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    Clinical Trial Results:
    A randomized, double blind, placebo-controlled, dose response, phase II, multicentre trial to evaluate the efficacy, safety and pharmacokinetics of oral CR6086 administered at the doses of 30, 90 or 180 mg bid for 12 weeks in combination with methotrexate, in DMARD-naïve patients with early rheumatoid arthritis

    Summary
    EudraCT number
    		 2016-004834-11
    Trial protocol
    		 DK   BG   PL   CZ   GB  
    Global end of trial date
    08 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2020
    First version publication date
    25 Jun 2020
    Other versions
    Summary report(s)
    		 CR6086-2-02 Summary of Results

    Trial information

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    Trial identification
    Sponsor protocol code
    CR6086-2-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03163966
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rottapharm Biotech S.r.l.
    Sponsor organisation address
    Via Valosa di Sopra 9, Monza, Italy, 20900
    Public contact
    Lucio Rovati, Rottapharm Biotech S.r.l., Via Valosa di Sopra 9, Monza, 20900, Italy, +39 039 9066104, lucio.rovati@rottapharmbiotech.com
    Scientific contact
    Lucio Rovati, Rottapharm Biotech S.r.l., Via Valosa di Sopra 9, Monza, 20900, Italy, +39 039 9066104, lucio.rovati@rottapharmbiotech.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
    09 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of oral CR6086 in combination with oral MTX over a 12-week treatment period in DMARD-naïve patients with early RA, in comparison with oral MTX alone.
    Protection of trial subjects
    Trial subjects have been strictly monitored, at a frequency higher that usual and with more intensive assessments. Patients were allowed to take oral corticosteroids (at doses <= 10mg/day) if this was required for a better control of symptoms and pain
    Background therapy
    		 Methotrexate 10-20 mg/week for 13 weeks
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2017
    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
    Denmark: 8
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Bulgaria: 105
    Country: Number of subjects enrolled
    Czech Republic: 37
    Country: Number of subjects enrolled
    Moldova, Republic of: 49
    Country: Number of subjects enrolled
    Romania: 5
    Worldwide total number of subjects
    248
    EEA total number of subjects
    199
    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)
    195
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: October 2017 - September 2018 Recruitment countries: CZ, BG, DK, MD, PL, RO, UK

    Pre-assignment
    Screening details
    		 478 patients were screened, 15 in DK, 64 in CZ, 66 in PL, 11 in RO, 114 in MD, 200 in BG, 8 in UK. 230 were screening failures. Most common reasons for failure: hsCRP <3mg/L (49%) and NO RF or ACPA (47%)

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    CR6086 30 mg, CR6086 90 mg, CR6086 180 mg and Placebo treatments were identical in appearance. Treatment packs were assigned by an e-system, according to the randomization list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CR6086 30 + MTX
    Arm description
    		 CR6086 30 mg bid in addition to MTX
    Arm type
    		 Experimental

    Investigational medicinal product name
    CR6086
    Investigational medicinal product code
    CR6086
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    CR6086 30 mg administered bid for 12 weeks

    Arm title
    		 CR6086 90 + MTX
    Arm description
    		 CR6086 90 mg administered bid for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    CR6086
    Investigational medicinal product code
    CR6086
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    CR6086 90 mg administered bid for 12 weeks

    Arm title
    		 CR6086 180 + MTX
    Arm description
    		 CR6086 180 mg bid in addition to MTX
    Arm type
    		 Experimental

    Investigational medicinal product name
    CR6086
    Investigational medicinal product code
    CR6086
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    CR6086 180 mg administered bid for 12 weeks

    Arm title
    		 Placebo + MTX
    Arm description
    		 Placebo bid + in addition to MTX
    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 administered bid for 12 weeks

    Number of subjects in period 1
    		CR6086 30 + MTX CR6086 90 + MTX CR6086 180 + MTX Placebo + MTX
    Started
    60
    61
    64
    63
    Completed
    53
    56
    51
    56
    Not completed
    7
    5
    13
    7
         Consent withdrawn by subject
    4
    3
    3
    2
         Physician decision
    -
    -
    -
    1
         Protocol Deviation
    1
    1
    -
    2
         Adverse event, non-fatal
    -
    1
    8
    1
         MTX first dose not tolerated
    2
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CR6086 30 + MTX
    Reporting group description
    		 CR6086 30 mg bid in addition to MTX

    Reporting group title
    CR6086 90 + MTX
    Reporting group description
    		 CR6086 90 mg administered bid for 12 weeks

    Reporting group title
    CR6086 180 + MTX
    Reporting group description
    		 CR6086 180 mg bid in addition to MTX

    Reporting group title
    Placebo + MTX
    Reporting group description
    		 Placebo bid + in addition to MTX

    Reporting group values
    		 CR6086 30 + MTX CR6086 90 + MTX CR6086 180 + MTX Placebo + MTX Total
    Number of subjects
    		 60 61 64 63 248
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 45 50 47 53 195
        From 65-84 years
    		 15 11 17 10 53
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.3 ( 13.1 ) 53.1 ( 11.5 ) 54.7 ( 12.8 ) 52.6 ( 10.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 42 48 51 180
        Male
    		 21 19 16 12 68
    Disease duration
    Patients with disease duration < 12 months were selected. Disease duration < 6 months from symptom onset is the ACR definition of early RA
    Units: Subjects
        < 6 months
    		 23 22 28 26 99
        >= 6 months
    		 37 39 36 37 149
    ACR Total score
    The ACR score is based on: -Joint involvement -Serology -Acute phase reactants -Duration of symptoms
    Units: Subjects
        score 7
    		 2 2 3 3 10
        score 8
    		 2 5 6 10 23
        score 9
    		 10 2 6 5 23
        score 10
    		 46 52 49 45 192

    End points

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    End points reporting groups
    Reporting group title
    CR6086 30 + MTX
    Reporting group description
    		 CR6086 30 mg bid in addition to MTX

    Reporting group title
    CR6086 90 + MTX
    Reporting group description
    		 CR6086 90 mg administered bid for 12 weeks

    Reporting group title
    CR6086 180 + MTX
    Reporting group description
    		 CR6086 180 mg bid in addition to MTX

    Reporting group title
    Placebo + MTX
    Reporting group description
    		 Placebo bid + in addition to MTX

    Primary: ACR20

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    End point title
    		 ACR20
    End point description
    ACR20 is defined as: 20% improvement in tender joint count and 20% improvement in swollen joint count and 20% improvement in at least 3/5 other scores (Patient’s assessment of arthritis pain, PtGA of arthritis, PhGA of arthritis, Patient’s assessment of physical function (HAQ-DI), Acute-phase reactant value (CRP)
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 CR6086 30 + MTX CR6086 90 + MTX CR6086 180 + MTX Placebo + MTX
    Number of subjects analysed
    59
    60
    63
    62
    Units: n of responders
    33
    42
    38
    37
    Statistical analysis title
    		 Superiority of each CR6086 dose over MTX
    Statistical analysis description
    Pairwise comparisons
    Comparison groups
    CR6086 30 + MTX v CR6086 90 + MTX v CR6086 180 + MTX v Placebo + MTX
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.2296 [2]
    Method
    		 normal approximation for the difference
    Confidence interval
    Notes
    [1] - Pairwise comparisons using the normal approximation for the difference in binomial proportions
    [2] - p value = 0.6765 for CR6086 30 mg + MTX p value = 0.2296 for CR6086 90 mg + MTX p value = 0.9418 for CR6086 180 mg + MTX

    Post-hoc: ACR20 in patients with 6-12 months disease duration

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    End point title
    		 ACR20 in patients with 6-12 months disease duration
    End point description
    ACR20 is defined as: 20% improvement in tender joint count and 20% improvement in swollen joint count and 20% improvement in at least 3/5 other scores (Patient’s assessment of arthritis pain, PtGA of arthritis, PhGA of arthritis, Patient’s assessment of physical function (HAQ-DI), Acute-phase reactant value (CRP)
    End point type
    Post-hoc
    End point timeframe
    12 weeks
    End point values
    		 CR6086 30 + MTX CR6086 90 + MTX CR6086 180 + MTX Placebo + MTX
    Number of subjects analysed
    36
    38
    35
    37
    Units: n of responders
    18
    26
    19
    18
    Statistical analysis title
    		 Superiority of each CR6086 dose over MTX
    Statistical analysis description
    Pairwise comparisons
    Comparison groups
    CR6086 30 + MTX v CR6086 90 + MTX v CR6086 180 + MTX v Placebo + MTX
    Number of subjects included in analysis
    146
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.07 [4]
    Method
    		 normal approximation for the difference
    Confidence interval
    Notes
    [3] - Pairwise comparisons using the normal approximation for the difference in binomial proportions
    [4] - P value=0.91 for CR6086 30 mg + MTX P value=0.07 for CR6086 90 mg + MTX P value=0.63 for CR6086 180 mg + MTX

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of CR6086 (second week of treatment) to the end of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    CR6086 30 + MTX
    Reporting group description
    		 CR6086 30 mg bid in addition to MTX

    Reporting group title
    CR6086 90 + MTX
    Reporting group description
    		 CR6086 90 mg administered bid for 12 weeks

    Reporting group title
    CR6086 180 + MTX
    Reporting group description
    		 CR6086 180 mg bid in addition to MTX

    Reporting group title
    Placebo + MTX
    Reporting group description
    		 Placebo bid + in addition to MTX

    Serious adverse events
    		 CR6086 30 + MTX CR6086 90 + MTX CR6086 180 + MTX Placebo + MTX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 60 (1.67%)
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Gastrointestinal disorders
    Constipation
    Additional description: 1 constipation and diverticulitis in the 180 mg CR6086/MTX group considered serious as per the hospitalization criterion and treatment related, in a 60-years-old male patient enrolled in Denmark
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Antisynthetase syndrome
    Additional description: 1 antisynthetase syndrome in the 90 mg CR6086/MTX group, considered serious as per the hospitalization and important medical event criteria and treatment not-related, in a 63-years-old female patient enrolled in Czech Republic
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
    Additional description: 1 bronchopneumonia in the placebo/MTX group considered serious as per the hospitalization criterion and treatment not-related, in a 57-years-old female patient enrolled in Czech Republic
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
    Additional description: 1 constipation and diverticulitis in the 180 mg CR6086/MTX group considered serious as per the hospitalization criterion and treatment related, in a 60-years-old male patient enrolled in Denmark
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CR6086 30 + MTX CR6086 90 + MTX CR6086 180 + MTX Placebo + MTX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 59 (42.37%)
    24 / 60 (40.00%)
    32 / 63 (50.79%)
    22 / 62 (35.48%)
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 60 (5.00%)
    7 / 63 (11.11%)
    0 / 62 (0.00%)
         occurrences all number
    0
    3
    7
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 60 (1.67%)
    4 / 63 (6.35%)
    4 / 62 (6.45%)
         occurrences all number
    1
    1
    4
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    3
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 59 (8.47%)
    3 / 60 (5.00%)
    3 / 63 (4.76%)
    3 / 62 (4.84%)
         occurrences all number
    5
    3
    3
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 59 (1.69%)
    4 / 60 (6.67%)
    4 / 63 (6.35%)
    2 / 62 (3.23%)
         occurrences all number
    1
    4
    5
    2
    Dyspepsia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 60 (0.00%)
    4 / 63 (6.35%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2017
    The exclusion criterion: 11. Allergy/sensitivity to lactose was changed in 11. Allergy/hypersensitivity/intolerance to any components in CR6086 and MTX, including excipients such as lactose (patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should be excluded), starch, magnesium stearate, cellulose.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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