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    Clinical Trial Results:
    A Randomised, Parallel Arm, Placebo-Controlled, Double-Blind, Study of the Safety and Efficacy of PRX167700 Added to Existing Non-steroidal Anti-inflammatory Therapy in Adults with Moderate-to-Severe Knee Pain Due to Osteoarthritis

    Summary
    EudraCT number
    		 2016-001443-39
    Trial protocol
    		 GB   HU   CZ   PL   ES  
    Global end of trial date
    29 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2019
    First version publication date
    23 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    167700-004CL
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Benevolent AI Cambridge Ltd.
    Sponsor organisation address
    Minerva Building 250, Babraham Research Campus, Cambridge, United Kingdom, CB22 3AT
    Public contact
    Clinical Trial Information, Benevolent AI Cambridge Ltd. (formerly Proximagen Ltd.), +44 1223 497 300, jackie.hunter@benevolent.ai
    Scientific contact
    Clinical Trial Information, Benevolent AI Cambridge Ltd. (formerly Proximagen Ltd.), +44 1223 497 300, jackie.hunter@benevolent.ai
    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
    29 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the effect of PRX167700 treatment on knee pain, on a background of stable oral non-steroidal anti-inflammatory drug (NSAID) therapy in subjects with moderate to severe pain caused by osteoarthritis (OA).
    Protection of trial subjects
    Independent ethics committees and institutional review boards: The clinical study protocol, informed consent documents, and any other appropriate study-related documents were reviewed and approved by an independent ethics committee (IEC)/institutional review board (IRB). Protocol amendments for administrative reasons were submitted to the IECs for information only. Ethical conduct of the study: This study was conducted in accordance with the good clinical practice (GCP) as required by the International Conference on Harmonization (ICH) E6 Guideline for GCP, 1 May 1996 (ICH E6) and ICH E6 (R2), in agreement with the standard operating procedures (SOPs) for clinical investigation and documentation. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki, and any local regulations were followed appropriately. The Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines were also followed. Subject information and informed consent: 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. Participation in the study and date of informed consent given by the subject was to be documented appropriately in the subject files.
    Background therapy
    		 The patients were on a background of stable NSAID therapy.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    26 Jan 2017
    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
    Poland: 48
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 70
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Hungary: 44
    Worldwide total number of subjects
    202
    EEA total number of subjects
    202
    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)
    127
    From 65 to 84 years
    75
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first subject was enrolled on 26 January 2017 & the last subject follow-up was completed on 29 October 2018. The study was conducted at 30 centres across the UK, Spain, Poland, Hungary & the Czech Republic. Subjects must have had pain in the target knee for ≥14 days per month in the 3 months preceding screening.

    Pre-assignment
    Screening details
    		 The duration per subject was approximately 9 to 12 weeks, including screening (up to 28 days, with a 14-day placebo run-in), treatment (42 days), & follow-up (7 to 10 days) periods. There were 9 study visits. Subjects who completed the placebo run-in & who still met all of the inclusion criteria & none of the exclusion criteria were randomized.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The Interactive Web-Based Response System (IWRS) was programmed with blind breaking instructions. The study blind could be broken if, in the opinion of the investigator, it was in the subject’s best interest to know the study treatment assignment. The date and reason that the blind was broken was recorded in the electronic case report form (eCRF).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PRX167700
    Arm description
    		 PRX167700 400mg oral tablet three times a day. Note: The started and completed information refers to the safety population.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PRX167700
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One PRX167700 400mg tablet was taken orally three times a day (6-8 hours apart) with water; each dose was taken within 30 minutes after eating. The tablet was uncoated before the study pause, and film-coated after the study pause.

    Arm title
    		 Placebo
    Arm description
    		 Placebo oral tablet three times a day.
    Arm type
    		 Placebo

    Investigational medicinal product name
    PRX167700
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One Placebo tablet was taken orally three times a day (6-8 hours apart) with water; each dose was taken within 30 minutes after eating. The tablet was uncoated before the study pause, and film-coated after the study pause.

    Number of subjects in period 1
    		PRX167700 Placebo
    Started
    101
    101
    Completed
    101
    101

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PRX167700
    Reporting group description
    		 PRX167700 400mg oral tablet three times a day. Note: The started and completed information refers to the safety population.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral tablet three times a day.

    Reporting group values
    		 PRX167700 Placebo Total
    Number of subjects
    		 101 101 202
    Age categorical
    Subjects were male or female, 50 to 75 years of age, with moderate to severe symptomatic knee OA for at least 3 months before screening, receiving a stable dose of an oral NSAID therapy. Subjects must have had pain in the target knee for ≥14 days per month in the 3 months preceding screening. Subjects who completed the placebo run-in and who still met all of the inclusion criteria and none of the exclusion criteria were randomized on Day 0 (Visit 3) using an IWRS.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 61 66 127
        From 65-84 years
    		 40 35 75
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 61.9 (50 to 75) 62.0 (50 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 61 57 118
        Male
    		 40 44 84

    End points

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    End points reporting groups
    Reporting group title
    PRX167700
    Reporting group description
    		 PRX167700 400mg oral tablet three times a day. Note: The started and completed information refers to the safety population.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral tablet three times a day.

    Primary: WOMAC Pain Score (mITT)

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    End point title
    		 WOMAC Pain Score (mITT)
    End point description
    The primary endpoint was analysed using a MMRM analysis that includes all WOMAC Pain Score changes from baseline through to 6 weeks of treatment. The main comparison was between treatment arms at 6 weeks. Least square mean changes were estimated for PRX167700 and placebo.
    End point type
    Primary
    End point timeframe
    WOMAC Pain Score (mITT) at Visit 8 (Day 42) in mITT population. Note: The data are presented as LS mean change in WOMAC pain score x 10. These number should be read as - ve numbers.
    End point values
    		 PRX167700 Placebo
    Number of subjects analysed
    92
    90
    Units: LS mean change
        LS mean change
    42
    39
    Statistical analysis title
    		 Mixed model repeated measures (MMRM) analysis
    Statistical analysis description
    The primary endpoint was analysed using a MMRM analysis that includes all WOMAC Pain Score changes from baseline to 1 week through to 6 weeks. These methods have in recent years become the preferred approach to longitudinal analysis because they utilise the observed data efficiently. Moreover, they naturally handle missing data, if the data are missing at random, in a way that produces unbiased estimates of the treatment effect.
    Comparison groups
    Placebo v PRX167700
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.563 [2]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.7
    Notes
    [1] - For the primary efficacy endpoint, the null (H0) and alternative (H1) hypotheses of the study were as follows: • H0: PRX167700 and placebo do not differ in their change from baseline in the WOMAC Pain Score at Visit 8 (Day 42). • H1: PRX167700 and placebo differ in their change from baseline in the WOMAC Pain Score at Visit 8 (Day 42).
    [2] - Nil.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were collected throughout the study including the follow-up visit.
    Adverse event reporting additional description
    Adverse event information was collected at each study visit. The information shown below is for Safety Population. The non-serious adverse events with frequency threshold 5% or more are reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    PRX167700
    Reporting group description
    		 PRX167700 400mg oral tablet three times a day.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral tablet three times a day.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious AEs over the 5% threshold for a given preferred term. In the safety population, the incidence of AEs was similar in both study arms: 40/101 (39.6%) of subjects had AEs during the double blind period in the PRX167700 arm versus 43/101 (42.6%) in the placebo arm. The total number of non-serious AE occurrences in PRX167700 and Placebo arms were 69 and 74 respectively.
    Serious adverse events
    		 PRX167700 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 101 (0.99%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Tibia fracture
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PRX167700 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 101 (0.00%)

    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? Yes
    Date
    Interruption
    Restart date
    20 Mar 2017
    Recruitment for the study commenced under protocol Version 4. Shortly after starting the study a potential unblinding issue arose concerning the investigational medicinal product (IMP) and an apparent taste difference. Recruitment was paused, and those in the study at the time were withdrawn. The 20 subjects randomized were considered evaluable for safety analysis but unevaluable for the efficacy analysis. At the time of study pause, only UK sites were active.
    15 Jan 2018

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The data under population of trial subjects are for treated subjects. Overall, a total of 520 subjects were enrolled in the study, of which 61.0% were screen failures. A total of 203 subjects were randomised, of which 202 received study drug.
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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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