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    Clinical Trial Results:
    A Double-blind, Randomized, Multicenter, Cross-over Study to Compare the Effect of Creon N and Creon® on Fat Digestion in Subjects ≥ 12 years of Age with Pancreatic Exocrine Insufficiency Due to Cystic Fibrosis

    Summary
    EudraCT number
    		 2013-002819-10
    Trial protocol
    		 HU   ES  
    Global end of trial date
    25 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Mar 2016
    First version publication date
    02 Mar 2016
    Other versions
    Summary report(s)
    		 Synopsis of the CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-621
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Abbott Laboratories GmbH
    Sponsor organisation address
    Freundallee 9A, Hannover, Germany, 30173
    Public contact
    Senior Clinical Trial Manager, Abbott Laboratories GmbH, +49 511 6750 2733, gregor.eibes@abbott.com
    Scientific contact
    Senior Clinical Trial Manager, Abbott Laboratories GmbH, +49 511 6750 2733, gregor.eibes@abbott.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
    23 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the therapeutic equivalence of Creon N 25000 with Creon® 25000 on coefficient of fat absorption (CFA) in adolescent and adult subjects with pancreatic exocrine insufficiency (PEI) due to cystic fibrosis (CF).
    Protection of trial subjects
    All study investigators expressly agreed not to disclose the identity of the patients treated and to abide by the confidentiality rules as regards data and information to which they had access by participating in the study. All the data related to the participating patients were recorded and treated according to the regulatory law of data protection. All information obtained as a result of this study was considered confidential until the sponsor deemed it appropriate. The investigator could only inform on the study conduct and results to the sponsor, EC, and regulatory authorities.
    Background therapy
    		 None
    Evidence for comparator
    		 Creon capsules contain pancreatin which is released in the stomach. The particles mix with the chyme in the stomach and do not dissolve due to the pH-resistant enteric coating. Upon entering the duodenum the coating dissolves to release the enzymes for food digestion, dependent on the pH of the duodenum. The pH-sensitive enteric-coated minimicrospheres have been developed to improve the delivery of active enzymes to the small intestine.
    Actual start date of recruitment
    02 Dec 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
    Spain: 15
    Country: Number of subjects enrolled
    Hungary: 26
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    12
    Adults (18-64 years)
    29
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited in 8 sites in Spain (4 sites) and Hungary (4 sites) from 31 January to 14 July 2014

    Pre-assignment
    Screening details
    		 Patients had to have a diagnosis of cystic fibrosis confirmed by two positive chloride sweat tests or gene analysis and a diagnosis of pancreatic exocrine insufficience proven by coefficient of fat absorption < 70% without supplementation or human fecal elastase <50 mcg/g stool

    Pre-assignment period milestones
    Number of subjects started
    		 41
    Number of subjects completed
    		 41

    Period 1
    Period 1 title
    Baseline period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    Blinded and packaged medication was provided to the investigational site and dispensed to the subjects. All the capsules were identical in appearance, shape, smell and taste, and packaged in the proper proportion to assure desired dosages and maintenance of the blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Creon N - Creon R
    Arm description
    		 Creon N during the first cross-over period followed by Creon R during the second cross-over period
    Arm type
    		 Experimental

    Investigational medicinal product name
    Creon N
    Investigational medicinal product code
    Creon N 25000
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Creon N 2500 was administered during the course of the meals and snacks. The capsules should be swallowed intact, without crushing or chewing, with enough fluid during or after each meal or snack. In-between the two-treatment periods, there was a wash-out period of 3 to 14 days where the subjects were treated with their usual pancreatic enzyme supplementation in the usual dose.

    Arm title
    		 Creon R - Creon N
    Arm description
    		 Creon R during the first cross-over period followed by Creon N
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Creon R
    Investigational medicinal product code
    Creon R 25000
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Creon R was taken during the course of the meals and snacks. The capsules were swallowed intact, without crushing or chewing, with enough fluid during or after each meal or snack. In-between the two-treatment periods, there was a wash-out period of 3 to 14 days where the subjects were treated with their usual pancreatic enzyme supplementation in the usual dose

    Number of subjects in period 1
    		Creon N - Creon R Creon R - Creon N
    Started
    20
    21
    Completed
    18
    21
    Not completed
    2
    0
         Consent withdrawn by subject
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Creon N - Creon R
    Reporting group description
    		 Creon N during the first cross-over period followed by Creon R during the second cross-over period

    Reporting group title
    Creon R - Creon N
    Reporting group description
    		 Creon R during the first cross-over period followed by Creon N

    Reporting group values
    		 Creon N - Creon R Creon R - Creon N Total
    Number of subjects
    		 20 21 41
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 8 4 12
        Adults (18-64 years)
    		 12 17 29
        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
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 21 ± 6.6 25.9 ± 8.6 -
    Gender categorical
    Units: Subjects
        Female
    		 14 13 27
        Male
    		 6 8 14
    Race
    Units: Subjects
        Asian
    		 0 0 0
        Black
    		 0 0 0
        White
    		 20 21 41
    Height
    Units: metres
        arithmetic mean (standard deviation)
    		 1.624 ± 0.101 1.665 ± 0.129 -
    Weight
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 51.68 ± 9.59 56.8 ± 14.98 -
    Body mass index
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 19.46 ± 2.43 20.2 ± 3.61 -
    Sitting Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 113.9 ± 10.93 114 ± 10.84 -
    Sitting Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 70.4 ± 7.29 71.38 ± 6.14 -
    Sitting pulse
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 78.55 ± 10.17 81.14 ± 9.32 -

    End points

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    End points reporting groups
    Reporting group title
    Creon N - Creon R
    Reporting group description
    		 Creon N during the first cross-over period followed by Creon R during the second cross-over period

    Reporting group title
    Creon R - Creon N
    Reporting group description
    		 Creon R during the first cross-over period followed by Creon N

    Primary: Equivalence of Creon N and Creon R

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    End point title
    		 Equivalence of Creon N and Creon R
    End point description
    The primary objective was to show that Creon N and Creon R were equivalent with regard to the coefficient of fat absorption (CFA). To prove equivalence, the 95% confidence interval for the treatment difference had to lie entirely within the equivalence range (-8%, 8%)
    End point type
    Primary
    End point timeframe
    Full cross-over period
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: Percentage
        least squares mean (standard error)
    89.1 ± 1.26
    87.8 ± 1.26
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    The model included sequence, period and treatment as fixed effects and subject within sequence as random effect
    Comparison groups
    Creon N - Creon R v Creon R - Creon N
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - The primary objective was to show that Creon N and Creon R were requivalent with regard to the CFA

    Secondary: Coefficient of Nitrogen Absorption

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    End point title
    		 Coefficient of Nitrogen Absorption
    End point description
    The coefficient of nitrogen absorption was analyzed in the same way as the coefficient of fat absorption (primary variable)
    End point type
    Secondary
    End point timeframe
    The full cross-over period
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: Percentage
        least squares mean (standard error)
    87.5 ± 0.84
    87.6 ± 0.84
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    The model included sequence, period and treatment as fixed effects and subject within sequence as random effect
    Comparison groups
    Creon N - Creon R v Creon R - Creon N
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Clinical symptomatology (number of stools)

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    End point title
    		 Clinical symptomatology (number of stools)
    End point description
    End point type
    Secondary
    End point timeframe
    The full cross-over periods
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: number of stools
        arithmetic mean (standard deviation)
    1.49 ± 0.547
    1.57 ± 0.576
    No statistical analyses for this end point

    Secondary: Clinical symptomatology (stool consistency)

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    End point title
    		 Clinical symptomatology (stool consistency)
    End point description
    End point type
    Secondary
    End point timeframe
    The full cross-over periods
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: percentage
    arithmetic mean (standard deviation)
        hard
    14.1 ± 23.9
    11.8 ± 17.78
        formed/normal
    73.6 ± 29.5
    79.8 ± 21.21
        soft
    12.4 ± 22.47
    7.9 ± 15.1
        watery
    0 ± 0
    0.5 ± 3.24
    No statistical analyses for this end point

    Secondary: Clinical symptomatology (abdominal pain)

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    End point title
    		 Clinical symptomatology (abdominal pain)
    End point description
    End point type
    Secondary
    End point timeframe
    The full cross-over periods
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: percentage of days
    arithmetic mean (standard deviation)
        None
    89.3 ± 19.67
    86.8 ± 22.91
        Mild
    8 ± 12.06
    11.1 ± 18.42
        Moderate
    2.6 ± 13.29
    2.1 ± 7.77
        Severe
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Clinical symptomatology (flatulence)

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    End point title
    		 Clinical symptomatology (flatulence)
    End point description
    End point type
    Secondary
    End point timeframe
    The fulll cross-over periods
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: percentage of days
    arithmetic mean (standard deviation)
        None
    57.5 ± 43.31
    51.6 ± 46.65
        Mild
    33.9 ± 38.45
    43.2 ± 42.24
        Moderate
    8.6 ± 24.07
    5.3 ± 11.09
        Severe
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Other pre-specified: Clinical Global Impression of Disease Symptoms

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    End point title
    		 Clinical Global Impression of Disease Symptoms
    End point description
    End point type
    Other pre-specified
    End point timeframe
    The full cross-over periods
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: number
    number (not applicable)
        None (Symptoms not present)
    11
    11
        Mild (symptoms present but not bothersome)
    21
    20
        Moderate (symptoms bothersome)
    6
    7
        Severe (symptoms interfere with normal activities)
    0
    0
        Incapacitating
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Total fat intake, total nitrogen excretion, total nitrogen intake

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    End point title
    		 Total fat intake, total nitrogen excretion, total nitrogen intake
    End point description
    End point type
    Other pre-specified
    End point timeframe
    The full cross-over periods
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: grams
    arithmetic mean (standard deviation)
        total fat intake (g)
    415.5 ± 124.61
    403.7 ± 117.61
        total fat excretion (g/72h)
    42.3 ± 27.05
    48.1 ± 43.28
        Total nitrogen intake (g)
    58 ± 13.2
    57.3 ± 12.85
        Total nitrogen excretion (g/72h)
    7.08 ± 3.088
    7.05 ± 3.633
    No statistical analyses for this end point

    Other pre-specified: Total stool weight

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    End point title
    		 Total stool weight
    End point description
    End point type
    Other pre-specified
    End point timeframe
    The full cross-over periods
    End point values
    		 Creon N - Creon R Creon R - Creon N
    Number of subjects analysed
    20
    21
    Units: grams
        arithmetic mean (standard deviation)
    552.8 ± 281.41
    555.4 ± 341.59
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events that started during a unique treatment or that already existed before the start of that unique treatment but worsened during the treatment, including any subsequent wash-out or post-treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Creon N
    Reporting group description
    		 Subjects treated with Creon N

    Reporting group title
    Creon R
    Reporting group description
    		 Subjects treated with Creon R

    Serious adverse events
    		 Creon N Creon R
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 39 (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: 2%
    Non-serious adverse events
    		 Creon N Creon R
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 41 (21.95%)
    9 / 39 (23.08%)
    Investigations
    gastric pH decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    arthropod bite
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    headache
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    3
    abdominal pain upper
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    abdominal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    abdominal pain lower
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    constipation
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    diarrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal hypermotility
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Steatorrhoea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    cough
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    viral rhinitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    decreased appetite
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 39 (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? Yes
    Date
    Amendment
    14 Apr 2014
    Change in the specified food subjects receive (2 snacks instead of 3) Addition of vital signs and clinical global impression at day 1 of second cross-over period (Visit 4) Addition of a GI diary at Day 6 or 7 only in case blue dye is passed on Day 6 Change in the reporting serious adverse events that would be done by email instead of fax

    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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