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    Clinical Trial Results:
    A 6-week randomised, double-blind, parallel-group trial evaluating compatibility and safety of FIAsp and insulin aspart with an external continuous subcutaneous insulin infusion system in adult subjects with type 1 diabetes

    Summary
    EudraCT number
    2013-002233-37
    Trial protocol
    DE  
    Global end of trial date
    14 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1218-3931
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01999322
    WHO universal trial number (UTN)
    U1111-1143-2316
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allè, Bagsvaerd, Denmark, 2860
    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
    12 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the compatibility of faster-acting insulin aspart (FIAsp) and insulin aspart with the external continuous subcutaneous insulin infusion (CSII) system over a 6-week treatment period.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice and 21 CFR 312.120.
    Background therapy
    Eligible subjects previously treated with a rapid-acting insulin analogue were to stay on their own NovoRapid®, insulin lispro or insulin glulisine in the screening period, after which all subjects received NovoRapid®, with no additional anti-diabetes treatment allowed, for a 2-week run-in period prior to randomisation.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    19 Nov 2013
    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
    United States: 10
    Country: Number of subjects enrolled
    Germany: 27
    Worldwide total number of subjects
    37
    EEA total number of subjects
    27
    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)
    31
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at two sites in two countries as follows: USA: one site; Germany one site.

    Pre-assignment
    Screening details
    Eligible subjects previously treated with a rapid acting insulin analogue were to stay in their own NovoRapid®, insulin lispro or insulin glulisine in the screening period after which the all subjects received NovoRapid®, with no additional antidiabetics allowed, for a 2-week run-in period prior to randomisation.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    This trial was double-blinded. The randomisation in this study was 2:1.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Faster-acting insulin aspart
    Arm description
    Subjects received faster-acting insulin aspart for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL). A 2:1 randomisation following the screening period was selected in order to ensure adequate exposure to faster-acting insulin aspart.
    Arm type
    Experimental

    Investigational medicinal product name
    Faster-acting insulin aspart
    Investigational medicinal product code
    Other name
    INSULIN ASPART
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Faster-acting insulin aspart was provided in 100U/ml 3 mL Penfill® and administered in accordance with the instructions provided by the pump manufacturer, preferably in the abdomen by subcutaneous infusion. Subjects were instructed in how to fill the reservoir from Penfill®. The subjects remained on their own external CSII system. Subjects were instructed to change infusion set and reservoir every 72 hours (± 4 hours) and only before 72 hours (± 4 hours) if there is any suspicion of occlusion, leakage, unexplained hyperglycaemic episode, infusion site reaction, technical reason or other reason. Infusion sites were to be rotated but the infusion set was to be inserted in a standardised way in a similar position. No maximum dose was specified. Doses were adjusted according to plasma glucose and the bolus dose was calculated manually or by using pump bolus calculator.

    Arm title
    NovoRapid®
    Arm description
    Subjects received NovoRapid® for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL).
    Arm type
    Active comparator

    Investigational medicinal product name
    NovoRapid®
    Investigational medicinal product code
    Other name
    INSULIN ASPART
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NovoRapid® was provided in 100U/ml 3 ml Penfill® and administered in accordance with the instructions provided by the pump manufacturer, preferably in the abdomen by subcutaneous infusion. The subjects remained on their own external CSII system. Subjects were instructed to change infusion set and reservoir every 72 hours (± 4 hours) and only before 72 hours (± 4 hours) if there is any suspicion of occlusion, leakage, unexplained hyperglycaemic episode, infusion site reaction, technical reason or other reason. Infusion sites were to be rotated but the infusion set was to be inserted in a standardised way in a similar position. No maximum dose was specified. Doses were adjusted according to plasma glucose and the bolus dose was calculated manually or by using pump bolus calcualtor.

    Number of subjects in period 1
    Faster-acting insulin aspart NovoRapid®
    Started
    25
    12
    Completed
    24
    12
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Faster-acting insulin aspart
    Reporting group description
    Subjects received faster-acting insulin aspart for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL). A 2:1 randomisation following the screening period was selected in order to ensure adequate exposure to faster-acting insulin aspart.

    Reporting group title
    NovoRapid®
    Reporting group description
    Subjects received NovoRapid® for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL).

    Reporting group values
    Faster-acting insulin aspart NovoRapid® Total
    Number of subjects
    25 12 37
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    19 12 31
        From 65-84 years
    6 0 6
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    11 4 15
        Male
    14 8 22

    End points

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    End points reporting groups
    Reporting group title
    Faster-acting insulin aspart
    Reporting group description
    Subjects received faster-acting insulin aspart for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL). A 2:1 randomisation following the screening period was selected in order to ensure adequate exposure to faster-acting insulin aspart.

    Reporting group title
    NovoRapid®
    Reporting group description
    Subjects received NovoRapid® for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL).

    Primary: Number of microscopically confirmed episodes of infusion set occlusions.

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    End point title
    Number of microscopically confirmed episodes of infusion set occlusions. [1]
    End point description
    Microscopy was conducted at the laboratory at routine weekly site visits and if the infusion set was sent in by the subject following a premature change because of leakage, unexplained hyperglycaemia or suspicion of occlusion (observation of a plug).
    End point type
    Primary
    End point timeframe
    6 weeks of treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no specification of an analysis in the protocol or in the statistical analysis plan.
    End point values
    Faster-acting insulin aspart NovoRapid®
    Number of subjects analysed
    25
    12
    Units: Number of subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of unexplained episodes of hyperglycaemia

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    End point title
    Number of unexplained episodes of hyperglycaemia
    End point description
    Unexplained hyperglycaemia was defined as a confirmed plasma glucose value ≥ 16.7 mmol/L (300 mg/dL) and was unexplained (i.e., no apparent medical, dietary, insulin dosage or pump failure reason)
    End point type
    Secondary
    End point timeframe
    During 6 weeks of treatment
    End point values
    Faster-acting insulin aspart NovoRapid®
    Number of subjects analysed
    25
    12
    Units: Number of events
    28
    16
    No statistical analyses for this end point

    Secondary: Number of possible infusion set occlusions

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    End point title
    Number of possible infusion set occlusions
    End point description
    Episodes of possible infusion set occlusions were defined as infusion sets changed due to suspicion of occlusion, leakage or unexplained hyperglycaemic episode. Possible occlusion excluded technical reasons. This endpoint was calculated from the recorded date/times of changes of infusion set combined with the subjects’ own assessment.
    End point type
    Secondary
    End point timeframe
    During 6 weeks of treatment
    End point values
    Faster-acting insulin aspart NovoRapid®
    Number of subjects analysed
    25
    12
    Units: Number of episodes
    7
    0
    No statistical analyses for this end point

    Secondary: Number of premature infusion set changes

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    End point title
    Number of premature infusion set changes
    End point description
    A premature infusion set change was defined as not being a routine change. This was defined as an infusion set changed at home due to "suspicion of occlusion", "leakage", "unexplained hyperglycaemic episode", "infusion site reaction", "technical reason", or "other". The change of infusion set at a site visit was considered a routine change unless an occlusion was actually suspected at the site.
    End point type
    Secondary
    End point timeframe
    During 6 weeks of treatment.
    End point values
    Faster-acting insulin aspart NovoRapid®
    Number of subjects analysed
    25
    12
    Units: Number of episodes
    21
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs to be reported within 24 hours.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    NovoRapid®
    Reporting group description
    Subjects received NovoRapid® for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL).

    Reporting group title
    Faster-acting insulin aspart
    Reporting group description
    Subjects received faster-acting insulin aspart for a duration of 6 weeks. The insulin dose adjustments were made based on frequent glucose measurements during contacts with the investigator. The following glycaemic targets were recommended: pre-prandial and bedtime glucose: below 6.0 mmol/L (108 mg/dL) and 2-hr postprandial glucose: below 7.8 mmol/L (140 mg/dL).

    Serious adverse events
    NovoRapid® Faster-acting insulin aspart
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    NovoRapid® Faster-acting insulin aspart
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 12 (50.00%)
    9 / 25 (36.00%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Sinus congestion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 25 (12.00%)
         occurrences all number
    1
    3
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0

    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.
    The trial was designed in accordance with the draft FDA guideline dated 1985, that 15−20 subjects with diabetes given the modified insulin should be included for 6 weeks. However the trial was not powered to detect differences between treatments.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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