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    Clinical Trial Results:
    An 8-week randomised, double-blind, parallel, multiple dose trial comparing NNC0123-0000-0338 in a tablet formulation and insulin glargine in subjects with type 2 diabetes currently treated with oral antidiabetic therapy

    Summary
    EudraCT number
    		 2014-002716-16
    Trial protocol
    		 DE  
    Global end of trial date
    31 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2017
    First version publication date
    07 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1953-4163
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02470039
    WHO universal trial number (UTN)
    		 U1111-1158-3620
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsværd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, 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
    22 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the glycaemic control after 8 weeks of treatment with oral insulin 338 in aGIPET® I tablet formulation versus s.c. insulin glargine, when both are administered once daily in combination with metformin ± DPP-4 inhibitor in subjects with T2DM inadequately controlled on oral antidiabetic therapy
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and ICH Good Clinical Practice (1996). The trial was conducted in accordance with FDA 21 CFR 312.120.
    Background therapy
    		 The non-investigational medicinal products in this trial were metformin and dipeptidyl-peptidase-4 (DPP-4) inhibitor (oral administration). The background treatment was open-label throughout the trial and subjects received their usual medication per prescription from their primary physician.
    Evidence for comparator
    		 Not Applicable
    Actual start date of recruitment
    01 Jun 2015
    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
    Germany: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    33
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 2 trial sites in Germany.

    Pre-assignment
    Screening details
    		 A 2-week run-in period: to avoid carryover effects from discontinued oral anti-diabetic treatment prior to randomisation and to ensure adequate time to achieve stable glycaemic control for evaluation of hypoglycaemia and pharmacodynamics effect. A maximum daily/tolerated dose of metformin±DPP-4 inhibitor was unchanged during the run-in period.

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    A double-blind trial; treatment was blinded by all subjects receiving active and placebo treatment. All tablets and solutions (active or placebo) were visually identical to ensure blinding. The trial drugs were packed blinded at Novo Nordisk A/S. The dumas were blinded within tablet strengths (i.e. a similar package for a duma with 900 nmol oral insulin 338 and a duma with oral placebo, etc.). A vial cover was used to blind the s.c. insulin glargine (Lantus®) and the placebo vial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oral Insulin 338
    Arm description
    		 Insulin 338/placebo (matched to insulin glargine - 10 ml) were taken orally/subcutaneously once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the comparator (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for oral insulin 338 was 2,700 nmol (a lower starting dose of 900-1,350 nmol could be selected at the discretion of the investigator) and the maximum allowed daily dose was 16,200 nmol. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NNCO123-0338
    Investigational medicinal product code
    Other name
    Insulin 338
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral Insulin 338 tablets (strengths of 900, 1350, 2700, 5400, 8100, 10,800 nmol) were taken orally once daily in about 100 ml of water in combination with metformin with or without DPP-4 inhibitor every morning of the 8 week treatment period. A maximum daily dose of 16,200 nmol oral insulin 338 was allowed.

    Investigational medicinal product name
    Placebo matched to Insulin Glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo solution (10 ml) was administered subcutaneously into a lifted skin fold on the anterior surface of the thigh once daily in combination with metformin with or without DPP-4 inhibitor every morning of the 8 week treatment period

    Arm title
    		 Subcutaneous Insulin Glargine
    Arm description
    		 Insulin glargine/placebo (matched to oral insulin 338 - 0 nmol) were taken subcutaneously/orally once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the investigational product (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for insulin glargine was 10 units (a lower starting dose of 3-5 units could be selected at the discretion of the investigator) and the maximum allowed daily dose was 60 units. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo matched to Insulin 338
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral placebo tablets (0 nmol) were taken orally once daily in about 100 ml of water in combination with metformin with or without DPP-4 inhibitor every morning of the 8 week treatment period

    Investigational medicinal product name
    Insulin Glargine
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous insulin glargine (100U/mL) was administered subcutaneously into a lifted skin fold on the anterior surface of the thigh once daily in combination with metformin with or without DPP-4 inhibitor every morning of the 8 week treatment period. A maximum daily dose of 60 units s.c. insulin glargine was allowed.

    Number of subjects in period 1
    		Oral Insulin 338 Subcutaneous Insulin Glargine
    Started
    25
    25
    Completed
    24
    25
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral Insulin 338
    Reporting group description
    		 Insulin 338/placebo (matched to insulin glargine - 10 ml) were taken orally/subcutaneously once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the comparator (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for oral insulin 338 was 2,700 nmol (a lower starting dose of 900-1,350 nmol could be selected at the discretion of the investigator) and the maximum allowed daily dose was 16,200 nmol. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.

    Reporting group title
    Subcutaneous Insulin Glargine
    Reporting group description
    		 Insulin glargine/placebo (matched to oral insulin 338 - 0 nmol) were taken subcutaneously/orally once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the investigational product (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for insulin glargine was 10 units (a lower starting dose of 3-5 units could be selected at the discretion of the investigator) and the maximum allowed daily dose was 60 units. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.

    Reporting group values
    		 Oral Insulin 338 Subcutaneous Insulin Glargine Total
    Number of subjects
    		 25 25 50
    Age, Customized
    Units: participants
        18-64 years
    		 15 18 33
        65-84 years
    		 10 7 17
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.2 ( 7.2 ) 60.8 ( 6.3 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 2 8 10
        Male
    		 23 17 40
    Study Specific Characteristic | Fasting Plasma Glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.7 ( 2.8 ) 9.13 ( 1.71 ) -

    End points

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    End points reporting groups
    Reporting group title
    Oral Insulin 338
    Reporting group description
    		 Insulin 338/placebo (matched to insulin glargine - 10 ml) were taken orally/subcutaneously once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the comparator (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for oral insulin 338 was 2,700 nmol (a lower starting dose of 900-1,350 nmol could be selected at the discretion of the investigator) and the maximum allowed daily dose was 16,200 nmol. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.

    Reporting group title
    Subcutaneous Insulin Glargine
    Reporting group description
    		 Insulin glargine/placebo (matched to oral insulin 338 - 0 nmol) were taken subcutaneously/orally once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the investigational product (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for insulin glargine was 10 units (a lower starting dose of 3-5 units could be selected at the discretion of the investigator) and the maximum allowed daily dose was 60 units. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.

    Primary: Fasting plasma glucose (FPG)

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    End point title
    		 Fasting plasma glucose (FPG)
    End point description
    Fasting plasma glucose after 8 weeks of treatment. Full analysis set included all randomised subjects receiving at least one dose of oral insulin 338 or subcutaneous insulin glargine. Number of subjects analyzed=subjects with data available for this endpoint.
    End point type
    Primary
    End point timeframe
    After 8 weeks of treatment
    End point values
    		 Oral Insulin 338 Subcutaneous Insulin Glargine
    Number of subjects analysed
    23
    25
    Units: mmol/L
        arithmetic mean (standard deviation)
    7.18 ( 1.86 )
    6.71 ( 0.94 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The results are from MMRM analysis from day 7, 14, 21, 28, 35, 42, 49, 55 and 56 with treatment and strata as factors and baseline FPG as a covariate, all nested within day. An unstructured covariance matrix describes the variability for the repeated measurements for a subject. The residual variance is depending on treatment. The treatment difference refers to "oral insulin 338 minus subcutaneous insulin glargine. There were 50 subjects, rather than 48 subjects contributing to this analysis.
    Comparison groups
    Oral Insulin 338 v Subcutaneous Insulin Glargine
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4567
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 1.06

    Secondary: 10-points plasma glucose profile

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    End point title
    		 10-points plasma glucose profile
    End point description
    Measurements were performed pre-dose, before and after (90 min after start of the meal) meals (i.e. break-fast, lunch, and main evening meals), at bedtime, at 04:00 in the morning and pre-dose on the following day. Full analysis set was evaluated. Here, 'n' specifies the number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment
    End point values
    		 Oral Insulin 338 Subcutaneous Insulin Glargine
    Number of subjects analysed
    25
    25
    Units: mmol/L
    arithmetic mean (standard deviation)
        Pre-dose (n=23, 25)
    7.18 ( 1.86 )
    6.71 ( 0.94 )
        Before breakfast (n=22, 25)
    7.03 ( 1.6 )
    6.39 ( 0.97 )
        90 min after breakfast (n=22, 25)
    11.9 ( 3.36 )
    10.97 ( 2.03 )
        Before Lunch (n=22, 25)
    8.06 ( 2.06 )
    6.77 ( 1.83 )
        90 min after lunch (n=22, 25)
    9.74 ( 3.1 )
    8.79 ( 1.82 )
        Before main evening meal (n=22, 25)
    7.14 ( 1.23 )
    6.51 ( 1.81 )
        90 min after main evening meal (n=22, 25)
    10.02 ( 2.39 )
    9.92 ( 1.68 )
        Bedtime (n=22, 25)
    9.19 ( 2.61 )
    8.67 ( 2.12 )
        At 4 am (n=22, 25)
    6.46 ( 1.37 )
    5.6 ( 0.92 )
        Pre-dose on following day (n=22, 25)
    6.85 ( 1.73 )
    6.44 ( 1 )
    No statistical analyses for this end point

    Secondary: Number of treatment emergent hypoglycaemic episodes

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    End point title
    		 Number of treatment emergent hypoglycaemic episodes
    End point description
    Treatment emergent episodes (American Diabetes Association) occurred from first trial product administration on day 1 until end of day 68 (visit 14). Safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or its comparator. The subjects in the SAS contributed to the evaluation ‘as treated’. Number of subjects analyzed=subjects with data available for this endpoint.
    End point type
    Secondary
    End point timeframe
    From start of treatment until Visit 14 (Day 68)
    End point values
    		 Oral Insulin 338 Subcutaneous Insulin Glargine
    Number of subjects analysed
    25
    25
    Units: events
    7
    11
    No statistical analyses for this end point

    Secondary: Area under the serum insulin concentration-time curve

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    End point title
    		 Area under the serum insulin concentration-time curve
    End point description
    AUCIns,τ,SS: Area under the serum insulin concentration-time curve during one dosing interval (0 to 24-hours) at steady state (days 56). Number of subjects analyzed=subjects with data available for this endpoint.
    End point type
    Secondary
    End point timeframe
    During one dosing interval (0 to 24 hours) at steady state (Day 56)
    End point values
    		 Oral Insulin 338 Subcutaneous Insulin Glargine
    Number of subjects analysed
    22
    25
    Units: pmol*h/L
        median (full range (min-max))
    666142 (160307 to 3358750)
    1988 (227 to 4252)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent AEs occurring after first dose on day 1 (visit 3) to end-of-day 68 (visit 14); end-of-treatment was on day 56 (visit 11).
    Adverse event reporting additional description
    Safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or its comparator. The subjects in the SAS contributed to the evaluation ‘as treated’.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Subcutaneous Insulin Glargine
    Reporting group description
    		 Insulin glargine/placebo (matched to oral insulin 338 - 0 nmol) were taken subcutaneously/orally once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the investigational product (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for insulin glargine was 10 units (a lower starting dose of 3-5 units could be selected at the discretion of the investigator) and the maximum allowed daily dose was 60 units. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.

    Reporting group title
    Oral Insulin 338
    Reporting group description
    		 Insulin 338/placebo (matched to insulin glargine - 10 ml) were taken orally/subcutaneously once daily for 8 weeks. The insulin dose was adjusted once weekly using the same titration algorithm as for the comparator (assuming that 2,700 nmol oral insulin 388 corresponded to 10 units s.c. insulin glargine) and was based on the mean of 3 preceding daily pre-dose self-measured plasma glucose (SMPG) values on 3 consecutive days. The starting dose for oral insulin 338 was 2,700 nmol (a lower starting dose of 900-1,350 nmol could be selected at the discretion of the investigator) and the maximum allowed daily dose was 16,200 nmol. Subjects continued pre-trial metformin with or without DPP-4 inhibitor throughout the entire trial.

    Serious adverse events
    		 Subcutaneous Insulin Glargine Oral Insulin 338
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Renal and urinary disorders
    Urogenital haemorrhage
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Subcutaneous Insulin Glargine Oral Insulin 338
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 25 (40.00%)
    10 / 25 (40.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 25 (12.00%)
         occurrences all number
    4
    4
    Dyspepsia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    5 / 25 (20.00%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2015
    1. Implementation of additional information in the protocol on local effects of oral insulin 338 in the gastro-intestinal tract. 2. Implementation of severe hypoglycaemic episodes as withdrawal criteria in protocol. 3. Revision of the subject information/informed consent form to include more information on local effects of oral insulin 338 in the gastro-intestinal tract. 4. Revision of the subject information/informed consent form changing the wording from “a large proportion” to “many” subjects with T2DM. 5. Revision of the subject information/informed consent form to include an explanation of the relationship between doses of oral insulin 338 (given in nmol) and s.c.insulin glargine (given in units).

    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.
    Analysis of pharmacokinetic data: the anti-drug antibody formation influence on the insulin 338 assay performances could not be ruled out. Also, insulin 338 and insulin glargine are different chemical entities and they should not be compared directly
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