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    Clinical Trial Results:
    A Phase III Placebo-Controlled Trial Of Celecoxib In Genotype Positive Subjects With Familial Adenomatous Polyposis (FAP)

    Summary
    EudraCT number
    		 2006-002228-40
    Trial protocol
    		 ES   SE   IT   GB   CZ   BE   DE   HU   SK   BG  
    Global end of trial date
    29 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    18 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A3191193
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00585312
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 1 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 1 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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?
    Yes
    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
    10 Mar 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of celecoxib versus placebo in the prevention and treatment of colorectal polyps growth in young subjects with FAP. Primary Objective: To compare the time from randomization to treatment failure for subjects treated with celecoxib versus subjects treated with placebo, where treatment failure is defined as the earliest occurrence of one or more of the following: a. Appearance of greater than or equal to (≥) 20 polyps at any colonoscopy during the study, or b. Diagnosis of colorectal malignancy
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Sep 2006
    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
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    United States: 64
    Worldwide total number of subjects
    106
    EEA total number of subjects
    35
    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)
    44
    Adolescents (12-17 years)
    62
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 305 subjects were screened, whereof 106 were randomized into the study, and of whom 101 took at least 1 dose of study drug. The clinical study was conducted in 18 centers across 13 countries: Belgium, Czech Republic, Hong Kong, Hungary, Israel, Italy, Slovakia, South Africa, Spain, Sweden, Ukraine, United Kingdom, and United States.

    Pre-assignment
    Screening details
    		 The randomization was to be stratified by center, age ( ≥12 years old versus less than [<] 12 years old), and FAP phenotype (negative versus positive). The subjects were randomized 1:1 to one of the 2 treatments celecoxib or placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Celecoxib
    Arm description
    		 Celecoxib up to a maximum dose of 400 milligram (mg) was given twice daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Celecoxib
    Investigational medicinal product code
    SC-58635
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Celecoxib, approximately 16 milligram per kilogram per day (mg/kg/day) adjusted for changes in body weight. Maximum dose was 400 mg twice daily.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Celecoxib.

    Number of subjects in period 1
    		Celecoxib Placebo
    Started
    55
    51
    Treated
    53
    48
    Completed
    4
    7
    Not completed
    51
    44
         Consent withdrawn by subject
    5
    1
         Adverse Event
    3
    -
         'Reason not specified '
    2
    -
         Study terminated by the sponsor
    34
    31
         Lost to follow-up
    1
    1
         Lack of efficacy
    6
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Celecoxib
    Reporting group description
    		 Celecoxib up to a maximum dose of 400 milligram (mg) was given twice daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo

    Reporting group values
    		 Celecoxib Placebo Total
    Number of subjects
    		 55 51 106
    Age categorical
    Units: Subjects
    Age continuous
    The intent-to-treat (ITT) population consisted of all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether the subjects received any study drug or received a different drug from that to which they were randomized.
    Units: years
        arithmetic mean (standard deviation)
    		 12.6 ( 2.2 ) 12.2 ( 1.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 29 28 57
        Male
    		 26 23 49

    End points

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    End points reporting groups
    Reporting group title
    Celecoxib
    Reporting group description
    		 Celecoxib up to a maximum dose of 400 milligram (mg) was given twice daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo

    Primary: Time to Disease Progression

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    End point title
    		 Time to Disease Progression [1]
    End point description
    Time to disease progression was defined as the time from randomization to the earliest occurrence of one or more of the following events: 1.Appearance of ≥20 polyps (greater than [>]2 millimeter [mm] in size) at any colonoscopy during the study (Polyps); or 2.Diagnosis of colorectal malignancy (ColMal). ITT population (N: 106) consisted of all subjects who were randomized and assigned to treatment. Primary outcome measure was met by 7 (Polyp:7,ColMal:0) subjects in the Celecoxib group and 13 (13,0) in the placebo group. Study was early terminated due to low enrollment and lower than expected endpoint rate. No analysis was performed.
    End point type
    Primary
    End point timeframe
    5 years
    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: Study was early terminated due to low enrollment and lower than expected endpoint rate. No statistical analysis was performed.
    End point values
    		 Celecoxib Placebo
    Number of subjects analysed
    7 [2]
    13 [3]
    Units: years
        arithmetic mean (standard deviation)
    2.2 ( 1.08 )
    1.8 ( 1.3 )
    Notes
    [2] - Subjects who met the primary outcome measure.
    [3] - Subjects who met the primary outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure

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    End point title
    		 Time to Treatment Failure
    End point description
    Time to treatment failure was defined as time from randomization to the earliest occurrence of one or more of the following: 1. Appearance of ≥20 polyps (>2 mm in size) at any colonoscopy during the study (Polyps), or 2. Diagnosis of colorectal malignancy (ColMal), or 3. Treatment related dropout (DO). The treatment related dropout was defined as insufficient clinical response, progression of disease, death, adverse event, treatment-related laboratory abnormality, subject no longer willing to participate in study, and other reasons that might be related to treatment as determined by treating physicians in a blind fashion before database release. ITT population (N: 106) consisted of all subjects who were randomized and assigned to treatment. Secondary outcome measure was met by 14 (Polyp:7, ColMal:0,DO:14) subjects in the Celecoxib and 14 (13,0,12) in the placebo group. Study was early terminated due to low enrollment and lower than expected endpoint rate. No analysis was performed.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Celecoxib Placebo
    Number of subjects analysed
    14 [4]
    14 [5]
    Units: years
        arithmetic mean (standard deviation)
    2 ( 1.12 )
    1.7 ( 1.3 )
    Notes
    [4] - Subjects who met the primary outcome measure.
    [5] - Subjects who met the primary outcome measure. 
    No statistical analyses for this end point

    Secondary: Total Number of Colorectal Polyps

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    End point title
    		 Total Number of Colorectal Polyps
    End point description
    Total number of colorectal polyps >2 mm in size, that were detected over Years 1 - 5 cumulatively. Weighted total number of colorectal polyps over Years 1 – 5 cumulatively was defined as the total number of colorectal polyps >2 mm in size, that were detected over Years 1 - 5, divided by the number of colonoscopies that the subject had during the study. ITT population (N: 106) consisted of all subjects who were randomized and assigned to a treatment. Study was early terminated due to low enrollment and lower than expected endpoint rate and no analysis was performed.
    End point type
    Secondary
    End point timeframe
    Year 1 to 5
    End point values
    		 Celecoxib Placebo
    Number of subjects analysed
    55
    51
    Units: polyps
    arithmetic mean (standard deviation)
        Year 1 (N: 27, 30)
    3 ( 2.68 )
    8.1 ( 7.32 )
        Year 2 (N: 21, 25)
    8.8 ( 6.63 )
    13.7 ( 10.51 )
        Year 3 (N: 16, 14)
    13.4 ( 11.31 )
    22.3 ( 11.74 )
        Year 4 (N: 8, 7)
    18.6 ( 17.65 )
    36.4 ( 22.5 )
        Year 5 (N: 2, 2)
    30.5 ( 21.92 )
    46.5 ( 34.65 )
        Years 1 - 5 cumulatively (N: 33, 36)
    4.3 ( 3.58 )
    8.6 ( 7.12 )
    No statistical analyses for this end point

    Secondary: Colorectal Polyp Burden

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    End point title
    		 Colorectal Polyp Burden
    End point description
    The polyp burden was defined as the sum of the largest diameters of all polyps (>2 mm in size) over Years 1 - 5 cumulatively. Weighted colorectal polyp burden over Years 1 – 5 cumulatively was defined as the polyp burden over Years 1 - 5 divided by the number of colonoscopies that the subject had during the study. ITT population (N: 106) consisted of all subjects who were randomized and assigned to a treatment. Study was early terminated due to low enrollment and lower than expected endpoint rate and no analysis was performed.
    End point type
    Secondary
    End point timeframe
    Year 1 to 5
    End point values
    		 Celecoxib Placebo
    Number of subjects analysed
    55
    51
    Units: millimeter(s)
    arithmetic mean (standard deviation)
        Year 1 (N: 27, 30)
    4 ( 1.97 )
    4.2 ( 2.05 )
        Year 2 (N: 21, 25)
    6.9 ( 2.28 )
    8.1 ( 4.06 )
        Year 3 (N: 16, 14)
    9.6 ( 3.14 )
    11.6 ( 4.05 )
        Year 4 (N: 8, 7)
    12.9 ( 3.31 )
    18.7 ( 5.88 )
        Year 5 (N: 2, 2)
    20 ( 7.07 )
    20 ( 4.24 )
        Year 1 - 5 cumulatively (N: 33, 36)
    4.1 ( 1.68 )
    4.3 ( 1.61 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Events were reported from randomization through and including 30 calendar days after the last administration of the study drug
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as non serious in another subject, or one subject may have experienced both a serious and non serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Celecoxib
    Reporting group description
    		 Celecoxib, approximately 16 mg/kg/day (adjusted for changes in body weight). Maximum dose was 400 mg twice daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo.

    Serious adverse events
    		 Celecoxib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Periorbital cellulitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Celecoxib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 53 (67.92%)
    30 / 48 (62.50%)
    Investigations
    Albumin urine present
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 53 (30.19%)
    14 / 48 (29.17%)
         occurrences all number
    60
    59
    Migraine
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 48 (8.33%)
         occurrences all number
    2
    4
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 48 (2.08%)
         occurrences all number
    7
    1
    Fatigue
         subjects affected / exposed
    6 / 53 (11.32%)
    4 / 48 (8.33%)
         occurrences all number
    10
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 48 (10.42%)
         occurrences all number
    2
    7
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    9 / 53 (16.98%)
    4 / 48 (8.33%)
         occurrences all number
    10
    4
    Abdominal pain
         subjects affected / exposed
    9 / 53 (16.98%)
    10 / 48 (20.83%)
         occurrences all number
    20
    22
    Abdominal pain upper
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 48 (6.25%)
         occurrences all number
    6
    3
    Diarrhoea
         subjects affected / exposed
    6 / 53 (11.32%)
    4 / 48 (8.33%)
         occurrences all number
    8
    6
    Nausea
         subjects affected / exposed
    8 / 53 (15.09%)
    8 / 48 (16.67%)
         occurrences all number
    14
    14
    Rectal haemorrhage
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 48 (6.25%)
         occurrences all number
    6
    3
    Vomiting
         subjects affected / exposed
    9 / 53 (16.98%)
    9 / 48 (18.75%)
         occurrences all number
    16
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 53 (15.09%)
    6 / 48 (12.50%)
         occurrences all number
    10
    8
    Dyspnoea
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 48 (2.08%)
         occurrences all number
    5
    1
    Epistaxis
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Oropharyngeal pain
         subjects affected / exposed
    6 / 53 (11.32%)
    5 / 48 (10.42%)
         occurrences all number
    9
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 48 (4.17%)
         occurrences all number
    3
    3
    Pain in extremity
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 48 (10.42%)
         occurrences all number
    2
    6
    Infections and infestations
    Ear infection
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    Gastroenteritis
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 48 (4.17%)
         occurrences all number
    3
    4
    Gastroenteritis viral
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    Influenza
         subjects affected / exposed
    6 / 53 (11.32%)
    1 / 48 (2.08%)
         occurrences all number
    7
    1
    Nasopharyngitis
         subjects affected / exposed
    6 / 53 (11.32%)
    4 / 48 (8.33%)
         occurrences all number
    7
    6
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 53 (7.55%)
    9 / 48 (18.75%)
         occurrences all number
    4
    9
    Viral infection
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 May 2007
    Enhanced renal monitoring and additional AE management sections were added.
    17 Oct 2011
    Change of post-colonoscopy interval pre-randomization from 30 to 90 days, provision for re-screening screen failures, drug-induced liver injury and change of polyp count from 20 to 30 were added.
    12 Mar 2013
    Study discontinuation criteria was updated: If a subject did not return for a scheduled visit, every effort was made to contact the subject. If all efforts to contact the subject, including direct mail, telephone contact, contact through the next of kin, contact through the subject’s family physician or neighbors failed, then subject was declared lost-to-follow-up.

    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 study was early terminated on 22 July 2013, due to the low number of subjects and no efficacy analysis was performed. Only descriptive statistics was performed.
    For support, Contact us.
    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
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