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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 48-weeks treatment with gastro-resistant phosphatidylcholine (LT-02) versus placebo versus mesalamine for maintenance of remission in patients with ulcerative colitis

    Summary
    EudraCT number
    		 2013-001205-84
    Trial protocol
    		 DE   PL   LT   LV   SK   BE   AT   HU  
    Global end of trial date
    05 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jan 2020
    First version publication date
    02 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCG-4/UCR
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02280629
    WHO universal trial number (UTN)
    		 -
    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,
    Scientific contact
    Dep't of Research and Development, Dr Falk Pharma GmbH, +49 761-1514-0,
    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
    13 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To prove the superiority of a 48-weeks treatment with 3.2 g/day delayed-release phosphatidylcholine (LT-02) versus placebo for the maintenance of remission in patients with ulcerative colitis (UC)
    Protection of trial subjects
    Close supervision of subjects by implementing interim visits at week 4, 12, and then every 3 months, every 4 weeks during the open-label re-induction phase and at every 3 months during the open-label extension phase, to guarantee their safety and wellbeing. Prior to recruitment of patients, all relevant documents of the clinical study were submitted and approved 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
    		 According to current consensus guidelines, mesalamine preparations are the mainstay of treatment for maintenance of remission in mild-to-moderate UC and have been shown to be superior to placebo.
    Actual start date of recruitment
    01 Oct 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
    Poland: 29
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Germany: 69
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Lithuania: 3
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Ukraine: 27
    Country: Number of subjects enrolled
    Israel: 2
    Worldwide total number of subjects
    150
    EEA total number of subjects
    109
    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)
    144
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total number of 150 patients were randomized to LT-02 1.6 g two times daily, or Placebo, or Mesalamine 0.5 g 3 times daily. The initally planned patient-number could not be reached due to the premature termination of preceding induction trial PCG-2 (EudraCT # 2012-003702-27) causing a premature end of recruitment into PCG-4

    Pre-assignment
    Screening details
    		 Screening criteria: 1. Signed informed consent 2. Aged 18 to 70 years 3. Either in deep remission or remission at baseline, i.e. at the end of the preceding PCG-2 study.

    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, Assessor
    Blinding implementation details
    The appearance and taste of sachets for oral administration were indistinguishable among the three treatment groups due to double-dummy-packaging. All patients took the same amount of sachets at the same times of the day.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 1.6 g phosphatidylcholine in LT-02 BID
    Arm type
    		 Experimental

    Investigational medicinal product name
    LT-02 gastro-resistant granules
    Investigational medicinal product code
    Not applicable
    Other name
    Pharmaceutical forms
    Gastro-resistant granules
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing: 1.6 g phosphatidylcholine in LT-02 sachets twice daily taken in the morning and in the evening, plus mesalamine placebo sachets taken in the morning, at lunchtime and in the evening. Administration: LT-02 sachets: 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. Mesalamine placebo sachets: The content of 1 sachet each has to be swallowed in the morning, at noon, and in the evening with plenty of water. Chewing of the study medication has to be avoided.

    Arm title
    		 Group B
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    LT-02 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: LT-02 placebo sachets twice daily taken in the morning and in the evening, plus mesalamine placebo sachets taken in the morning, at lunchtime and in the evening. Administration: LT-02 placebo sachets: 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. Mesalamine placebo sachets: The content of 1 sachet each has to be swallowed in the morning, at noon, and in the evening with plenty of water. Chewing of the study medication has to be avoided.

    Investigational medicinal product name
    Mesalamine 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: LT-02 placebo sachets twice daily taken in the morning and in the evening, plus mesalamine placebo sachets taken in the morning, at lunchtime and in the evening. Administration: LT-02 placebo sachets: 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. Mesalamine placebo sachets: The content of 1 sachet each has to be swallowed in the morning, at noon, and in the evening with plenty of water. Chewing of the study medication has to be avoided.

    Arm title
    		 Group C
    Arm description
    		 Mesalamine 0,5 g TID
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Mesalamine 0,5 g TID
    Investigational medicinal product code
    Other name
    Salofalk® 500 mg gastro-resistant prolonged-release granules
    Pharmaceutical forms
    Gastro-resistant granules
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing: Mesalamine 0,5 g TID with mesalamine-sachets taken in the morning, at lunchtime and in the evening; plus LT-02 placebo sachets twice daily taken in the morning and in the evening. Administration: Mesalamine sachets: The content of 1 sachet each has to be swallowed in the morning, at noon, and in the evening with plenty of water. Chewing of the study medication has to be avoided. LT-02 placebo sachets: 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
    75
    37
    38
    Completed
    40
    16
    20
    Not completed
    35
    21
    18
         Lack of patient cooperation
    -
    -
    1
         Adverse event, non-fatal
    1
    -
    -
         Lack of patient's cooperation
    10
    -
    -
         unspecified
    -
    2
    -
         Lack of efficacy
    24
    19
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 1.6 g phosphatidylcholine in LT-02 BID

    Reporting group title
    Group B
    Reporting group description
    		 Placebo

    Reporting group title
    Group C
    Reporting group description
    		 Mesalamine 0,5 g TID

    Reporting group values
    		 Group A Group B Group C Total
    Number of subjects
    		 75 37 38 150
    Age categorical
    Based on year of birth
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 1 1
        Adults (18-64 years)
    		 72 35 37 144
        From 65-84 years
    		 3 2 0 5
        85 years and over
    		 0 0 0 0
    Age continuous
    Based on year of birth
    Units: years
        arithmetic mean (standard deviation)
    		 39.5 ± 11.28 42.0 ± 13.04 40.7 ± 11.66 -
    Gender categorical
    Assumed to be representative for overall patient population
    Units: Subjects
        Female
    		 32 13 18 63
        Male
    		 43 24 20 87
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS: full analysis set

    Subject analysis sets values
    		 FAS
    Number of subjects
    150
    Age categorical
    Based on year of birth
    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)
    1
        Adults (18-64 years)
    144
        From 65-84 years
    5
        85 years and over
    0
    Age continuous
    Based on year of birth
    Units: years
        arithmetic mean (standard deviation)
    40.4 ± 11.80
    Gender categorical
    Assumed to be representative for overall patient population
    Units: Subjects
        Female
    63
        Male
    87

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 1.6 g phosphatidylcholine in LT-02 BID

    Reporting group title
    Group B
    Reporting group description
    		 Placebo

    Reporting group title
    Group C
    Reporting group description
    		 Mesalamine 0,5 g TID

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS: full analysis set

    Primary: Primary endpoint: Proportion of patients who are relapse-free and are not a treatment failure after 48 weeks

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    End point title
    		 Primary endpoint: Proportion of patients who are relapse-free and are not a treatment failure after 48 weeks
    End point description
    Proportion of patients who are relapse-free and are not a treatment failure after 48 weeks. Relapse defined as a rectal bleeding score of ≥ 1 and a mucosal appearance score of ≥ 2 as described in the mDAI score; ‘treatment failure’ defined as premature withdrawal (whatever the reason) during the double-blind phase.
    End point type
    Primary
    End point timeframe
    Double-blind phase
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    75
    37
    38
    Units: Percentage
    75
    37
    38
    Statistical analysis title
    		 Confirmative analysis: LT-02 1.6 g BID vs Placebo
    Statistical analysis description
    Confirmatory statistical analysis by comparison of LT-02 1.6 g BID vs Placebo
    Comparison groups
    Group B v Group A
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 inverse normal method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.5
         upper limit
    		 26.6

    Secondary: Secondary: Change from Baseline of total mDAI

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    End point title
    		 Secondary: Change from Baseline of total mDAI
    End point description
    Change from Baseline of total mDAI at week 48 (LOCF). Analysis was only performed for LT-02 compared to placebo
    End point type
    Secondary
    End point timeframe
    week 48/EOT
    End point values
    		 Group A Group B Group C
    Number of subjects analysed
    54
    30
    33
    Units: Total mDAI score
        least squares mean (standard error)
    2.17 ± 0.425
    2.45 ± 0.570
    2.64 ± 0.543
    Statistical analysis title
    		 Analysis of change of total mDAI from Baseline
    Statistical analysis description
    Analysis of change from Baseline of total mDAI at week 48 (LOCF)
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3462
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 1.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.711

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event 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
    		 1.6 g phosphatidylcholine in LT-02 BID

    Reporting group title
    Group B
    Reporting group description
    		 Placebo

    Reporting group title
    Group C
    Reporting group description
    		 Mesalamine 0,5 g TID

    Serious adverse events
    		 Group A Group B Group C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 75 (5.33%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Cerebrovascular accident
    Additional description: Investigator term: Stroke left capsula interna
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 38 (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
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: Investigator term: right-sided upper abdominal pain
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 38 (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
    Small intestinal obstruction
    Additional description: Investigator term: Adhesive small bowel obstruction
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 38 (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
    Pancreatitis acute
    Additional description: Investigator term: acute pancreatitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
    Additional description: Investigator term: hepatic cholestasis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 38 (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
    Infections and infestations
    Osteomyelitis
    Additional description: Investigator term: Osteomyelitis left lower jaw
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 38 (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
    46 / 75 (61.33%)
    25 / 37 (67.57%)
    25 / 38 (65.79%)
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 37 (5.41%)
    0 / 38 (0.00%)
         occurrences all number
    4
    2
    0
    Colitis ulcerative
         subjects affected / exposed
    27 / 75 (36.00%)
    20 / 37 (54.05%)
    19 / 38 (50.00%)
         occurrences all number
    27
    20
    19
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 75 (0.00%)
    3 / 37 (8.11%)
    0 / 38 (0.00%)
         occurrences all number
    0
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 75 (9.33%)
    2 / 37 (5.41%)
    4 / 38 (10.53%)
         occurrences all number
    7
    2
    4

    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.
    Due to early termination of preceding induction trial PCG-2 (for futility), the recruitment into maintenance trial PCG-4 came to an end prematurely: Instead of the initially planned number of 400 patients, only 150 patients were randomised.
    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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