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    Clinical Trial Results:
    A randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy, safety and tolerability of CR4056 administered for 2 weeks in patients with osteoarthritis of the knee with moderate to severe chronic pain

    Summary
    EudraCT number
    		 2015-001136-37
    Trial protocol
    		 GB   PL  
    Global end of trial date
    05 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jul 2017
    First version publication date
    30 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CR4056-2-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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., +39 0399066104, lucio.rovati@rottapharmbiotech.com
    Scientific contact
    Lucio Rovati, Rottapharm Biotech S.r.l., +39 0399066104, 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
    31 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is the first, proof-of-concept clinical trial of the first-in-class imidazoline-2 ligand CR4056 as an analgesic in humans. The main objective of the study is to assess the efficacy of CR4056 on pain in patients with knee osteoarthritis (OA) phenotypes.
    Protection of trial subjects
    IDMC in charge of periodic review of safety data Stopping rules based on safety issues
    Background therapy
    		 Paracetamol, as rescue medication
    Evidence for comparator
    		 Not applicable, placebo comparator only - No active comparator was used
    Actual start date of recruitment
    21 Dec 2015
    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: 165
    Country: Number of subjects enrolled
    United Kingdom: 48
    Worldwide total number of subjects
    213
    EEA total number of subjects
    213
    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)
    136
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 165 patients were randomized in Poland and 48 patients were randomized in UK, for a total of 213 patients

    Pre-assignment
    Screening details
    		 Patients were selected according to inclusion/exclusion criteria after screening a total of 338 patients (252 in Poland and 86 in UK, respectively). Patients should have had a diagnosis of knee OA at least 6 months before the inclusion and those who were using analgesics should agree to stop them for the whole study duration.

    Period 1
    Period 1 title
    Treatment period (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
    Indistinguishable CR4056 and placebo according to randomization

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CR4056
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    CR4056
    Investigational medicinal product code
    CR4056
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    14 days of administration - Females 100 mg bid and males 200 mg bid to ensure similar exposure levels due to slight PK gender differences.

    Arm title
    		 Placebo
    Arm description
    		 Placebo comparator; 1:2 ratio with active
    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
    14 days of administration bid

    Number of subjects in period 1
    		CR4056 Placebo
    Started
    144
    69
    Completed
    136
    63
    Not completed
    8
    6
         Consent withdrawn by subject
    4
    4
         Adverse event, non-fatal
    4
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 All patients randomized in the study who received at least one dose of study medication (intention-to-treat)

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 213 213
    Age categorical
    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)
    		 0 0
        Adults (18-64 years)
    		 136 136
        From 65-84 years
    		 77 77
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.9 ± 8.7 -
    Gender categorical
    Units: Subjects
        Female
    		 137 137
        Male
    		 76 76
    BMI
    Body Mass Index, since obesity is a major risk factor for knee OA and a typical disease phenotype. The WHO cut-off BMI for pre-obesity was predetermined in this study (27.5 kg/m2)
    Units: Subjects
        BMI ≥27.5 kg/m2
    		 156 156
        BMI <27.5 kg/m2
    		 57 57

    End points

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    End points reporting groups
    Reporting group title
    CR4056
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo comparator; 1:2 ratio with active

    Primary: Change (EOT vs Baseline) in WOMAC Pain Subscale

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    End point title
    		 Change (EOT vs Baseline) in WOMAC Pain Subscale
    End point description
    The WOMAC Pain Subscale (i.e. the first 5 questions of the WOMAC Index questionnaire) is the most widely-used primary outcome measure for knee OA pain.
    End point type
    Primary
    End point timeframe
    Baseline to End of Treatment
    End point values
    		 CR4056 Placebo
    Number of subjects analysed
    144
    69
    Units: points
        median (full range (min-max))
    -16 (-80 to 22)
    -10 (-64 to 14)
    Statistical analysis title
    		 Comparison (primary) CR4056 vs Placebo
    Statistical analysis description
    This small and short-term proof-of-concept study demonstrated a strong trend for superiority of CR4056 vs placebo in the primary endpoint for pain relief.
    Comparison groups
    CR4056 v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change (EOT vs Baseline) in WOMAC Pain Subscale Q1

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    End point title
    		 Change (EOT vs Baseline) in WOMAC Pain Subscale Q1
    End point description
    Question 1 (Q1) – “How much pain do you have walking on a flat surface?” - is the question that better evaluates the impact of an experimental treatment on knee OA pain, and it is widely used as an endpoint in clinical trials.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment
    End point values
    		 CR4056 Placebo
    Number of subjects analysed
    144
    69
    Units: points
        median (full range (min-max))
    -10 (-80 to 30)
    0 (-80 to 20)
    Statistical analysis title
    		 Comparison (secondary) CR4056 vs Placebo
    Statistical analysis description
    The principal secondary analysis on this well validated end point, showed superiority of CR4056 vs placebo in pain control in knee OA.
    Comparison groups
    CR4056 v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0386
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Change (EOT vs Baseline) in WOMAC Pain Subscale in Patients with BMI ≥27.5 kg/m2

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    End point title
    		 Change (EOT vs Baseline) in WOMAC Pain Subscale in Patients with BMI ≥27.5 kg/m2
    End point description
    Primary endpoint analysis on the most prevalent knee OA phenotype in the study (73% of study population)
    End point type
    Other pre-specified
    End point timeframe
    Baseline to End of Treatment
    End point values
    		 CR4056 Placebo
    Number of subjects analysed
    105
    51
    Units: points
        median (full range (min-max))
    -14 (-80 to 22)
    0 (-56 to 8)
    Statistical analysis title
    		 Comparison CR4056 vs Placebo
    Statistical analysis description
    There was a clear superiority of CR4056 vs placebo in the pre-specified analysis of the primary end point conducted in overweight patients, i.e. the most prevalent phenotype in knee OA and in this study.
    Comparison groups
    CR4056 v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from the time of Informed Consent signature to the end of study visit. In addition, any SAEs the Investigators became aware of at any time after study completion were to be reported to the Sponsor.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    CR4056
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo comparator; 1:2 ratio with active

    Serious adverse events
    		 CR4056 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 69 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 CR4056 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 144 (41.67%)
    23 / 69 (33.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 144 (13.89%)
    5 / 69 (7.25%)
         occurrences all number
    25
    7
    Somnolence
         subjects affected / exposed
    7 / 144 (4.86%)
    3 / 69 (4.35%)
         occurrences all number
    7
    3
    Dizziness
         subjects affected / exposed
    4 / 144 (2.78%)
    3 / 69 (4.35%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    5 / 144 (3.47%)
    1 / 69 (1.45%)
         occurrences all number
    5
    1
    Nausea
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 69 (0.00%)
         occurrences all number
    3
    0
    Skin burning sensation
         subjects affected / exposed
    2 / 144 (1.39%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 144 (2.78%)
    1 / 69 (1.45%)
         occurrences all number
    4
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 144 (2.08%)
    1 / 69 (1.45%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 144 (2.08%)
    1 / 69 (1.45%)
         occurrences all number
    3
    1

    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.
    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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