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    Clinical Trial Results:
    A Phase II, Multicenter, Parallel-Group, Active-Controlled, Randomized, Double-blind, Dose-Ranging Study to Evaluate the Efficacy and Safety of Different Doses of Creon IR in Subjects with Pancreatic Exocrine Insufficiency due to Cystic Fibrosis

    Summary
    EudraCT number
    2014-004519-35
    Trial protocol
    HU   CZ   ES   GB  
    Global end of trial date
    07 Jul 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jun 2016
    First version publication date
    04 Jun 2016
    Other versions
    Summary report(s)
    Synopsis of the CSR (PANC2002- synopsis- SOLID

    Trial information

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    Trial identification
    Sponsor protocol code
    PANC2002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02415959
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Abbott Laboratories GmbH
    Sponsor organisation address
    Freundallee 9A, Hannover, Germany, 30173
    Public contact
    Gregor Eibes, Abbott Laboratories GmbH, +31 29447 7367, gregor.eibes@abbott.com
    Scientific contact
    Gregor Eibes, Abbott Laboratories GmbH, +31 29447 7367, gregor.eibes@abbott.com
    Sponsor organisation name
    Abbott Laboratories GmbH
    Sponsor organisation address
    Freundallee 9A, Hannover, Germany, 30173
    Public contact
    Suntje Sander-Struckmeier, Abbott Laboratories GmbH, 0049 1167503254, suntje.sander@abbott.com
    Scientific contact
    Suntje Sander-Struckmeier, Abbott Laboratories GmbH, 0049 1167503254, suntje.sander@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
    17 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare and model the efficacy of four different doses of Creon Immediate Release (IR) capsule formulation and the currently registered active control (Creon® (Delayed Release/Gastro-Resistant) [Creon® DR/GR] capsules) in subjects with pancreatic exocrine insufficiency (PEI) due to cystic fibrosis (CF). The primary efficacy objective is based on the evaluation of fat digestion as measured by coefficient of fat absorption (CFA) (%).
    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, ethics committee, and regulatory authorities.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Mar 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
    Poland: 30
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Hungary: 15
    Worldwide total number of subjects
    70
    EEA total number of subjects
    70
    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)
    22
    Adults (18-64 years)
    48
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited at 16 sites: 2 in the Czech Republic, 3 in Hungary, 5 in Poland, and 6 in Spain from 05 March 2015 to 03 June 2015.

    Pre-assignment
    Screening details
    Patients 12 years of age or older with confirmed diagnosis of PEI and cystic fibrosis (CF) whose PEI was controlled under treatment with a commercially available pancreatic enzyme replacement therapy and with a human fecal elastase <100μg/g stool at screening.

    Period 1
    Period 1 title
    Overall Trial (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 study drug was provided to the clinical site and administered in a double-blind manner. Study drug for all study arms had identical appearance (same number of capsules, appearance, shapes, smells, and tastes) and were packaged to maintain proper dosage proportions. If emergency unblinding occurred, IWRS was to be used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Creon IR 300
    Arm description
    Creon IR low dose, 300 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 30,000 lipase units)
    Arm type
    Experimental

    Investigational medicinal product name
    Pancreatin
    Investigational medicinal product code
    Creon IR 300
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug capsules were swallowed intact (capsules were not to be crushed, chewed, or opened), and were taken at the start of a meal or taken with a snack; sufficient fluids were taken at administration. Treatment was administered to each subject by the clinical site personnel.

    Arm title
    Creon IR 1,200
    Arm description
    Creon IR medium dose, 1,200 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 120,000 lipase units).
    Arm type
    Experimental

    Investigational medicinal product name
    Pancreatin
    Investigational medicinal product code
    Creon IR 1,200
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug capsules were swallowed intact (capsules were not to be crushed, chewed, or opened), and were taken at the start of a meal or taken with a snack; sufficient fluids were taken at administration. Treatment was administered to each subject by the clinical site personnel.

    Arm title
    Creon IR 2,400
    Arm description
    Creon IR high dose, 2,400 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 240,000 lipase units)
    Arm type
    Experimental

    Investigational medicinal product name
    Pancreatin
    Investigational medicinal product code
    Creon IR 2,400
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug capsules were swallowed intact (capsules were not to be crushed, chewed, or opened), and were taken at the start of a meal or taken with a snack; sufficient fluids were taken at administration. Treatment was administered to each subject by the clinical site personnel.

    Arm title
    Creon IR 4,000
    Arm description
    Creon IR maximum dose, 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)
    Arm type
    Experimental

    Investigational medicinal product name
    Pancreatin
    Investigational medicinal product code
    Creon IR 4,000
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug capsules were swallowed intact (capsules were not to be crushed, chewed, or opened), and were taken at the start of a meal or taken with a snack; sufficient fluids were taken at administration. Treatment was administered to each subject by the clinical site personnel.

    Arm title
    Creon (DR/GR)
    Arm description
    Creon® 25,000 (DR/GR), 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)
    Arm type
    Active comparator

    Investigational medicinal product name
    Pancreatin
    Investigational medicinal product code
    Creon (DR/GR)
    Other name
    Creon 25,000 DR/GR
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug capsules were swallowed intact (capsules were not to be crushed, chewed, or opened), and were taken at the start of a meal or taken with a snack; sufficient fluids were taken at administration. Treatment was administered to each subject by the clinical site personnel.

    Number of subjects in period 1
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Started
    14
    14
    14
    14
    14
    Completed
    14
    13
    14
    13
    14
    Not completed
    0
    1
    0
    1
    0
         Protocol deviation
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Creon IR 300
    Reporting group description
    Creon IR low dose, 300 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 30,000 lipase units)

    Reporting group title
    Creon IR 1,200
    Reporting group description
    Creon IR medium dose, 1,200 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 120,000 lipase units).

    Reporting group title
    Creon IR 2,400
    Reporting group description
    Creon IR high dose, 2,400 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 240,000 lipase units)

    Reporting group title
    Creon IR 4,000
    Reporting group description
    Creon IR maximum dose, 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)

    Reporting group title
    Creon (DR/GR)
    Reporting group description
    Creon® 25,000 (DR/GR), 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)

    Reporting group values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR) Total
    Number of subjects
    14 14 14 14 14 70
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.7 ± 7.6 22.9 ± 8.5 22 ± 7.3 19.7 ± 8.4 22.6 ± 7.1 -
    Gender categorical
    Units: Subjects
        Female
    6 9 7 5 6 33
        Male
    8 5 7 9 8 37
    Race
    Units: Subjects
        Asian
    0 0 0 0 0 0
        Black
    0 0 0 0 0 0
        White
    14 14 14 14 14 70
        Other
    0 0 0 0 0 0
    Country
    Number of patients of each treatment group in each country.
    Units: Subjects
        Czech Republic
    1 1 1 1 1 5
        Hungary
    3 3 3 3 3 15
        Poland
    6 6 6 6 6 30
        Spain
    4 4 4 4 4 20
    Height
    Heigth of each subject.
    Units: meters
        arithmetic mean (standard deviation)
    1.675 ± 0.108 1.626 ± 0.12 1.646 ± 0.128 1.666 ± 0.12 1.671 ± 0.067 -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    58.48 ± 9.53 54.11 ± 10.27 59.44 ± 11.82 57.31 ± 13.4 55.98 ± 8.31 -
    BMI
    Body mass index of each patient, calculated as weight (kg) / body surface area (m^2).
    Units: kg/m^2
        arithmetic mean (standard deviation)
    20.79 ± 2.42 20.29 ± 2.06 21.73 ± 2.43 20.38 ± 2.59 19.96 ± 1.97 -
    Sitting Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    116.4 ± 12.2 112.3 ± 14.4 118.8 ± 14.9 115.7 ± 13.4 112 ± 14.3 -
    Sitting Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    69.6 ± 8.9 70.9 ± 8.8 72 ± 10.1 71.1 ± 6.9 68.4 ± 7.5 -
    Sitting Pulse
    Units: Beats per minute (bpm)
        arithmetic mean (standard deviation)
    78.4 ± 13.2 83.7 ± 10.8 75.9 ± 19.2 81.9 ± 11.2 76.4 ± 10.7 -

    End points

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    End points reporting groups
    Reporting group title
    Creon IR 300
    Reporting group description
    Creon IR low dose, 300 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 30,000 lipase units)

    Reporting group title
    Creon IR 1,200
    Reporting group description
    Creon IR medium dose, 1,200 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 120,000 lipase units).

    Reporting group title
    Creon IR 2,400
    Reporting group description
    Creon IR high dose, 2,400 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 240,000 lipase units)

    Reporting group title
    Creon IR 4,000
    Reporting group description
    Creon IR maximum dose, 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)

    Reporting group title
    Creon (DR/GR)
    Reporting group description
    Creon® 25,000 (DR/GR), 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)

    Primary: Coefficient of Fat Absorption (CFA)

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    End point title
    Coefficient of Fat Absorption (CFA)
    End point description
    End point type
    Primary
    End point timeframe
    7 days
    End point values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Number of subjects analysed
    13
    13
    14
    13
    13
    Units: Percentage
        arithmetic mean (confidence interval 95%)
    71.5 (64.7 to 78.4)
    71.7 (64.8 to 78.5)
    72.5 (65.9 to 79.1)
    76.5 (69.7 to 83.3)
    92.8 (86 to 99.6)
    Statistical analysis title
    Pairwise differences
    Statistical analysis description
    The model included country and treatment as fixed effects
    Comparison groups
    Creon IR 300 v Creon IR 1,200 v Creon IR 2,400 v Creon IR 4,000 v Creon (DR/GR)
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.05
    Method
    ANOVA
    Parameter type
    Least Squares Mean (LSM)
    Confidence interval
    Notes
    [1] - No formal statistical analysis provided for the CFA, only pairwise differences derived between the treatment groups

    Secondary: Coefficient of Nitrogen Absorption (CNA)

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    End point title
    Coefficient of Nitrogen Absorption (CNA)
    End point description
    End point type
    Secondary
    End point timeframe
    7 days
    End point values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Number of subjects analysed
    13
    13
    14
    13
    13
    Units: Percentage
        arithmetic mean (confidence interval 95%)
    71.6 (67.2 to 75.9)
    73.9 (69.5 to 78.2)
    76.7 (72.5 to 80.9)
    80.5 (76.2 to 84.8)
    85.4 (81.1 to 89.7)
    Statistical analysis title
    Pairwise differences
    Statistical analysis description
    The model included country and treatment as fixed effects
    Comparison groups
    Creon IR 300 v Creon IR 1,200 v Creon IR 2,400 v Creon IR 4,000 v Creon (DR/GR)
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    [2]
    P-value
    < 0.05
    Method
    ANOVA
    Parameter type
    Least Squares Mean (LSM)
    Confidence interval
    Notes
    [2] - No formal statistical analysis provided for the CNA, only pairwise differences derived between the treatment groups

    Secondary: Total Fat Excretion (Stool Fat)

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    End point title
    Total Fat Excretion (Stool Fat)
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Number of subjects analysed
    13
    13
    14
    13
    13
    Units: gram/72 hours
        arithmetic mean (standard deviation)
    301.8 ± 4.43
    299.7 ± 5.23
    300 ± 6.41
    303 ± 5.18
    302.9 ± 3.13
    No statistical analyses for this end point

    Secondary: Total Fat Excretion

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    End point title
    Total Fat Excretion
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Number of subjects analysed
    13
    13
    14
    13
    13
    Units: grams / 72 hours
        arithmetic mean (standard deviation)
    87.5 ± 37.5
    87.1 ± 40.95
    84.1 ± 44.86
    73 ± 28.2
    23.5 ± 11.27
    No statistical analyses for this end point

    Secondary: Total Nitrogen Intake

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    End point title
    Total Nitrogen Intake
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Number of subjects analysed
    13
    13
    14
    13
    13
    Units: grams / 72 hours
        arithmetic mean (standard deviation)
    36.4 ± 5.3
    35.1 ± 5.76
    37.3 ± 5
    36 ± 4.93
    36.3 ± 5.86
    No statistical analyses for this end point

    Secondary: Total Nitrogen Excretion

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    End point title
    Total Nitrogen Excretion
    End point description
    End point type
    Secondary
    End point timeframe
    72 hous
    End point values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Number of subjects analysed
    13
    13
    14
    13
    13
    Units: grams / 72 hours
        arithmetic mean (standard deviation)
    10.47 ± 3.884
    9.21 ± 1.886
    8.81 ± 3.062
    7.26 ± 2.951
    5.56 ± 1.97
    No statistical analyses for this end point

    Secondary: Total Stool Weight

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    End point title
    Total Stool Weight
    End point description
    End point type
    Secondary
    End point timeframe
    Dye marker period (48 hours)
    End point values
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Number of subjects analysed
    13
    13
    14
    13
    13
    Units: grams
        arithmetic mean (standard deviation)
    889 ± 294.2
    905.3 ± 225.7
    793.8 ± 279.8
    755.7 ± 383.2
    545.7 ± 256.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14 days including a 7 day safety follow up.
    Adverse event reporting additional description
    AEs were reported per-subject, counting events in subjects rather than separate events. If a subject suffered the same AE(s) repeatedly, events were counted only once for any given period. Repeated events per subject were classified the worst severity, according to the closest relationship to the study drug and the earliest starting date.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Creon IR 300
    Reporting group description
    Creon IR low dose, 300 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 30,000 lipase units)

    Reporting group title
    Creon IR 1,200
    Reporting group description
    Creon IR medium dose, 1,200 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 120,000 lipase units).

    Reporting group title
    Creon IR 2,400
    Reporting group description
    Creon IR high dose, 2,400 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 240,000 lipase units)

    Reporting group title
    Creon IR 4,000
    Reporting group description
    Creon IR maximum dose, 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)

    Reporting group title
    Creon (DR/GR)
    Reporting group description
    Creon® 25,000 (DR/GR), 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)

    Serious adverse events
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Creon IR 300 Creon IR 1,200 Creon IR 2,400 Creon IR 4,000 Creon (DR/GR)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 14 (71.43%)
    9 / 14 (64.29%)
    7 / 14 (50.00%)
    9 / 14 (64.29%)
    7 / 14 (50.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    0
    0
    1
    Haemptysis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 14 (42.86%)
    8 / 14 (57.14%)
    6 / 14 (42.86%)
    4 / 14 (28.57%)
    2 / 14 (14.29%)
         occurrences all number
    6
    8
    6
    4
    2
    Flatulence
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 14 (14.29%)
    6 / 14 (42.86%)
    3 / 14 (21.43%)
    2 / 14 (14.29%)
         occurrences all number
    2
    2
    6
    3
    2
    Abdominal distension
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 14 (21.43%)
    0 / 14 (0.00%)
    2 / 14 (14.29%)
    1 / 14 (7.14%)
         occurrences all number
    3
    3
    0
    2
    1
    Diarrhoea
         subjects affected / exposed
    4 / 14 (28.57%)
    4 / 14 (28.57%)
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
         occurrences all number
    4
    4
    2
    1
    1
    Faeces soft
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    2 / 14 (14.29%)
         occurrences all number
    2
    1
    1
    1
    2
    Toothache
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    2 / 14 (14.29%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Steatorrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2015
    Protocol Amendment 1 became effective on 03 MAR 2015, prior to inclusion of the first subject into the study, and introduced several clarifications regarding study schedule and stool collection, physical examination, body weight measurement, and diary data. Protein range intake was adapted from 50-60 g to 50-90 g since this was considered more appropriate for adult subjects. Several concomitant medication criteria were changed: Steroids, as well as prebiotic or probiotic drugs, were allowed; however, such drugs should have been taken by the subject for more than 4 weeks before start of the study at the prescribed dose, and the dose should not have been changed during the course of the study. Fat- or protein-containing nutritional supplements were prohibited because the determination of the coefficient of fat absorption and the coefficient of nitrogen absorption must be based on diet and not on content of nutritional supplements. Additionally, the amendment prohibited subjects from being treated with intravenous antibiotics during the study because of possible effects on gastrointestinal motility. Since Protocol Amendment 1 became effective prior to first subject first visit, no impact on the study was expected to occur.
    24 Apr 2015
    Protocol Amendment 2 became effective on 24 APR 2015 and allowed a prolonged screening period of an extra 14 days inclusive, introduced the possibility of re-screening, and clarified that the daily fat intake could be 100 to 105 g to account for an acceptable variation in meals of 5 g of dietary fat. No impact on the study results was expected to occur by adoption of Protocol Amendment 2.

    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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