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    Clinical Trial Results:
    A Double-Blind, Randomised, Exploratory Study to Investigate the Safety, Efficacy and Pharmacokinetics of PRX167700 in Subjects with Knee Osteoarthritis.

    These results have been removed from public view whilst they are reviewed and may need to be corrected before being returned to public view
    Summary
    EudraCT number
    2013-001970-33
    Trial protocol
    GB  
    Global end of trial date
    28 Aug 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Jul 2016
    First version publication date
    24 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    167700-002CL
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Proximagen Limited
    Sponsor organisation address
    Minerva Building 250, Babraham Research Campus, Cambridge, United Kingdom, CB22 3AT
    Public contact
    Clinical Trial Information, Proximagen Limited, 0044 1223 497 300, info@proximagen.com
    Scientific contact
    Clinical Trial Information, Proximagen Limited, 0044 1223 497 300, info@proximagen.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
    16 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of PRX167700 treatment on Pain Intensity after walking and at rest in subjects with moderate to severe pain caused by osteoarthritis (OA) of the knee.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice as required by the International Conference on Harmonisation E6 Guideline. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki and any local regulations and applicable laws were followed appropriately. Prior to the conduct of any study-related procedures, informed consent was obtained from all subjects. Before obtaining informed consent, information was given in a language and at a level of complexity understandable to the subject in both oral and written form by the Investigator. Each subject had the opportunity to discuss the study and its alternatives with the Investigator. Subjects were also informed of their right to withdraw from the study at any time.
    Background therapy
    Prohibited concomitant therapy: All analgesic therapy, including over-the-counter pain medications and topical analgesics for OA pain. Medications considered to be analgesics for the treatment of OA pain included non-selective NSAIDs, COX-2 selective NSAIDs, paracetamol, tramadol, and opioid-containing preparations Oral corticosteroids. Therapeutic injections into the target knee joint (e. g., corticosteroid and hyaluronic acid). Other therapies such as methotrexate, gold salts, penicillamine, antimalarials, sulfasalazine, azathioprine, cyclosporine and any anti-inflammatory biological therapy which could be used off-label for the treatment of OA were not permitted. Strong inhibitors of CYP3A4 and CYP2D6 and strong inducers of CYP3A4 were also not permitted. Permitted concomitant therapy: Medications, other than the prohibited medications listed above, for the treatment of other underlying diseases or conditions were permitted and were to be maintained at a stable dose during the treatment period, unless a change was medically indicated. All concomitant medications used by the subject at screening (Visit 1), changes to those medications, or introduction of new medications after screening were to be recorded in the electronic consent record form. Subjects who were taking a stable dose of chondroitin or keratin sulphate, glucosamine, non-specific rubefacients, and nutraceutical products were permitted to continue treatment at the same dose. An established physiotherapy programme could be continued provided it had commenced at least 2 weeks before screening and the session duration or frequency was continued during the study. Low dose aspirin (≤75 mg/day) as prophylactic cardioprotective therapy was also permitted if continued at the same dose. Rescue medication: Paracetamol (1000 mg) was permitted on an as-needed basis as rescue analgesia during the study, up to a total dose of 4 g per day.
    Evidence for comparator
    Not applicable; no comparators were used.
    Actual start date of recruitment
    09 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 74
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    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)
    24
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first subject first visit was on 09 September 2013 and the last subject last visit was on 28 August 2014.

    Pre-assignment
    Screening details
    Screening was performed 7-10 days before start of the treatment period. After screening, eligible subjects were enrolled in a washout period (placebo therapy), and subjects still eligible at the end of this period (7-10 days) were randomised to treatment groups.

    Pre-assignment period milestones
    Number of subjects started
    176 [1]
    Number of subjects completed
    74

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Not deemed eligible for randomisation: 102
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 176 subjects entered the washout period, of which 74 eligible subjects were randomised and treated in the treatment period, as planned in the study protocol.
    Period 1
    Period 1 title
    Overall trial period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The Sponsor and personnel at the study site were blinded to the treatment allocated to individual subjects, except when a medical emergency required knowledge of the treatment randomisation. If the randomisation code for a subject was broken by the study site, the subject was withdrawn from the study and a final assessment completed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    PRX167700
    Arm description
    Subjects who received PRX167700 400mg 3 times per day.
    Arm type
    Experimental

    Investigational medicinal product name
    PRX167700
    Investigational medicinal product code
    PRX167700
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    PRX167700 400 mg 3 times per day (separated by 6 to 8 hours)

    Arm title
    Placebo
    Arm description
    Subjects who received Placebo taken 3 times per day.
    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 (lactose capsules) was taken 3 times per day (separated by 6 to 8 hours).

    Number of subjects in period 1
    PRX167700 Placebo
    Started
    36
    38
    Completed
    35
    35
    Not completed
    1
    3
         Protocol deviation
    -
    1
         Adverse event, non-fatal
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PRX167700
    Reporting group description
    Subjects who received PRX167700 400mg 3 times per day.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received Placebo taken 3 times per day.

    Reporting group values
    PRX167700 Placebo Total
    Number of subjects
    36 38 74
    Age categorical
    Units: Subjects
    Age continuous
    Subject age
    Units: years
        arithmetic mean (standard deviation)
    65.3 ± 7.24 66.1 ± 6.33 -
    Gender categorical
    Units: Subjects
        Female
    14 18 32
        Male
    22 20 42
    Race
    Units: Subjects
        White
    35 36 71
        Asian
    1 0 1
        Afro-Caribbean
    0 1 1
        Other
    0 1 1
    Body mass index
    Units: kg/square metre
        arithmetic mean (standard deviation)
    29.14 ± 3.842 29.74 ± 3.713 -
    Pain Intensity Assessment Score - Rest
    Pain Intensity at rest at Visit 2 measured using the 11-point numerical rating scale.
    Units: Assessment scale (1-11)
        arithmetic mean (standard deviation)
    4.72 ± 1.892 4.89 ± 1.984 -
    Pain Intensity Assessment Score - Post-walk
    Pain Intensity after walking 100m on a flat course at Visit 2 measured using the 11-point numerical rating scale.
    Units: Assessment scale (1-11)
        arithmetic mean (standard deviation)
    6.67 ± 1.549 7.03 ± 1.619 -
    WOMAC Index (total score)
    Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index completed at Visit 2. The paper questionnaire (5-point Likert scale version) consisted of 3 sections (subscales) assessing pain, stiffness, and difficulty performing daily activities.
    Units: Rating scale
        arithmetic mean (standard deviation)
    57.91 ± 11.126 57.37 ± 11.748 -

    End points

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    End points reporting groups
    Reporting group title
    PRX167700
    Reporting group description
    Subjects who received PRX167700 400mg 3 times per day.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received Placebo taken 3 times per day.

    Primary: Pain Intensity Assessment Score - Visit 6

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    End point title
    Pain Intensity Assessment Score - Visit 6
    End point description
    The average of the 3 assessments in the target knee joint performed at 1, 2, and 3 hours post-dose. Baseline was the pre-walk (rest) or post-walk value recorded at Visit 2. Change from baseline values are reported.
    End point type
    Primary
    End point timeframe
    At specified study visit.
    End point values
    PRX167700 Placebo
    Number of subjects analysed
    35
    34
    Units: Assessment scale (1-11)
    arithmetic mean (standard deviation)
        Rest
    -1.67 ± 2.031
    -0.93 ± 2.135
        Post-walk
    -3.21 ± 2.013
    -2.43 ± 2.188
    Statistical analysis title
    Pain intensity at rest - 3 hours post-dose
    Comparison groups
    PRX167700 v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.1242
    Method
    Mixed models analysis
    Parameter type
    Treatment effect
    Point estimate
    -0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.73
         upper limit
    0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.49
    Notes
    [1] - Mixed effect model with repeated measurement to determine the treatment effect over time.
    Statistical analysis title
    Pain intensity post-walk - 3 hours post-dose
    Comparison groups
    PRX167700 v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.153
    Method
    Mixed models analysis
    Parameter type
    Treatment effect
    Point estimate
    -0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.79
         upper limit
    0.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.52
    Notes
    [2] - Mixed effect model with repeated measurement to determine the treatment effect over time.

    Primary: Pain Intensity Responder Analysis - Visit 6

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    End point title
    Pain Intensity Responder Analysis - Visit 6 [3]
    End point description
    Subjects with pain intensity response (percentage decrease from baseline).
    End point type
    Primary
    End point timeframe
    At specified study visit.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Pain intensity response (percentage change from baseline) is displayed showing number of subjects in each category of response. Statistical analysis was performed on pain intensity assessment scores, and is reported under these endpoints.
    End point values
    PRX167700 Placebo
    Number of subjects analysed
    36
    38
    Units: Number of subjects
        Pre-walk ≥ 30%
    20
    14
        Pre-walk ≥ 50%
    13
    11
        Pre-walk ≥ 70%
    6
    6
        Post-walk ≥ 30%
    26
    16
        Post-walk ≥ 50%
    17
    11
        Post-walk ≥ 70%
    8
    9
    No statistical analyses for this end point

    Secondary: Total WOMAC Index score

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    End point title
    Total WOMAC Index score
    End point description
    Total Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index score.
    End point type
    Secondary
    End point timeframe
    At specified study visit.
    End point values
    PRX167700 Placebo
    Number of subjects analysed
    36
    38
    Units: Rating scale
    arithmetic mean (standard deviation)
        Visit 6
    37.27 ± 18.71
    49.56 ± 16.022
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were collected from the time of signature of informed consent throughout the washout, treatment, and follow-up periods.
    Adverse event reporting additional description
    If a subject experienced more than one AE, they were counted once for each system organ class and preferred term.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    PRX167700
    Reporting group description
    Subjects treated with PRX167700

    Reporting group title
    Placebo
    Reporting group description
    Subjects receiving placebo

    Serious adverse events
    PRX167700 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Musculoskeletal and connective tissue disorders
    Lower limb fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    PRX167700 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 36 (38.89%)
    21 / 38 (55.26%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    2
    0
    Fatigue
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Thirst
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Nightmare
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Penile pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Excoriation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Platelet count increased
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 38 (2.63%)
         occurrences all number
    1
    1
    Cough
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 38 (5.26%)
         occurrences all number
    2
    2
    Dizziness
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Somnolence
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 36 (11.11%)
    1 / 38 (2.63%)
         occurrences all number
    4
    1
    Abdominal pain
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 38 (2.63%)
         occurrences all number
    3
    1
    Dyspepsia
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 38 (5.26%)
         occurrences all number
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 38 (2.63%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Onychoclasis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 38 (2.63%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 38 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0

    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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