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    Clinical Trial Results:
    A trial comparing NNC0148-0287 C (insulin 287) versus insulin glargine U100, both in combination with metformin, with or without DPP4 inhibitors and with or without SGLT2 inhibitors, in insulin-naïve subjects with type 2 diabetes mellitus

    Summary
    EudraCT number
    2018-003406-11
    Trial protocol
    DE   SK   PL   HU   ES   HR  
    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
    NN1436-4465
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03951805
    WHO universal trial number (UTN)
    U1111-1219-5474
    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
    10 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 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
    The main objective of the trial was to compare the effect on glycaemic control of once weekly insulin 287 using 3 different titration algorithms, versus once daily insulin glargine U100, both in combination with metformin ± dipeptidyl peptidase 4 inhibitor (DPP4i) ± sodium-glucose cotransporter 2 inhibitor (SGLT2i) in insulin-naïve type 2 diabetes mellitus (T2DM) subjects.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (64th World Medical Association (WMA) general assembly; October 2013), International Council for Harmonisation (ICH) Good Clinical Practice, including archiving of essential documents, (09 November 2016) and 21 United States Code of Federal Regulations (CFR) 312.120 (Foreign Clinical Studies not Conducted Under an investigational new drug (IND), 2015).
    Background therapy
    Subjects were to receive metformin with or without dipeptidyl peptidase-4 inhibitors (DPP4i) and with or without sodium-glucose cotransporter 2 inhibitors (SGLT2i) in accordance with standard of care or local label in the individual country. Doses were to be maintained at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2019
    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
    Croatia: 29
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Slovakia: 27
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    205
    EEA total number of subjects
    174
    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)
    129
    From 65 to 84 years
    76
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 38 sites in 7 countries as follows: Croatia (4), Germany (9), Hungary (3), Poland (4), Slovakia (5), Spain (4), United States (9). In addition, 1 site in Slovakia and 3 sites in the United States screened, but didn’t randomise any subjects.

    Pre-assignment
    Screening details
    Subjects were randomised to receive once weekly insulin 287 using one of 3 different titration algorithms (A, B, C), or once daily insulin glargine (titration algorithm D).

    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
    Insulin 287 (Titration algorithm A)
    Arm description
    Subjects were to receive once weekly subcutaneous (s.c.) injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 units (U). The dose was adjusted weekly during the treatment period using titration algorithm A with American Diabetes Association (ADA) glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 21 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 21 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0148-0287 formulation 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 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm A with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 21 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 21 U.

    Arm title
    Insulin 287 (Titration algorithm B)
    Arm description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm B with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0148-0287 formulation 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 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm B with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 28 U.

    Arm title
    Insulin 287 (Titration algorithm C)
    Arm description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm C with glycaemic target of 3.9-6.0 mmol/L (70-108 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 3.9 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 3.9-6.0 mmol/L: no adjustment; > 6.0 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.
    Arm type
    Experimental

    Investigational medicinal product name
    NNC0148-0287 formulation 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 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm C with glycaemic target of 3.9-6.0 mmol/L (70-108 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 3.9 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 3.9-6.0 mmol/L: no adjustment; > 6.0 mmol/L: insulin dose increased by 28 U.

    Arm title
    Insulin glargine (Titration algorithm D)
    Arm description
    Subjects were to receive once daily s.c. injection of Insulin glargine for 16 weeks, using SoloSTAR pre-filled pen-injector at a starting dose of 10 U. The dose was adjusted weekly during the treatment period using titration algorithm D with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 4 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 4 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.
    Arm type
    Active comparator

    Investigational medicinal product name
    Insulin glargine U100
    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 for 16 weeks, using SoloSTAR pre-filled pen-injector at a starting dose of 10 U. The dose was adjusted weekly during the treatment period using titration algorithm D with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 4 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 4 U.

    Number of subjects in period 1
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Started
    51
    51
    52
    51
    Completed
    50
    51
    52
    51
    Not completed
    1
    0
    0
    0
         Adverse event, non-fatal
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin 287 (Titration algorithm A)
    Reporting group description
    Subjects were to receive once weekly subcutaneous (s.c.) injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 units (U). The dose was adjusted weekly during the treatment period using titration algorithm A with American Diabetes Association (ADA) glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 21 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 21 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin 287 (Titration algorithm B)
    Reporting group description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm B with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin 287 (Titration algorithm C)
    Reporting group description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm C with glycaemic target of 3.9-6.0 mmol/L (70-108 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 3.9 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 3.9-6.0 mmol/L: no adjustment; > 6.0 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin glargine (Titration algorithm D)
    Reporting group description
    Subjects were to receive once daily s.c. injection of Insulin glargine for 16 weeks, using SoloSTAR pre-filled pen-injector at a starting dose of 10 U. The dose was adjusted weekly during the treatment period using titration algorithm D with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 4 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 4 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D) Total
    Number of subjects
    51 51 52 51 205
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    59.8 ± 9.1 61.2 ± 8.0 61.4 ± 8.0 60.2 ± 8.1 -
    Gender Categorical
    Units: Subjects
        Female
    24 23 24 24 95
        Male
    27 28 28 27 110

    End points

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    End points reporting groups
    Reporting group title
    Insulin 287 (Titration algorithm A)
    Reporting group description
    Subjects were to receive once weekly subcutaneous (s.c.) injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 units (U). The dose was adjusted weekly during the treatment period using titration algorithm A with American Diabetes Association (ADA) glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast self-measured plasma glucose (SMPG) values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 21 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 21 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin 287 (Titration algorithm B)
    Reporting group description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm B with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin 287 (Titration algorithm C)
    Reporting group description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm C with glycaemic target of 3.9-6.0 mmol/L (70-108 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 3.9 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 3.9-6.0 mmol/L: no adjustment; > 6.0 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin glargine (Titration algorithm D)
    Reporting group description
    Subjects were to receive once daily s.c. injection of Insulin glargine for 16 weeks, using SoloSTAR pre-filled pen-injector at a starting dose of 10 U. The dose was adjusted weekly during the treatment period using titration algorithm D with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 4 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 4 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Primary: Time in target range 3.9–10.0 mmol/L (70-180 mg/dL) measured using continuous glucose monitoring (CGM)

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    End point title
    Time in target range 3.9–10.0 mmol/L (70-180 mg/dL) measured using continuous glucose monitoring (CGM)
    End point description
    Time spent in glycaemic target range was calculated as 100 times the number of recorded measurements in glycaemic target range 3.9–10.0 mmol/L (70-180 mg/dL), both inclusive divided by the total number of recorded measurements. The endpoint was evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a subject was considered exposed to trial product, excluding any period after initiation of a non-randomised insulin treatment (rescue medication). The endpoint is based on data recorded by CGM system. It was required that at least 70% of the planned CGM measurements during weeks 15-16 were available for endpoint data to be included in the analysis. FAS included all randomised subjects. Number of subjects analyzed = Number of subjects who contributed to the analysis.
    End point type
    Primary
    End point timeframe
    During the last 2 weeks of treatment (week 15 and 16)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    51
    50
    Units: Percentage of time
        least squares mean (standard error)
    76.65 ± 1.81
    82.97 ± 1.80
    80.89 ± 1.81
    75.89 ± 1.82
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The response and change from baseline in response during the last two weeks of treatment (week 15 and 16) are analysed using an analysis of covariance (ANCOVA) model with treatment and SGLT2i use as fixed factors, and baseline response as covariate. Missing endpoint values are imputed using multiple imputation based on own treatment arm with baseline response as a covariate. Each imputed dataset is analysed separately and estimates are combined using Rubin's rules.
    Comparison groups
    Insulin 287 (Titration algorithm A) v Insulin glargine (Titration algorithm D)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7675
    Method
    ANCOVA
    Parameter type
    Treatment difference
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.28
         upper limit
    5.8
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The response and change from baseline in response during the last two weeks of treatment (week 15 and 16) are analysed using an analysis of covariance (ANCOVA) model with treatment and SGLT2i use as fixed factors, and baseline response as covariate. Missing endpoint values are imputed using multiple imputation based on own treatment arm with baseline response as a covariate. Each imputed dataset is analysed separately and estimates are combined using Rubin's rules.
    Comparison groups
    Insulin 287 (Titration algorithm B) v Insulin glargine (Titration algorithm D)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0051
    Method
    ANCOVA
    Parameter type
    Treatment difference
    Point estimate
    7.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.12
         upper limit
    12.04
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The response and change from baseline in response during the last two weeks of treatment (week 15 and 16) are analysed using an analysis of covariance (ANCOVA) model with treatment and SGLT2i use as fixed factors, and baseline response as covariate. Missing endpoint values are imputed using multiple imputation based on own treatment arm with baseline response as a covariate. Each imputed dataset is analysed separately and estimates are combined using Rubin's rules.
    Comparison groups
    Insulin 287 (Titration algorithm C) v Insulin glargine (Titration algorithm D)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0519
    Method
    ANCOVA
    Parameter type
    Treatment difference
    Point estimate
    5.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.04
         upper limit
    10.05

    Secondary: Change in HbA1c

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    End point title
    Change in HbA1c
    End point description
    Estimated mean change in HbA1c (glycated haemoglobin) from baseline (week 0, visit 2) to end of treatment (week 16, visit 18) is presented. The endpoint was evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a subject was considered exposed to trial product, excluding any period after initiation of a non-randomised insulin treatment (rescue medication). FAS included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 16 (V18)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    52
    51
    Units: Percentage point of HbA1c
        least squares mean (standard error)
    -1.00 ± 0.08
    -1.22 ± 0.08
    -1.38 ± 0.08
    -1.02 ± 0.08
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose (FPG)

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    End point title
    Change in fasting plasma glucose (FPG)
    End point description
    Estimated mean change in FPG from baseline (week 0, visit 2) to end of treatment (week 16, visit 18) is presented. The endpoint was evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a subject was considered exposed to trial product, excluding any period after initiation of a non-randomised insulin treatment (rescue medication). FAS included all randomised subjects. Number of subjects analyzed = Number of subjects who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 16 (V18)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    50
    51
    49
    Units: Millimoles per liter (mmol/L)
        least squares mean (standard error)
    -2.23 ± 0.17
    -2.42 ± 0.17
    -3.01 ± 0.17
    -2.34 ± 0.17
    No statistical analyses for this end point

    Secondary: Change in body weight

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    End point title
    Change in body weight
    End point description
    Estimated mean change in body weight from baseline (week 0, visit 2) to end of treatment (week 16, visit 18) is presented. The endpoint was evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a subject was considered exposed to trial product, excluding any period after initiation of a non-randomised insulin treatment (rescue medication). FAS included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 16 (V18)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    52
    51
    Units: Kilogram (Kg)
        least squares mean (standard error)
    0.87 ± 0.35
    1.11 ± 0.35
    1.25 ± 0.35
    0.63 ± 0.35
    No statistical analyses for this end point

    Secondary: Weekly insulin dose

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    End point title
    Weekly insulin dose
    End point description
    Estimated mean average weekly insulin dose during the last 2 weeks of treatment is presented. The endpoint was evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a subject was considered exposed to trial product, excluding any period after initiation of a non-randomised insulin treatment (rescue medication). FAS included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    During the last 2 weeks of treatment (week 15 and 16)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    52
    51
    Units: Units of insulin
        least squares mean (confidence interval 95%)
    142.47 (119.78 to 169.45)
    176.38 (148.30 to 209.78)
    208.90 (175.94 to 248.04)
    145.56 (122.38 to 173.12)
    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
    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 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. Safety analysis set (SAS) included all subjects exposed to at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 21 (V20)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    52
    51
    Units: Count of events
    44
    67
    58
    45
    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 16 are presented. SAS included all subjects exposed to at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 16 (V18)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    52
    51
    Units: Count of events
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of clinically significant hypoglycaemic episodes (level 2) (below 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) (below 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 blood glucose (BG) meter or severe hypoglycaemic episodes (level 3) that occured from week 0 to week 16 are presented. SAS included all subjects exposed to at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 16 (V18)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    52
    51
    Units: Count of events
    1
    2
    8
    0
    No statistical analyses for this end point

    Secondary: Number of hypoglycaemic alert episodes (level 1) (equal to or above 3.0 and below 3.9 mmol/L (equal to or above 54 and below 70 mg/dL), confirmed by BG meter)

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    End point title
    Number of hypoglycaemic alert episodes (level 1) (equal to or above 3.0 and below 3.9 mmol/L (equal to or above 54 and below 70 mg/dL), confirmed by 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 < 3.9 mmol/L (>= 54 and < 70 mg/dL) confirmed by BG meter. Number of hypoglycaemic alert episodes (level 1) that occured from week 0 to week 16 are presented. SAS included all subjects exposed to at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 16 (V18)
    End point values
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Number of subjects analysed
    51
    51
    52
    51
    Units: Count of events
    14
    20
    110
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Weeks 0-21 Results are based on the safety analysis set which included all subjects exposed to at least one dose of trial product. All presented adverse events are treatment emergent adverse events (TEAEs).
    Adverse event reporting additional description
    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 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.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Insulin 287 (Titration algorithm A)
    Reporting group description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm A with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 21 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 21 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin 287 (Titration algorithm B)
    Reporting group description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm B with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin 287 (Titration algorithm C)
    Reporting group description
    Subjects were to receive once weekly s.c. injection of insulin 287 for 16 weeks, using PDS290 prefilled pen-injector at a starting dose of 70 U. The dose was adjusted weekly during the treatment period using titration algorithm C with glycaemic target of 3.9-6.0 mmol/L (70-108 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 3.9 mmol/L: insulin dose reduced by 28 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 3.9-6.0 mmol/L: no adjustment; > 6.0 mmol/L: insulin dose increased by 28 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Reporting group title
    Insulin glargine (Titration algorithm D)
    Reporting group description
    Subjects were to receive once daily s.c. injection of Insulin glargine for 16 weeks, using SoloSTAR pre-filled pen-injector at a starting dose of 10 U. The dose was adjusted weekly during the treatment period using titration algorithm D with ADA glycaemic target of 4.4-7.2 mmol/L (80-130 mg/dL), based on 3 pre-breakfast SMPG values measured on 2 previous days and on the day of the contact. If at least one pre-breakfast SMPG value was: < 4.4 mmol/L: insulin dose reduced by 4 U. Otherwise, the dose adjustment was based on the mean of SMPG values. If the mean was between 4.4-7.2 mmol/L: no adjustment; > 7.2 mmol/L: insulin dose increased by 4 U. All subjects used metformin with or without DPP4i and with or without SGLT2i at the stable, pre-trial dose and at the same frequency during the entire treatment period unless due to safety concerns related to the background medication.

    Serious adverse events
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Choroid neoplasm
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastasis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Insulin 287 (Titration algorithm A) Insulin 287 (Titration algorithm B) Insulin 287 (Titration algorithm C) Insulin glargine (Titration algorithm D)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 51 (17.65%)
    10 / 51 (19.61%)
    7 / 52 (13.46%)
    9 / 51 (17.65%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 51 (5.88%)
    5 / 52 (9.62%)
    2 / 51 (3.92%)
         occurrences all number
    0
    3
    7
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 51 (9.80%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    5
    3
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 51 (9.80%)
    7 / 51 (13.73%)
    2 / 52 (3.85%)
    6 / 51 (11.76%)
         occurrences all number
    7
    7
    2
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2019
    The following changes were made as per this amendment: • Addition of the wording ‘with or without SGLT2i inhibitors’ in title page • Inclusion criteria updated to allow subjects on SGLT2 inhibitors in addition to metformin ± DPP4i inhibitors, to be included in the trial • In connection to mentioning of background medication (metformin and DPP4i) SGLT2i was added in synopsis and statistical considerations • Addition of stratification of subjects based on whether or not they are entering the trial on SGLT2i or not in trial design and statistical consideration

    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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