-point)
    End point description
    Change in HbA1c from baseline (week 0) to week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. The Full analysis set (FAS) included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Primary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    122
    120
    Units: Percentage point (%-point) of HbA1c
    least squares mean (standard error)
        %-point
    -1.33 ( 0.07 )
    -1.15 ( 0.07 )
    Statistical analysis title
    		 Insulin 287 vs Insulin glargine
    Statistical analysis description
    The change from baseline in response after 26 weeks is analysed using a linear mixed model for repeated measures (MMRM) with an unstructured covariance matrix and treatment, region, use of DPP-4 inhibitor and visit as fixed factors, and baseline response as covariate. Furthermore, the model includes the interaction between visit and all explanatory variables.
    Comparison groups
    Insulin 287 v Insulin glargine
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0818
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 0.02

    Primary: Change in glycated haemoglobin (HbA1c) (mmol/mol)

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    End point title
    		 Change in glycated haemoglobin (HbA1c) (mmol/mol)
    End point description
    Change in HbA1c from baseline (week 0) to 26 weeks of treatment is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, started at the date of first dose of trial product until the last dose of trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/-DPP4i, or increased the dose of metformin or DPP4i, or the end of the treatment if no ancillary treatment was initiated. The FAS included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Primary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    122
    120
    Units: millimoles per mole (mmol/mol)
        least squares mean (standard error)
    -14.51 ( 0.79 )
    -12.54 ( 0.80 )
    Statistical analysis title
    		 Insulin 287 vs Insulin glargine
    Statistical analysis description
    The change from baseline in response after 26 weeks is analysed using a linear mixed model for repeated measures (MMRM) with an unstructured covariance matrix and treatment, region, use of DPP-4 inhibitor and visit as fixed factors, and baseline response as covariate. Furthermore, the model includes the interaction between visit and all explanatory variables.
    Comparison groups
    Insulin 287 v Insulin glargine
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0818
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.19
         upper limit
    		 0.25

    Secondary: Change in fasting plasma glucose (mmol/l)

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    End point title
    		 Change in fasting plasma glucose (mmol/l)
    End point description
    Change in fasting plasma glucose (PG) from baseline (week 0) to week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. The FAS included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    121
    116
    Units: Millimoles per liter (mmol/l)
        least squares mean (standard error)
    -3.20 ( 0.16 )
    -2.99 ( 0.16 )
    No statistical analyses for this end point

    Secondary: Nine (9)-point profile (individual self-measured plasma glucose (SMPG) values) (mmol/l)

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    End point title
    		 Nine (9)-point profile (individual self-measured plasma glucose (SMPG) values) (mmol/l)
    End point description
    Subjects measured their plasma glucose (PG) using blood glucose meters (as plasma equivalent values of capillary whole blood glucose) at 9 time points represented in the table. 9-point SMPG profile after 26 weeks is presented. Results are based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product +5 weeks for once daily insulin and +6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, increase of the dose of metformin or DPP4i.The FAS included all randomised participants. The 'n' refers to the number of subjects contributing to the analysis for specific time point of the 9-point profile.
    End point type
    Secondary
    End point timeframe
    At week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    125
    122
    Units: mmol/l
    least squares mean (standard error)
        Before breakfast (n = 109,108)
    5.70 ( 0.19 )
    6.19 ( 0.19 )
        90 minutes after start of breakfast (n = 103, 107)
    7.90 ( 0.19 )
    8.51 ( 0.19 )
        Before lunch (n = 109, 106)
    6.09 ( 0.19 )
    6.19 ( 0.19 )
        90 minutes after start of lunch (n = 107, 106)
    7.83 ( 0.19 )
    8.50 ( 0.19 )
        Before main evening meal (n = 108, 107)
    6.55 ( 0.19 )
    6.96 ( 0.19 )
        90min after start of main evening meal(n=106,104)
    8.01 ( 0.19 )
    8.47 ( 0.19 )
        Before bedtime (n = 104, 105)
    7.35 ( 0.19 )
    7.87 ( 0.19 )
        At 4:00 a.m. (n = 101, 102)
    5.72 ( 0.19 )
    5.98 ( 0.19 )
        Before breakfast the following day (n = 109, 108)
    5.74 ( 0.19 )
    6.05 ( 0.19 )
    No statistical analyses for this end point

    Secondary: Change in mean of the 9-point profile, defined as the area under the profile divided by measurement time (mmol/l)

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    End point title
    		 Change in mean of the 9-point profile, defined as the area under the profile divided by measurement time (mmol/l)
    End point description
    Subjects measured their PG levels using blood glucose meters at 9 time points. Change from baseline (week 0) to week 26 is presented. Mean of the 9-point profile was defined as the area under the profile divided by measurement time. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i.The FAS included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    112
    111
    Units: mmol/l
        least squares mean (standard error)
    -2.70 ( 0.12 )
    -2.26 ( 0.12 )
    No statistical analyses for this end point

    Secondary: Fluctuations of the 9-point profile (defined as the integrated absolute distance from the mean profile value divided by measurement time) (mmol/l)

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    End point title
    		 Fluctuations of the 9-point profile (defined as the integrated absolute distance from the mean profile value divided by measurement time) (mmol/l)
    End point description
    Subjects measured their PG levels using blood glucose meters at 9 time points. Presented fluctuation in 9-point SMPG profile is the integrated absolute distance from the mean profile value divided by measurement time. Results are based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product +5 weeks for once daily insulin and +6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/-DPP4i, or increase of the dose of metformin or DPP4i.The FAS included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Secondary
    End point timeframe
    At week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    112
    111
    Units: mmol/l
        least squares mean (confidence interval 95%)
    0.92 (0.84 to 1.01)
    0.94 (0.86 to 1.03)
    No statistical analyses for this end point

    Secondary: Change in fasting C-peptide

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    End point title
    		 Change in fasting C-peptide
    End point description
    Fasting C-peptide at week 26 is presented (absolute value). The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. The FAS included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    115
    112
    Units: Nanomoles per liter (nmol/l)
        least squares mean (confidence interval 95%)
    0.44 (0.40 to 0.48)
    0.47 (0.43 to 0.51)
    No statistical analyses for this end point

    Secondary: Change in body weight (kilogram)

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    End point title
    		 Change in body weight (kilogram)
    End point description
    Change in body weight from baseline (week 0) to week 26 is presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. The FAS included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    122
    119
    Units: Kilogram
        least squares mean (standard error)
    1.49 ( 0.36 )
    1.56 ( 0.37 )
    No statistical analyses for this end point

    Secondary: Weekly dose of insulin 287 and weekly dose of IGlar (U)

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    End point title
    		 Weekly dose of insulin 287 and weekly dose of IGlar (U)
    End point description
    Weekly dose of insulin 287 and weekly dose of glargine from week 24 visit to week 26 visit (at week 25 and week 26) are presented. The endpoint was evaluated based on the data from on-treatment without ancillary treatment period, starting at the date of first dose of trial product until the follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin, or initiation of any diabetes treatment other than trial products and metformin +/- DPP4i, or increase of the dose of metformin or DPP4i. The FAS included all randomised participants. The number of subject analyzed is the number of subjects contributing to the analysis.
    End point type
    Secondary
    End point timeframe
    Week 24-26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    120
    117
    Units: Units of Insulin (U)
        least squares mean (confidence interval 95%)
    229.06 (205.08 to 255.83)
    284.05 (253.97 to 317.71)
    No statistical analyses for this end point

    Secondary: Number of treatment emergent adverse events (TEAEs)

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    End point title
    		 Number of treatment emergent adverse events (TEAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical trial subject administered or using a medicinal product, whether or not considered related to the medicinal product or usage. A TEAE was defined as an event that had onset date (or increase in severity) during the on-treatment observation period. The endpoint was evaluated based on the data from on-treatment period, starting at the date of first dose of trial product, and ending at follow-up visit, or the last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly insulin. The safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or comparator.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0)-week 31
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    125
    122
    Units: Number of events
    229
    158
    No statistical analyses for this end point

    Secondary: Number of hypoglycaemic alert episodes (level 1) (greater than or equal to 3.0 and less than 3.9 mmol/L (greater than or equal to 54 and less than70 mg/dL), confirmed by blood glucose (BG) meter)

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    End point title
    		 Number of hypoglycaemic alert episodes (level 1) (greater than or equal to 3.0 and less than 3.9 mmol/L (greater than or equal to 54 and less than70 mg/dL), confirmed by blood glucose (BG) meter)
    End point description
    Hypoglycaemia alert value (level 1) was defined as episodes that were sufficiently low for treatment with fast-acting carbohydrate and dose adjustment of glucose-lowering therapy with plasma glucose value of equal to or above (>=) 3.0 and less than (<) 3.9 mmol/L (>= 54 and < 70 mg/dL) confirmed by BG meter. Number of hypoglycaemic alert episodes (level 1) that occurred from week 0 to week 26 are presented. The SAS included all subjects who received at least one dose of the investigational product or comparator.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0)-week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    125
    122
    Units: Number of events
    358
    145
    No statistical analyses for this end point

    Secondary: Number of clinically significant hypoglycaemic episodes (level 2) (less than 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3)

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    End point title
    		 Number of clinically significant hypoglycaemic episodes (level 2) (less than 3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3)
    End point description
    Clinically significant hypoglycaemic episodes (level 2) were defined as episodes that were sufficiently low to indicate serious, clinically important hypoglycaemia with plasma glucose value of less than (<) 3.0 mmol/L (54 mg/dL). Severe hypoglycaemic episodes (level 3) were defined as episodes that were associated with severe cognitive impairment requiring external assistance for recovery. Number of clinically significant hypoglycaemic episodes (level 2), confirmed by BG meter or severe hypoglycaemic episodes (level 3) that occurred from week 0 to week 26 are presented. The SAS included all subjects who received at least one dose of the investigational product or comparator.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0)-week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    125
    122
    Units: Number of events
    38
    31
    No statistical analyses for this end point

    Secondary: Number of severe hypoglycaemic episodes (level 3)

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    End point title
    		 Number of severe hypoglycaemic episodes (level 3)
    End point description
    Severe hypoglycaemic episodes (level 3) were defined as episodes that were associated with severe cognitive impairment requiring external assistance for recovery. Number of severe hypoglycaemic episodes that occurred from week 0 to week 26 are presented. The SAS included all subjects who received at least one dose of the investigational product or comparator.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0)-week 26
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    125
    122
    Units: Number of events
    1
    0
    No statistical analyses for this end point

    Secondary: Change in anti-insulin 287 antibodies level

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    End point title
    		 Change in anti-insulin 287 antibodies level
    End point description
    Change in anti-insulin 287 antibodies level is not assessed because change in anti-insulin 287 antibody titres is a more meaningful way of describing the change in antibody levels. The results for change in anti-insulin 287 antibody titres are reported as a separate endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0)-week 31
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: % bound over total insulin 287 (%B/T)
        number (not applicable)
    Notes
    [1] - Change in anti-insulin 287 antibody titres was measured to assess the change in antibody levels.
    [2] - Change in anti-insulin 287 antibody titres was measured to assess the change in antibody levels.
    No statistical analyses for this end point

    Secondary: Change in anti-insulin 287 antibody titres

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    End point title
    		 Change in anti-insulin 287 antibody titres [3]
    End point description
    Samples from the insulin 287 arm of the study were analysed for anti-insulin 287 antibodies. Confirmed anti-insulin 287 antibody positive samples had an antibody titre value determined. The endpoint was evaluated based on the data from in-trial period, starting at randomisation, and ending at the last direct participant-site contact, or when participant withdrew their informed consent, or the last participant-investigator contact for participants lost to follow-up, or death. The SAS included all subjects who received at least one dose of the investigational product or comparator.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0)-week 31
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable only for Insulin 287 reporting group
    End point values
    		 Insulin 287
    Number of subjects analysed
    119
    Units: No Unit
        arithmetic mean (standard deviation)
    979.9 ( 3177.9 )
    No statistical analyses for this end point

    Secondary: Change in cross-reactive anti-human insulin antibody status (positive/negative)

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    End point title
    		 Change in cross-reactive anti-human insulin antibody status (positive/negative)
    End point description
    Anti-insulin 287 or glargine antibodies were classified as negative if % B/T was below a certain cut point. Samples positive for anti-insulin 287 or glargine antibodies were further tested for cross-reactivity to endogenous insulin. Samples not further tested are categorised as not applicable (NA). Unknown refers to samples with insufficient volume to perform analysis. The endpoint was evaluated based on the data from in-trial period, starting at randomisation, and ending at the last direct subject-site contact, or when subject withdrew their informed consent, or the last subject-investigator contact for subjects lost to follow-up, or death. The SAS included all subjects who received at least one dose of the investigational product or comparator. The 'n' refers to number of subjects with sample available.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0)-week 31
    End point values
    		 Insulin 287 Insulin glargine
    Number of subjects analysed
    125
    122
    Units: Number of subjects
    number (not applicable)
        Week 0 - Negative (n=125,122)
    0
    1
        Week 0 - Positive (n=125,122)
    0
    0
        Week 0 - Unknown (n=125,122)
    1
    9
        Week 0 - Not applicable (n=125,122)
    124
    112
        Week 31- Negative (n=120,115)
    9
    0
        Week 31- Positive (n=120,115)
    86
    26
        Week 31- Unknown (n=120,115)
    0
    0
        Week 31- Not Applicable (n=120,115)
    25
    89
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 0 to Week 31 Results are based on the SAS which included all subjects who received at least one dose of Insulin 287 or Insulin glargine. The SAS included all subjects who received at least one dose of the investigational product or comparator.
    Adverse event reporting additional description
    A TEAE was defined as an event that had onset date (or increase in severity) during the on-treatment observation period. The on-treatment observation period was the time period from 1st dose of trial product (week 0) until follow-up visit (week 31) or last date on trial product +5 weeks for once daily insulin and +6 weeks for once weekly insulin.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Insulin 287
    Reporting group description
    		 Subjects were to receive once weekly s.c. injection of insulin 287 using PDS290 prefilled pen-injector and once daily placebo for 26 weeks.

    Reporting group title
    Insulin glargine
    Reporting group description
    		 Subjects were to receive once daily s.c injection of Insulin glargine using 10 ml vial and syringe and once weekly placebo for 26 weeks.

    Serious adverse events
    		 Insulin 287 Insulin glargine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 125 (1.60%)
    3 / 122 (2.46%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral disorder
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Melaena
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatosplenomegaly
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         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 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Emphysematous pyelonephritis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         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
    		 Insulin 287 Insulin glargine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 125 (20.80%)
    16 / 122 (13.11%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 125 (11.20%)
    3 / 122 (2.46%)
         occurrences all number
    31
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 125 (8.00%)
    8 / 122 (6.56%)
         occurrences all number
    12
    9
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 125 (5.60%)
    6 / 122 (4.92%)
         occurrences all number
    7
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32960514
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