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    Clinical Trial Results:
    A Phase III Randomized, Double Blind, Placebo-controlled, Multicenter, Parallel Group Study to Assess the Efficacy and Safety of Fixed-dose Combination RHB-104 in Subjects with Moderately to Severely Active Crohn’s Disease

    Summary
    EudraCT number
    		 2015-001179-36
    Trial protocol
    		 PL   CZ   SK   BG  
    Global end of trial date
    30 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions
    Summary report(s)
    		 RHB-104-01 Clinical Study Report Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    RHB-104-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01951326
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    RedHill Biopharma Ltd.
    Sponsor organisation address
    21 Ha’arba’a St, Tel Aviv, Israel, 6473921
    Public contact
    Aida Bibliowicz, VP Clinical Affairs EU, RedHill Biopharma Ltd., +972 3-541-3131, aida@redhillbio.com
    Scientific contact
    Aida Bibliowicz, VP Clinical Affairs EU, RedHill Biopharma Ltd., +972 3-541-3131, aida@redhillbio.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
    11 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess whether subjects randomized to receive RHB-104 have a higher probability of being in a state of remission at the 26 week assessment as compared to subjects randomized to receive placebo.
    Protection of trial subjects
    Safety data were reviewed by medical monitors, and summary information was reviewed by an external Data Safety Monitoring Board (DSMB) approximately one-third (21 November 2016) and two-thirds (25 July 2017) of the way through the study. On 25 July 2017, the DSMB reviewed the unblinded interim safety and efficacy data and recommended continuing the study through enrolment with no changes to the protocol, investigator’s brochure, study conduct, or informed consent form (ICF).
    Background therapy
    		 Subjects were allowed to have anti-TNF background therapy and randomization was performed within strata defined by whether subjects used protocol permitted anti-TNF agents (yes or no).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2013
    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
    Australia: 11
    Country: Number of subjects enrolled
    Poland: 61
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    United States: 164
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Israel: 39
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Serbia: 22
    Worldwide total number of subjects
    331
    EEA total number of subjects
    76
    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)
    0
    Adults (18-64 years)
    326
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were be assessed for study eligibility during the screening visit (Day -42 to -7). Screening assessments included medical history, CDAI diary collection and assessment, uveitis assessment, 12-lead ECG, hematology, biochemistry, serology, pregnancy test, CRP, TB test, stool sampling for C. difficile and fecal calprotectine and other

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RHB-104 - Active Therapy
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    RHB-104
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects took 5 capsules bid with food.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching RHB-104
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects took 5 capsules bid with food

    Number of subjects in period 1
    		RHB-104 - Active Therapy Placebo
    Started
    166
    165
    Completed
    87
    87
    Not completed
    79
    78
         Consent withdrawn by subject
    25
    26
         Physician decision
    6
    5
         Adverse event, non-fatal
    29
    33
         Pregnancy
    -
    1
         Administrative decisions and others
    -
    5
         Lost to follow-up
    6
    7
         Administrative and other reasons
    6
    -
         Protocol deviation
    7
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RHB-104 - Active Therapy
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 RHB-104 - Active Therapy Placebo Total
    Number of subjects
    		 166 165 331
    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
    Males and females of 18 to 75 years of age
    Units: years
        arithmetic mean (standard deviation)
    		 39 ± 12.51 39.3 ± 12.56 -
    Gender categorical
    Units: Subjects
        Female
    		 75 67 142
        Male
    		 91 98 189
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 0 1 1
        Black or African American
    		 8 12 20
        White
    		 156 150 306
        Other
    		 2 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 3 9
        Non Hispanic or Latino
    		 160 162 322
    Baseline Crohn's Disease Activity Index (CDAI) Score
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    		 297.77 ± 57.02 293.44 ± 53.18 -

    End points

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    End points reporting groups
    Reporting group title
    RHB-104 - Active Therapy
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Remission at Week 26

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    End point title
    		 Remission at Week 26
    End point description
    Remission was defined as CDAI score of <150; subjects who had CDAI ≥150 or who did not have a CDAI measurement at Week 26 were classified as not having achieved remission.
    End point type
    Primary
    End point timeframe
    Week 26
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    166
    165
    Units: Subjects
    61
    37
    Statistical analysis title
    		 Cochran-Mantel-Haenszel chi-square test
    Comparison groups
    Placebo v RHB-104 - Active Therapy
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Proportion diference
    Point estimate
    14.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.6
         upper limit
    		 24

    Secondary: Response at Week 26

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    End point title
    		 Response at Week 26
    End point description
    Response was defined as reduction from baseline of ≥100 in CDAI score; subjects who had a change from baseline to Week 26 in CDAI score which was not a reduction of ≥100 or who did not have a change from baseline to Week 26 in CDAI score were classified as not having experienced response.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    166
    165
    Units: Subjects
    73
    50
    No statistical analyses for this end point

    Secondary: Remission at Week 52

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    End point title
    		 Remission at Week 52
    End point description
    Remission at Week 52 was defined CDAI score of <150 at Week 52. Subjects who had a CDAI score ≥150 or who did not have a CDAI measurement at Week 52 were classified as not having achieved remission.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    166
    165
    Units: Subjects
    47
    32
    No statistical analyses for this end point

    Secondary: Durable Remission Week 26 through Week 52

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    End point title
    		 Durable Remission Week 26 through Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Week 26 through Week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    166
    165
    Units: Subjects
    33
    21
    No statistical analyses for this end point

    Secondary: Early Remission Week 16

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    End point title
    		 Early Remission Week 16
    End point description
    Subjects who had a CDAI ≥150 or who did not have a CDAI measurement at Week 16 were classified as not having achieved remission.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    166
    165
    Units: Subjects
    70
    48
    No statistical analyses for this end point

    Secondary: Steroid-Free Remission Week 52

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    End point title
    		 Steroid-Free Remission Week 52
    End point description
    Steroid-free remission Week 52 was defined as a subject having a CDAI score of <150, and subject must have been maintained off steroids for at least 3 weeks (ie., by Week 49) to be determined to be in steroid-free remission at Week 52. Subjects who had a CDAI measurement ≥150 or who did not have a CDAI measurement at Week 52 or who were not off steroids by Week 49 were classified as not having achieved remission.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    57
    55
    Units: Subjects
    11
    5
    No statistical analyses for this end point

    Secondary: Time to Remission

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    End point title
    		 Time to Remission
    End point description
    Time to remission = [date of first observed remission (CDAI score < 150) – date of first dose or date of randomization if not dosed + 1] / 7 days. Subjects who never experienced remission during the study were censored at the date of their last CDAI assessment. Percentages were based on the number of subjects in the population.
    End point type
    Secondary
    End point timeframe
    Baseline through week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    101
    78
    Units: Weeks
        number (confidence interval 95%)
    12.1 (8.43 to 12.71)
    19.9 (13 to 52.43)
    No statistical analyses for this end point

    Secondary: Duration of Remission

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    End point title
    		 Duration of Remission
    End point description
    Duration of remission was defined as the number of weeks the subject was in remission (CDAI score <150). It was calculated as the first date following remission at which CDAI was ≥150 minus the date of first remission, plus 1 day, divided by 7. Subjects who experienced remission and continued to be in remission at the time of their last CDAI assessment were censored at the date of their last CDAI assessment.
    End point type
    Secondary
    End point timeframe
    Baseline through week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    101
    78
    Units: Weeks
        number (confidence interval 95%)
    27.1 (16.14 to 46.86)
    16.7 (10.14 to 30.00)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to Response = [Date of first observed response (a reduction from baseline of ≥100 in CDAI score) – Date of first dose or date of randomization if not dosed + 1] / 7 Days. Subjects who never experienced response during the study were censored at the date of their last CDAI assessment.
    End point type
    Secondary
    End point timeframe
    Baseline through week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    115
    92
    Units: Weeks
        number (confidence interval 95%)
    8.3 (8.00 to 9.14)
    12.1 (8.14 to 15.71)
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response was defined as the number of weeks the subjects were in a state of response (a reduction from baseline of ≥100 in CDAI score). It was calculated as the first date after response at which the reduction from baseline in CDAI was <100 minus the date of first response, plus 1 day, divided by 7. Subjects who experienced response and continued to be in response at the time of their last CDAI assessment were censored at the date of their last CDAI assessment.
    End point type
    Secondary
    End point timeframe
    Baseline through week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    115
    92
    Units: Weeks
        number (confidence interval 95%)
    40.1 (22.14 to 52.29)
    22.1 (12.14 to 32.00)
    No statistical analyses for this end point

    Secondary: Durable Remission Week 16 through Week 52

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    End point title
    		 Durable Remission Week 16 through Week 52
    End point description
    Durable remission was defined as maintaining CDAI score <150 from Week 16 through Week 52 assessments. Subjects experiencing a CDAI score ≥150 at any visit time point assessment from Week 16 through Week 52 or who had no CDAI measurement Week 16 or Week 52 were classified as not having achieved durable remission.
    End point type
    Secondary
    End point timeframe
    Week 16 through Week 52
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    166
    165
    Units: Subjects
    31
    14
    No statistical analyses for this end point

    Secondary: Early Response at Week 16

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    End point title
    		 Early Response at Week 16
    End point description
    Subjects who had a change from baseline to Week 16 CDAI score which was not a reduction of ≥100 or who did not have a change from baseline to Week 16 in CDAI score were classified as not having experienced a response.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 RHB-104 - Active Therapy Placebo
    Number of subjects analysed
    166
    165
    Units: Subjects
    79
    60
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The time from the first study drug administration to the end of study visit at week 56 (last study drug dose was at week 52).
    Adverse event reporting additional description
    The safety analysis set included all subjects who received at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    RHB-104
    Reporting group description
    		 RHB-104; a fixed-dose combination of 95 mg clarithromycin, 45 mg rifabutin, and 10 mg clofazimine. The target dose of RHB-104 was 5 capsules administered bid via oral administration.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo is a capsule with a similar appearance as RHB-104. Dosage was 5 capsules bid via oral administration.

    Serious adverse events
    		 RHB-104 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 166 (18.67%)
    31 / 165 (18.79%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    noncardiac chest pain
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    10 / 166 (6.02%)
    8 / 165 (4.85%)
         occurrences causally related to treatment / all
    10 / 10
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 166 (1.81%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 166 (1.81%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal fluid collection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 166 (0.00%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 166 (0.60%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 166 (0.60%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraspinal abscess
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 166 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 RHB-104 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    145 / 166 (87.35%)
    135 / 165 (81.82%)
    Investigations
    Weight decreased
         subjects affected / exposed
    6 / 166 (3.61%)
    4 / 165 (2.42%)
         occurrences all number
    6
    4
    Weight increased
         subjects affected / exposed
    2 / 166 (1.20%)
    7 / 165 (4.24%)
         occurrences all number
    2
    7
    Hepatic enzyme increased
         subjects affected / exposed
    5 / 166 (3.01%)
    0 / 165 (0.00%)
         occurrences all number
    5
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 166 (9.64%)
    17 / 165 (10.30%)
         occurrences all number
    16
    17
    Dizziness
         subjects affected / exposed
    5 / 166 (3.01%)
    5 / 165 (3.03%)
         occurrences all number
    5
    5
    Dysgeusia
         subjects affected / exposed
    7 / 166 (4.22%)
    19 / 165 (11.52%)
         occurrences all number
    7
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 166 (6.02%)
    6 / 165 (3.64%)
         occurrences all number
    10
    6
    Leukopenia
         subjects affected / exposed
    4 / 166 (2.41%)
    1 / 165 (0.61%)
         occurrences all number
    4
    1
    Neutropenia
         subjects affected / exposed
    4 / 166 (2.41%)
    0 / 165 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 166 (5.42%)
    6 / 165 (3.64%)
         occurrences all number
    9
    6
    Fatigue
         subjects affected / exposed
    8 / 166 (4.82%)
    4 / 165 (2.42%)
         occurrences all number
    8
    4
    Oedema peripheral
         subjects affected / exposed
    4 / 166 (2.41%)
    2 / 165 (1.21%)
         occurrences all number
    4
    2
    Peripheral swelling
         subjects affected / exposed
    4 / 166 (2.41%)
    1 / 165 (0.61%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    21 / 166 (12.65%)
    25 / 165 (15.15%)
         occurrences all number
    21
    25
    Abdominal pain
         subjects affected / exposed
    24 / 166 (14.46%)
    19 / 165 (11.52%)
         occurrences all number
    24
    19
    Nausea
         subjects affected / exposed
    22 / 166 (13.25%)
    12 / 165 (7.27%)
         occurrences all number
    22
    12
    Diarrhoea
         subjects affected / exposed
    11 / 166 (6.63%)
    8 / 165 (4.85%)
         occurrences all number
    11
    8
    Vomiting
         subjects affected / exposed
    12 / 166 (7.23%)
    7 / 165 (4.24%)
         occurrences all number
    12
    7
    Abdominal tenderness
         subjects affected / exposed
    4 / 166 (2.41%)
    9 / 165 (5.45%)
         occurrences all number
    4
    9
    Abdominal distension
         subjects affected / exposed
    8 / 166 (4.82%)
    3 / 165 (1.82%)
         occurrences all number
    8
    3
    Dry mouth
         subjects affected / exposed
    6 / 166 (3.61%)
    3 / 165 (1.82%)
         occurrences all number
    6
    3
    Dyspepsia
         subjects affected / exposed
    7 / 166 (4.22%)
    2 / 165 (1.21%)
         occurrences all number
    7
    2
    Flatulence
         subjects affected / exposed
    7 / 166 (4.22%)
    25 / 165 (15.15%)
         occurrences all number
    7
    2
    Small intestinal obstruction
         subjects affected / exposed
    4 / 166 (2.41%)
    4 / 165 (2.42%)
         occurrences all number
    4
    4
    Tooth discolouration
         subjects affected / exposed
    7 / 166 (4.22%)
    0 / 165 (0.00%)
         occurrences all number
    7
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 166 (1.20%)
    4 / 165 (2.42%)
         occurrences all number
    2
    4
    Abdominal pain lower
         subjects affected / exposed
    0 / 166 (0.00%)
    4 / 165 (2.42%)
         occurrences all number
    0
    4
    Constipation
         subjects affected / exposed
    4 / 166 (2.41%)
    0 / 165 (0.00%)
         occurrences all number
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 166 (3.01%)
    2 / 165 (1.21%)
         occurrences all number
    5
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 166 (0.60%)
    5 / 165 (3.03%)
         occurrences all number
    1
    5
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    7 / 166 (4.22%)
    17 / 165 (10.30%)
         occurrences all number
    7
    1
    Skin discolouration
         subjects affected / exposed
    6 / 166 (3.61%)
    0 / 165 (0.00%)
         occurrences all number
    6
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    42 / 166 (25.30%)
    2 / 165 (1.21%)
         occurrences all number
    42
    2
    Haematuria
         subjects affected / exposed
    1 / 166 (0.60%)
    6 / 165 (3.64%)
         occurrences all number
    1
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 166 (1.81%)
    5 / 165 (3.03%)
         occurrences all number
    3
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 166 (9.64%)
    7 / 165 (4.24%)
         occurrences all number
    16
    7
    Back pain
         subjects affected / exposed
    4 / 166 (2.41%)
    8 / 165 (4.85%)
         occurrences all number
    4
    8
    Myalgia
         subjects affected / exposed
    5 / 166 (3.01%)
    3 / 165 (1.82%)
         occurrences all number
    5
    3
    Pain in extremity
         subjects affected / exposed
    7 / 166 (4.22%)
    1 / 165 (0.61%)
         occurrences all number
    7
    1
    Neck pain
         subjects affected / exposed
    1 / 166 (0.60%)
    4 / 165 (2.42%)
         occurrences all number
    1
    4
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    4 / 166 (2.41%)
    14 / 165 (8.48%)
         occurrences all number
    4
    14
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 166 (4.82%)
    9 / 165 (5.45%)
         occurrences all number
    8
    9
    Influenza
         subjects affected / exposed
    6 / 166 (3.61%)
    10 / 165 (6.06%)
         occurrences all number
    6
    10
    Viral upper respiratory tract infection
         subjects affected / exposed
    7 / 166 (4.22%)
    9 / 165 (5.45%)
         occurrences all number
    7
    9
    Rash
         subjects affected / exposed
    8 / 166 (4.82%)
    8 / 165 (4.85%)
         occurrences all number
    8
    8
    Urinary tract infection
         subjects affected / exposed
    7 / 166 (4.22%)
    5 / 165 (3.03%)
         occurrences all number
    7
    5
    Bronchitis
         subjects affected / exposed
    5 / 166 (3.01%)
    3 / 165 (1.82%)
         occurrences all number
    5
    3
    Gastroenteritis
         subjects affected / exposed
    4 / 166 (2.41%)
    3 / 165 (1.82%)
         occurrences all number
    4
    3
    Pneumonia
         subjects affected / exposed
    2 / 166 (1.20%)
    4 / 165 (2.42%)
         occurrences all number
    2
    4
    Anal abscess
         subjects affected / exposed
    1 / 166 (0.60%)
    4 / 165 (2.42%)
         occurrences all number
    1
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 166 (3.01%)
    1 / 165 (0.61%)
         occurrences all number
    5
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Oct 2016
    Major changes in the Version 9.0 were as follows: • Adequate time to demonstrate lack of efficacy in baseline anti-TNF agents was reflected. • Increased estimated number of subjects and participating centers in the study. • Reference to the open-label rescue study was made. • Clarification due to allowance of colonoscopies without biopsy as per investigator requests. • Addition of SES-CD alongside CDEIS as an exploratory outcome measure of endoscopic changes to be assessed in those subjects who consented to colonoscopy.
    29 Mar 2017
    Major changes in the Version 10.0 were as follows: • Endpoints clarified to represent those clinically most relevant after the primary objective as key secondary objectives, followed by selected other supportive objectives and finally other exploratory objectives. • Updates to the exclusion criteria were made to include quinolones in the list of medications that caused QT prolongation or Torsades de Pointe. • Clarification that subjects not in remission at Week 26, could elect to continue participation in the RHB-104-01 study, and would remain in the RHB-104-01 study until study drug administration in the RHB-104-04 study, if applicable. This allowed for subjects to transition into the RHB-104-04 study after Week 26 in cases where the RHB-104-04 study was not yet IRB approved and clarified that AEs from the RHB 104 01 would be captured until the day before the start of dosing in RHB-104-04. • Clarification that minimum overall compliance had to be approximately 80%, upon which a subject could be discontinued from treatment after a discussion with the medical monitor. • Clarification that subject would be considered a treatment failure in the steroid-free remission analysis if the subject experienced a worsening of disease activity during the taper, and further steroid dose decreases were suspended, and/or the oral corticosteroid dose increased. • Clarification that the administration of the morning dose from a newly dispensed treatment bottle would not be considered a protocol deviation. The study drug administration
    29 Sep 2017
    Major changes in Protocol Version 11.0 were as follows: • It reflected curtailment of study recruitment and representation of power as initial estimates were overly conservative did not account for accrual trends. Curtailment to a target sample size of approximately 324 subjects would effectively provide 86% of the necessary sample size while still maintaining statistical power of over 80% with a treatment effect of 15%. • Some additional sensitivity analyses were added.

    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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