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    Clinical Trial Results:
    A randomised, double blind, active-controlled, two-treatment, crossover multinational, multicentre trial to compare two pancreatic enzyme products in the treatment of exocrine pancreatic insufficiency in subjects with cystic fibrosis

    Summary
    EudraCT number
    		 2009-012842-21
    Trial protocol
    		 GB   DE   IT   BG   BE   HU  
    Global end of trial date
    03 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2019
    First version publication date
    06 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PR-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergan plc
    Sponsor organisation address
    Harborside Financial Center Plaza V, Suite 1900, Jersey City, United States, 07302
    Public contact
    Steven Shiff, MD, Allergan plc, steven.shiff@allergan.com
    Scientific contact
    Steven Shiff, MD, Allergan plc, steven.shiff@allergan.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the safety and efficacy of EUR-1008 as compared to Creon in the treatment of EPI associated with CF in subjects 12 years of age and older, and able to swallow the capsules whole.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical practices and applicable regulatory requirements. Written informed consent and assent from minors (according to national legal requirements) were obtained before initiating study-related assessments or procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Italy: 24
    Worldwide total number of subjects
    96
    EEA total number of subjects
    96
    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)
    51
    Adults (18-64 years)
    45
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 96 subjects aged 12 years or older, with a definite diagnosis of Cystic Fibrosis (CF) were enrolled in the study.

    Period 1
    Period 1 title
    Overall trial by sequence (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence 1: EUR-1008/Kreon
    Arm description
    		 Subjects received EUR-1008 or Kreon in Treatment Periods 1 and 2, respectively. EUR-1008 and Kreon were administered at a dose as close as possible to their stabilised, existing PEP treatment for 28 days (± 2 days), to a maximum dose of 10,000 lipase units/kg of body weight per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    EUR-1008
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    EUR-1008 was administered orally, during meals, at a dose as close as possible to the stabilised, existing PEP treatment but not exceeding 10,000 lipase units/kg of body weight per day or 4000 lipase units/g of fat ingested per day.

    Investigational medicinal product name
    Kreon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Kreon was administered orally, during meals, at a dose as close as possible to the stabilised, existing PEP treatment but not exceeding 10,000 lipase units/kg of body weight per day or 4000 lipase units/g of fat ingested per day.

    Arm title
    		 Sequence 2: Kreon/EUR-1008
    Arm description
    		 Subjects received Kreon or EUR-1008 in Treatment Periods 1 and 2, respectively. Kreon and EUR-1008 were administered at a dose as close as possible to their stabilised, existing PEP treatment for 28 days (± 2 days), to a maximum dose of 10,000 lipase units/kg of body weight per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kreon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Kreon was administered orally, during meals, at a dose as close as possible to the stabilised, existing PEP treatment but not exceeding 10,000 lipase units/kg of body weight per day or 4000 lipase units/g of fat ingested per day.

    Investigational medicinal product name
    EUR-1008
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    EUR-1008 was administered orally, during meals, at a dose as close as possible to the stabilised, existing PEP treatment but not exceeding 10,000 lipase units/kg of body weight per day or 4000 lipase units/g of fat ingested per day.

    Number of subjects in period 1
    		Sequence 1: EUR-1008/Kreon Sequence 2: Kreon/EUR-1008
    Started
    48
    48
    Completed
    42
    44
    Not completed
    6
    4
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    2
    1
         Protocol deviation
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence 1: EUR-1008/Kreon
    Reporting group description
    		 Subjects received EUR-1008 or Kreon in Treatment Periods 1 and 2, respectively. EUR-1008 and Kreon were administered at a dose as close as possible to their stabilised, existing PEP treatment for 28 days (± 2 days), to a maximum dose of 10,000 lipase units/kg of body weight per day.

    Reporting group title
    Sequence 2: Kreon/EUR-1008
    Reporting group description
    		 Subjects received Kreon or EUR-1008 in Treatment Periods 1 and 2, respectively. Kreon and EUR-1008 were administered at a dose as close as possible to their stabilised, existing PEP treatment for 28 days (± 2 days), to a maximum dose of 10,000 lipase units/kg of body weight per day.

    Reporting group values
    		 Sequence 1: EUR-1008/Kreon Sequence 2: Kreon/EUR-1008 Total
    Number of subjects
    		 48 48 96
    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)
    		 21 30 51
        Adults (18-64 years)
    		 27 18 45
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 19 19 38
        Male
    		 29 29 58
    Subject analysis sets

    Subject analysis set title
    Sequence 1 - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) Population consists of randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon).

    Subject analysis set title
    Sequence 2 - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) Population consists of all randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon).

    Subject analysis set title
    Sequence 1 - Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consists of all randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon)

    Subject analysis set title
    Sequence 2 - Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consists of all randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon).

    Subject analysis set title
    Sequence 1 - Completers Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Completers Population consists of all subjects from the ITT Population who completed both treatment periods and had non-missing CFA-72h in both periods.

    Subject analysis set title
    Sequence 2 - Completers Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Completers Population consists of all subjects from the ITT Population who completed both treatment periods and had non-missing CFA-72h in both periods.

    Subject analysis set title
    Sequence 1 - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) Population consists of all subjects from the Completers Population with no significant protocol deviations.

    Subject analysis set title
    Sequence 2 - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) Population consists of all subjects from the Completers Population with no significant protocol deviations.

    Subject analysis sets values
    		 Sequence 1 - ITT Sequence 2 - ITT Sequence 1 - Safety Population Sequence 2 - Safety Population Sequence 1 - Completers Population Sequence 2 - Completers Population Sequence 1 - PP Sequence 2 - PP
    Number of subjects
    48
    48
    48
    48
    41
    42
    35
    32
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    30
    0
    0
    0
    0
        Adolescents (12-17 years)
    21
    30
    21
    18
    18
    27
    17
    21
        Adults (18-64 years)
    27
    18
    27
    0
    23
    15
    18
    11
        From 65-84 years
    0
    0
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1: EUR-1008/Kreon
    Reporting group description
    		 Subjects received EUR-1008 or Kreon in Treatment Periods 1 and 2, respectively. EUR-1008 and Kreon were administered at a dose as close as possible to their stabilised, existing PEP treatment for 28 days (± 2 days), to a maximum dose of 10,000 lipase units/kg of body weight per day.

    Reporting group title
    Sequence 2: Kreon/EUR-1008
    Reporting group description
    		 Subjects received Kreon or EUR-1008 in Treatment Periods 1 and 2, respectively. Kreon and EUR-1008 were administered at a dose as close as possible to their stabilised, existing PEP treatment for 28 days (± 2 days), to a maximum dose of 10,000 lipase units/kg of body weight per day.

    Subject analysis set title
    Sequence 1 - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) Population consists of randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon).

    Subject analysis set title
    Sequence 2 - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) Population consists of all randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon).

    Subject analysis set title
    Sequence 1 - Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consists of all randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon)

    Subject analysis set title
    Sequence 2 - Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population consists of all randomised subjects who received at least 1 dose of study drug (EUR-1008 or Kreon).

    Subject analysis set title
    Sequence 1 - Completers Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Completers Population consists of all subjects from the ITT Population who completed both treatment periods and had non-missing CFA-72h in both periods.

    Subject analysis set title
    Sequence 2 - Completers Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Completers Population consists of all subjects from the ITT Population who completed both treatment periods and had non-missing CFA-72h in both periods.

    Subject analysis set title
    Sequence 1 - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) Population consists of all subjects from the Completers Population with no significant protocol deviations.

    Subject analysis set title
    Sequence 2 - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol (PP) Population consists of all subjects from the Completers Population with no significant protocol deviations.

    Primary: Coefficient of fat absorption over 72 hours

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    End point title
    		 Coefficient of fat absorption over 72 hours
    End point description
    The coefficient of fat absorption (CFA) was determined by measurement of fat and protein dietary intake and fat and protein excretion in the stools. CFA-72h was assessed during the two 72-hour stool collection periods at the end of each of the treatment periods using dietary fat intake and stool fat excretion data.
    End point type
    Primary
    End point timeframe
    The coefficient of fat absorption over 72 hours (CFA-72h) is calculated from stools collected during the last 3 days (72 consecutive hours) of each treatment period.
    End point values
    		 Sequence 1 - ITT Sequence 2 - ITT Sequence 1 - Completers Population Sequence 2 - Completers Population Sequence 1 - PP Sequence 2 - PP
    Number of subjects analysed
    48
    48
    41
    42
    35
    32
    Units: percent
    arithmetic mean (standard deviation)
        Period 1
    82.28 ( 10.792 )
    85.85 ( 8.72 )
    82.16 ( 10.894 )
    85.61 ( 8.671 )
    81.04 ( 11.189 )
    85.59 ( 9.376 )
        Period 2
    85.06 ( 9.618 )
    85.63 ( 11.182 )
    85.06 ( 9.618 )
    86.01 ( 11.041 )
    83.85 ( 9.788 )
    86.76 ( 9.736 )
    Statistical analysis title
    		 Non-inferiority Analysis
    Comparison groups
    Sequence 1 - Completers Population v Sequence 2 - Completers Population
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.2428
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were collected from the time the ICF was signed through the end of the 7-day Follow-up Period, except for serious adverse events (SAEs), which were to be reported through 30 days after the last dose of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    EUR-1008 - Safety Population
    Reporting group description
    		 -

    Reporting group title
    Kreon - Safety Population
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse events occurred at frequency of occurrence of 5% or greater in any study arm.
    Serious adverse events
    		 EUR-1008 - Safety Population Kreon - Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 48 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Urethral repair
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EUR-1008 - Safety Population Kreon - Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2012
    The following changes were implemented with Amendment 1: change in the comparator drug formulation, inclusion of a two-sided confidence interval in relation to the relative efficacy of EUR-1008 and Kreon, changes in exclusion criteria and other clarifications.
    14 Dec 2012
    The following changes were implemented with Amendment 2: updated number of countries and regions participating in the study, changes to inclusion/exclusion criteria and other clarifications.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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