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    Clinical Trial Results:
    Randomized, double-blind, double-dummy, placebo-controlled, Phase III clinical trial on the efficacy and safety of a 12-weeks add-on treatment with LT-02 (gastro-resistant phosphatidylcholine granules) vs. placebo in patients with ulcerative colitis refractory to standard treatment with mesalamine

    Summary
    EudraCT number
    		 2012-003702-27
    Trial protocol
    		 DE   BE   AT   CZ   SK   HU   LT   LV   NL   PL  
    Global end of trial date
    16 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Mar 2019
    First version publication date
    09 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCG-2/UCA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02142725
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 PROTECT-1: Acronym
    Sponsors
    Sponsor organisation name
    Dr Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstrasse 5, Freiburg, Germany, 79108
    Public contact
    Dep't of Research and Development, Dr Falk Pharma GmbH, +49 761-1514-0, zentrale@drfalkpharma.de
    Scientific contact
    Dep't of Research and Development, Dr Falk Pharma GmbH, +49 761-1514-0, zentrale@drfalkpharma.de
    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
    28 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To prove the superiority of a 12-week add-on treatment with 3.2 g/day gastro-resistant phosphatidylcholine granules (LT-02) in at least one of two different dosing regimens versus LT-02 placebo for the induction of remission in patients with ulcerative colitis (UC) refractory to standard treatment with mesalamine.
    Protection of trial subjects
    Close supervision of subjects by implementing interim visits every 14 days and once more after 4 weeks during the 12 weeks double-blind phase and after 4 and after 8 weeks during the 12 weeks open-label phase, to guarantee their safety and wellbeing. Prior to recruitment of patients, all relevant documents of the clinical study were submitted and proved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2014
    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
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 73
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Austria: 12
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Germany: 238
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Latvia: 11
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Ukraine: 49
    Worldwide total number of subjects
    465
    EEA total number of subjects
    378
    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)
    1
    Adults (18-64 years)
    443
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 468 patients were randomised to treatment with LT-02 0.8 g four times daily (QID), LT-02 1.6 g two times daily (BID), or placebo. Of these, 465 patients received at least one dose of study medication and had at least one follow-up value for the safety variables to be analysed.

    Pre-assignment
    Screening details
    		 Screening details: Screening criteria: 1. Signed informed consent 2. Aged 18 to 70 years 3. Mesalamine (5-ASA) refractory disease defined as a total mDAI Score of ≥ 4 and ≤ 10

    Period 1
    Period 1 title
    Double-blind phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The appearance and taste of sachets for oral administration were indistinguishable among the three treatment groups due to the double-dummy-packaging. All patients took the same amount of sachets at the same times of the day (2 in the morning, 1 at lunch-time, 1 in the afternoon, 2 in the evening).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 0.8 g PC in LT-02 QID (four times daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    phosphatidylcholine (LT-02, gastro-resistant granules)
    Investigational medicinal product code
    Other name
    phosphatidylcholine
    Pharmaceutical forms
    Gastro-resistant granules
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing: 0.8 g phosphatidylcholine in LT-02 four times daily, with placebo sachets taken with morning and evening doses as part of double-dummy packaging. Administration: Ingest contents of one sachet 30 to 60 minutes before meal along with a glass of water. Alternatively, mix the content of the sachet with water, juice, or yoghurt; in this case, ingest the mixture immediately after preparation. Do not chew.

    Arm title
    		 Group B
    Arm description
    		 1.6 g PC in LT-02 BID (twice daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    phosphatidylcholine (LT-02, gastro-resistant granules)
    Investigational medicinal product code
    Other name
    phosphatidylcholine
    Pharmaceutical forms
    Gastro-resistant granules
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing: 1.6 g PC in LT-02 twice daily, with placebo sachets taken during lunchtime and afternoon doses, as part of double-dummy packaging. Administration: Ingest contents of one sachet 30 to 60 minutes before meal along with a glass of water. Alternatively, mix the content of the sachet with water, juice, or yoghurt; in this case, ingest the mixture immediately after preparation. Do not chew.

    Arm title
    		 Group C
    Arm description
    		 Placebo QID (four times daily)
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo gastro-resistant granules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gastro-resistant granules
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing: Placebo sachets taken four times daily (QID). Administration: Ingest contents of one sachet 30 to 60 minutes before meal along with a glass of water. Alternatively, mix the content of the sachet with water, juice, or yoghurt; in this case, ingest the mixture immediately after preparation. Do not chew.

    Number of subjects in period 1
    		Group A Group B Group C
    Started
    155
    155
    155
    Completed
    109
    112
    109
    Not completed
    46
    43
    46
         Lack of patient cooperation
    7
    4
    3
         Adverse event, non-fatal
    -
    1
    -
         Other (unspecified)
    -
    10
    -
         unspecified
    14
    -
    10
         Lack of efficacy
    25
    28
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-blind phase
    Reporting group description
    		 -

    Reporting group values
    		 Double-blind phase Total
    Number of subjects
    		 465 465
    Age categorical
    Based on year of birth
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 443 443
        From 65-84 years
    		 21 21
        85 years and over
    		 0 0
    Age continuous
    based on year of birth
    Units: years
        arithmetic mean (standard deviation)
    		 39.9 ± 12.83 -
    Gender categorical
    assumed representative for overall patient population
    Units: Subjects
        Female
    		 200 200
        Male
    		 265 265

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 0.8 g PC in LT-02 QID (four times daily)

    Reporting group title
    Group B
    Reporting group description
    		 1.6 g PC in LT-02 BID (twice daily)

    Reporting group title
    Group C
    Reporting group description
    		 Placebo QID (four times daily)

    Subject analysis set title
    Confirmative analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) defined according to the intention-to-treat (ITT) principle was the primary population for analysis and included all randomized patients (as randomized) who received at least one dose of an IMP and who had UC at baseline or in whom UC could not definitely be excluded. The intention-to-treat principle was preserved despite the exclusion of patients who took no IMP, as the decision of whether or not to begin treatment could not be influenced by knowledge of the assigned treatment.

    Primary: Proportion of patients in Deep clinical remission at week 12 (LOCF)

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    End point title
    		 Proportion of patients in Deep clinical remission at week 12 (LOCF)
    End point description
    Deep clinical remission was defined as a modified DAI Score <= 1 with '0' points for rectal bleeding and stool frequency, and >= 1 point reduction from baseline in the mucosal appearance score, at week 12 (LOCF)
    End point type
    Primary
    End point timeframe
    12 weeks (LOCF)
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    155
    155
    155
    Units: Patients
    15
    22
    21
    Statistical analysis title
    		 Confirmative analysis: 0.8 g QID vs placebo
    Statistical analysis description
    Confirmatory statistical analysis by comparison of 0.8 g QID against placebo
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.2875 [2]
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.032
    Notes
    [1] - closed testing procedure with Simes intersection test (α = 0.025, one-sided)
    [2] - Testing of H0 (πPla > π0.8 g QID) by means of the normal approximation test for rates (α = 0.025 one-sided). A closed testing procedure with the Simes intersection test was used to adjust for multiplicity testing of both verum groups versus placebo.
    Statistical analysis title
    		 Confirmative analysis: 1.6 g BID vs placebo
    Statistical analysis description
    Confirmatory statistical analysis by comparison of 1.6 g BID against placebo.
    Comparison groups
    Group B v Group C
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.8695 [4]
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.006
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.083
    Notes
    [3] - Closed testing procedure with Simes intersection test (α = 0.025 one-sided)
    [4] - Testing of H0 (πPla > π1.6 g BID) by means of the normal approximation test for rates (α = 0.025 one-sided). A closed testing procedure with the Simes intersection test was used to adjust for multiplicity testing of both verum groups versus placebo.

    Secondary: Proportion of patients in Remission at Week 12 (LOCF)

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    End point title
    		 Proportion of patients in Remission at Week 12 (LOCF)
    End point description
    Remission: defined as total mDAI score <= 2 with no sub-score > 1
    End point type
    Secondary
    End point timeframe
    12 weeks (LOCF)
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    155
    155
    155
    Units: Patients
    21
    16
    15
    No statistical analyses for this end point

    Secondary: Proportion of patients with Clinical Improvement in mDAI at week 12 (LOCF)

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    End point title
    		 Proportion of patients with Clinical Improvement in mDAI at week 12 (LOCF)
    End point description
    Clinical Improvement defined as total mDAI score decrease of at least 3 points
    End point type
    Secondary
    End point timeframe
    12 weeks (LOCF)
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    155
    155
    155
    Units: Patients
    28
    38
    33
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed from baseline to final visit
    Adverse event reporting additional description
    Treatment emergent adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 LT-02 0.8 g QID

    Reporting group title
    Group B
    Reporting group description
    		 LT-02 1.6 g BID

    Reporting group title
    Group C
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Group A Group B Group C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 155 (3.23%)
    8 / 155 (5.16%)
    4 / 155 (2.58%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Surgical and medical procedures
    Cartilage graft
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Unintended pregnancy
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pseudopolyp
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    0 / 155 (0.00%)
    0 / 155 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    3 / 155 (1.94%)
    3 / 155 (1.94%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine scar
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 155 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 155 (0.00%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A Group B Group C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 155 (51.61%)
    83 / 155 (53.55%)
    82 / 155 (52.90%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 155 (7.74%)
    13 / 155 (8.39%)
    22 / 155 (14.19%)
         occurrences all number
    12
    13
    22
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    21 / 155 (13.55%)
    18 / 155 (11.61%)
    21 / 155 (13.55%)
         occurrences all number
    21
    18
    21
    Nausea
         subjects affected / exposed
    8 / 155 (5.16%)
    3 / 155 (1.94%)
    4 / 155 (2.58%)
         occurrences all number
    8
    3
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 155 (7.74%)
    10 / 155 (6.45%)
    14 / 155 (9.03%)
         occurrences all number
    12
    10
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Per recommendation from the IDMC the study was early terminated due to futility
    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
    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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