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    Clinical Trial Results:
    The primary objective of this study was to demonstrate the efficacy, safety, and tolerability of fulranumab subcutaneous (SC) injections as adjunctive therapy to opioid treatment compared with placebo SC injections in subjects who had signs and symptoms of osteoarthritis (OA) of the hip or knee that were not adequately controlled by their current pain therapy and who were planning a joint replacement surgery.

    Summary
    EudraCT number
    		 2013-001830-16
    Trial protocol
    		 DE   GB   HU   PL  
    Global end of trial date
    16 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2017
    First version publication date
    09 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    42160443PAI3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02336685
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development LLC
    Sponsor organisation address
    Archimedesweg 29, Leiden, Netherlands, 2333CM
    Public contact
    Clinical Registry group, Janssen Research & Development LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry group, Janssen Research & Development LLC, ClinicalTrialsEU@its.jnj.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 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Sep 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the efficacy, safety, and tolerability of fulranumab subcutaneous (SC) injections as adjunctive therapy to opioid treatment compared with placebo SC injections in subjects who had signs and symptoms of osteoarthritis (OA) of the hip or knee that were not adequately controlled by their current pain therapy and who were planning a joint replacement surgery.
    Protection of trial subjects
    Safety was evaluated throughout the study and included monitoring of adverse event (AE), clinical laboratory testing, vital sign collection (including orthostatic testing), neurologic evaluation (abbreviated neurologic examination including an assessment of pupillary light reflex and signs consistent with carpal tunnel syndrome, Total Neuropathy Score-nurse [TNSn], Mini Mental State Examination [MMSE], autonomic nervous system dysfunction history, and carpal tunnel syndrome questionnaire), joint-related event evaluations (joint examinations and radiographs), numerical rating scale (NRS) for nonstudy joint pain, electrocardiograms (ECGs), physical examinations, and injection-site reactions. This study was conducted in accordance with the ethical principles that have their origin in the declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 13 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    78
    EEA total number of subjects
    22
    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)
    43
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 78 subjects were randomized: 26 in placebo group, 25 in fulranumab (FUL) 1 milligram (mg) every 4 week (Q4wk) group, and 27 in FUL 3 mg Q4wk group. The intent-to-treat (ITT) and safety analysis sets included all 78 subjects.

    Period 1
    Period 1 title
    Double Blind Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received 4 placebo subcutaneous (SC) injections (one injection every 4 week) for 16 weeks during double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 4 placebo SC injections (one injection every 4 week) for 16 weeks during double-blind treatment phase.

    Arm title
    		 Fulranumab 1 mg
    Arm description
    		 Subjects received fulranumab 1 mg injection every 4 weeks for 16 weeks during double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulranumab 1mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received fulranumab 1mg injection every 4 weeks for 16 weeks during double-blind treatment phase.

    Arm title
    		 Fulranumab 3 mg
    Arm description
    		 Subjects received fulranumab 3 mg injection every 4 weeks for 16 weeks during double-blind treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulranumab 3mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received fulranumab 3 mg injection every 4 weeks for 16 weeks during double-blind treatment phase.

    Number of subjects in period 1
    		Placebo Fulranumab 1 mg Fulranumab 3 mg
    Started
    26
    25
    27
    Completed
    7
    7
    8
    Not completed
    19
    18
    19
         Consent withdrawn by subject
    -
    1
    1
         Study terminated by sponsor
    18
    17
    17
         Protocol deviation
    1
    -
    -
         Lack of efficacy
    -
    -
    1
    Period 2
    Period 2 title
    24 Week Follow-up Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Subjects who received placebo in treatment phase were followed for 24 weeks in this period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Fulranumab 1 mg
    Arm description
    		 Subjects who received fulranumab 1 mg in treatment phase were followed for 24 weeks in this period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Fulranumab 3 mg
    Arm description
    		 Subjects who received fulranumab 3 mg in treatment phase were followed for 24 weeks in this period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Placebo Fulranumab 1 mg Fulranumab 3 mg
    Started
    12
    10
    13
    Completed
    9
    8
    11
    Not completed
    3
    2
    2
         Consent withdrawn by subject
    -
    1
    1
         Study terminated by sponsor
    3
    -
    1
         Lost to follow-up
    -
    1
    -
    Period 3
    Period 3 title
    Limited Safety Follow-up Phase (LSFU)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Subjects who received placebo in treatment phase were followed for 24 weeks after the last injection of study drug in this follow up phase. Subjects who discontinued from the 24- week follow-up phase were also asked to enter the LSFU phase.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Fulranumab 1 mg
    Arm description
    		 Subjects who received fulranumab 1 mg in treatment phase were followed for 24 weeks after the last injection of study drug in this follow up phase. Subjects who discontinued from the 24- week follow-up phase were also asked to enter the LSFU phase.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Fulranumab 3 mg
    Arm description
    		 Subjects who received fulranumab 3 mg in treatment phase were followed for 24 weeks after the last injection of study drug in this follow up phase. Subjects who discontinued from the 24- week follow-up phase were also asked to enter the LSFU phase.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Placebo Fulranumab 1 mg Fulranumab 3 mg
    Started
    1
    4
    3
    Completed
    1
    1
    3
    Not completed
    0
    3
    0
         Study terminated by sponsor
    -
    1
    -
         Lost to follow-up
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 4 placebo subcutaneous (SC) injections (one injection every 4 week) for 16 weeks during double-blind treatment phase.

    Reporting group title
    Fulranumab 1 mg
    Reporting group description
    		 Subjects received fulranumab 1 mg injection every 4 weeks for 16 weeks during double-blind treatment phase.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    		 Subjects received fulranumab 3 mg injection every 4 weeks for 16 weeks during double-blind treatment phase.

    Reporting group values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg Total
    Number of subjects
    		 26 25 27 78
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 12 15 16 43
        From 65 to 84 years
    		 14 10 11 35
        85 years and over
    		 0 0 0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    		 66 (34 to 82) 63 (42 to 82) 61 (50 to 80) -
    Title for Gender
    Units: subjects
        Female
    		 18 18 15 51
        Male
    		 8 7 12 27

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 4 placebo subcutaneous (SC) injections (one injection every 4 week) for 16 weeks during double-blind treatment phase.

    Reporting group title
    Fulranumab 1 mg
    Reporting group description
    		 Subjects received fulranumab 1 mg injection every 4 weeks for 16 weeks during double-blind treatment phase.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    		 Subjects received fulranumab 3 mg injection every 4 weeks for 16 weeks during double-blind treatment phase.
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received placebo in treatment phase were followed for 24 weeks in this period.

    Reporting group title
    Fulranumab 1 mg
    Reporting group description
    		 Subjects who received fulranumab 1 mg in treatment phase were followed for 24 weeks in this period.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    		 Subjects who received fulranumab 3 mg in treatment phase were followed for 24 weeks in this period.
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received placebo in treatment phase were followed for 24 weeks after the last injection of study drug in this follow up phase. Subjects who discontinued from the 24- week follow-up phase were also asked to enter the LSFU phase.

    Reporting group title
    Fulranumab 1 mg
    Reporting group description
    		 Subjects who received fulranumab 1 mg in treatment phase were followed for 24 weeks after the last injection of study drug in this follow up phase. Subjects who discontinued from the 24- week follow-up phase were also asked to enter the LSFU phase.

    Reporting group title
    Fulranumab 3 mg
    Reporting group description
    		 Subjects who received fulranumab 3 mg in treatment phase were followed for 24 weeks after the last injection of study drug in this follow up phase. Subjects who discontinued from the 24- week follow-up phase were also asked to enter the LSFU phase.

    Primary: Change from Baseline to DB-LOCF in Patient Global Assessment (PGA) Score

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    End point title
    		 Change from Baseline to DB-LOCF in Patient Global Assessment (PGA) Score [1]
    End point description
    The PGA is a single item that the patient completes to indicate their perception of their osteoarthritis status, on an 11-point numerical rating scale from 0 (Very Good) to 10 (Very Bad).The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects who were evaluable for this outcome measure at specific timepoint.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17 and DB-LOCF
    Notes
    [1] - 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: No statistical analyses have been specified for this primary end point.
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    26
    25
    27
    Units: Units on Scale
    arithmetic mean (standard deviation)
        Baseline (n=26,25,27)
    8.5 ± 0.95
    7.8 ± 1.41
    7.9 ± 1.22
        Change at Week 5 (n=26,24,27)
    -1.2 ± 1.29
    -1.6 ± 2.26
    -2.5 ± 2.69
        Change at Week 9 (n=16,19,19)
    -2.4 ± 1.82
    -2.1 ± 2.74
    -3 ± 1.76
        Change at Week 13 (n=14,14,13)
    -1.6 ± 1.74
    -2.6 ± 2.59
    -2.5 ± 2.44
        Change at Week 17 (n=8,11,9)
    -3.4 ± 2.07
    -2.1 ± 1.04
    -3 ± 2.29
        Change at DB-LOCF (n=26,25,27)
    -1.6 ± 1.86
    -2 ± 2.34
    -2.9 ± 2.36
    No statistical analyses for this end point

    Secondary: Change From Baseline to Double-Blind Phase, Last Observation Carried Forward (DB-LOCF) in Western Ontario and McMaster University Arthritis Index (WOMAC) Pain Subscale Score

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    End point title
    		 Change From Baseline to Double-Blind Phase, Last Observation Carried Forward (DB-LOCF) in Western Ontario and McMaster University Arthritis Index (WOMAC) Pain Subscale Score
    End point description
    The WOMAC 3.1 is a multi-dimensional, osteoarthritis (OA) specific self-administered questionnaire using 24 questions with a 48-hour recall that are grouped into 3 subscales (pain, stiffness, and physical function) associated with hip or knee OA. Pain, stiffness, and physical function is rated on a scale of 0-10, where 0=no pain to 10=extreme pain in the WOMAC pain subscale score. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects who were evaluable for this outcome measure at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17 and DB-LOCF
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    26
    25
    27
    Units: Units on Scale
    arithmetic mean (standard deviation)
        Baseline (n=26,25,27)
    7.88 ± 1.216
    7.34 ± 1.064
    7.6 ± 1.209
        Change at Week 5 (n=26,24,27)
    -1.32 ± 0.982
    -1.45 ± 1.749
    -2.74 ± 2.181
        Change at Week 9 (n=16,19,19)
    -2.5 ± 1.697
    -1.93 ± 2.265
    -3.26 ± 1.764
        Change at Week 13 (n=14,14,13)
    -2.19 ± 1.803
    -1.91 ± 2.275
    -3.09 ± 2.042
        Change at Week 17 (n=8,11,9)
    -3.03 ± 2.499
    -2.27 ± 2.098
    -3.58 ± 2.099
        Change at DB-LOCF (n=26,25,27)
    -1.7 ± 1.686
    -2.1 ± 2.168
    -3.3 ± 2.164
    No statistical analyses for this end point

    Secondary: Change From Baseline to DB-LOCF in Western Ontario and McMaster University Arthritis Index (WOMAC) Physical Function Subscale Score

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    End point title
    		 Change From Baseline to DB-LOCF in Western Ontario and McMaster University Arthritis Index (WOMAC) Physical Function Subscale Score
    End point description
    The WOMAC 3.1 is a multi-dimensional, osteoarthritis (OA) specific self-administered questionnaire using 24 questions with a 48-hour recall that are grouped into 3 subscales (pain, stiffness, and physical function) associated with hip or knee OA. Pain, stiffness, and physical function is rated on a scale of 0-10, where 0=no difficulty to 10=extreme difficulty in performing daily activities in the WOMAC physical function subscale score. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects who were evaluable for this outcome measure at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17 and DB-LOCF
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    26
    25
    27
    Units: Units on Scale
    arithmetic mean (standard deviation)
        Baseline (n=26,25,27)
    7.6878 ± 1.20182
    7.3553 ± 0.99892
    7.6057 ± 1.14654
        Change at Week 5 (n=26,24,27)
    -1.0656 ± 1.71032
    -1.3725 ± 1.86183
    -2.7495 ± 2.27528
        Change at Week 9 (n=16,19,19)
    -1.9301 ± 1.96899
    -2.0341 ± 2.21823
    -3.1115 ± 1.52222
        Change at Week 13 (n=14,14,13)
    -2.1134 ± 2.21598
    -2.2689 ± 2.09003
    -3.1584 ± 1.94835
        Change at Week 17 (n=8,11,9)
    -2.8382 ± 2.58149
    -2.615 ± 2.07612
    3.1634 ± 1.48632
        DB-LOCF (n=26,25,27)
    -1.3643 ± 1.85346
    -2.1694 ± 2.22666
    -3.0414 ± 1.9709
    No statistical analyses for this end point

    Secondary: Change From Baseline Through Week 20 in Daily Numerical Rating Scale (NRS) Score

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    End point title
    		 Change From Baseline Through Week 20 in Daily Numerical Rating Scale (NRS) Score
    End point description
    The numerical rating scale (NRS) uses an 11-point scale to assess OA pain ranging from 0 to 10 with high scores representing greater symptom severity (0=no pain and 10=pain as bad as you can imagine). The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 20
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    26
    25
    27
    Units: Units on Scale
    arithmetic mean (standard deviation)
        Baseline (n=26,25,27)
    7.7769 ± 1.44163
    6.8533 ± 1.09333
    7.4438 ± 1.28128
        Change at Week 1-4 (n=26,25,27)
    -1.1533 ± 1.36821
    -1.2905 ± 1.85651
    -2.1978 ± 2.17489
        Change at Week 5-8 (n=23,24,25)
    -1.7975 ± 1.73601
    -1.8026 ± 2.08613
    -2.8119 ± 2.0814
        Change at Week 9-12 (n=17,21,19)
    -2.0027 ± 1.91794
    -1.5794 ± 1.92197
    -2.9483 ± 2.69287
        Change at Week 13-16 (n=12,15,13)
    -2.9084 ± 2.37417
    -1.281 ± 1.75338
    -3.0143 ± 2.79967
        Change at Week 17-20 (n=5,8,6)
    -3.2362 ± 2.5395
    -2.4691 ± 1.95121
    -2.3238 ± 1.78483
    No statistical analyses for this end point

    Secondary: Change From Baseline to DB-LOCF in WOMAC Stiffness Subscale Score

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    End point title
    		 Change From Baseline to DB-LOCF in WOMAC Stiffness Subscale Score
    End point description
    The WOMAC 3.1 is a multi-dimensional, osteoarthritis (OA) specific self-administered questionnaire using 24 questions with a 48-hour recall that are grouped into 3 subscales (pain, stiffness, and physical function) associated with hip or knee OA. Pain, stiffness, and physical function is rated on a scale of 0-10, where 0=no stiffness to 10=extreme stiffness in the WOMAC stiffness subscale score. The intent-to-treat (ITT) analysis set was defined as all randomized subjects who received at least 1 dose of study drug. Here 'n' signifies number of subjects who were evaluable for this outcome measure at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17 and DB-LOCF
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    26
    25
    27
    Units: Units on Scale
    arithmetic mean (standard deviation)
        Baseline (n=26,25,27)
    7.92 ± 1.332
    7.34 ± 1.179
    7.8 ± 1.325
        Change at Week 5 (n=26,24,27)
    -1.1 ± 1.613
    -1.69 ± 2.413
    -3.07 ± 2.623
        Change at Week 9 (n=16,19,19)
    -2.34 ± 2.119
    -1.84 ± 2.135
    -3 ± 1.667
        Change at Week 13 (14,14,13)
    -2.54 ± 2.249
    -2.39 ± 2.305
    -3.65 ± 2.258
        Change at Week 17 (n=8,11,9)
    -3.31 ± 2.777
    -2.27 ± 1.967
    -3.89 ± 1.764
        Change at DB-LOCF (n=26,25,27)
    -1.56 ± 2.146
    -1.98 ± 2.138
    -3.31 ± 2.267
    No statistical analyses for this end point

    Secondary: Change From Baseline Through Double-blind Phase for Rescue Medication and Other Osteoarthritis (OA) Analgesia

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    End point title
    		 Change From Baseline Through Double-blind Phase for Rescue Medication and Other Osteoarthritis (OA) Analgesia
    End point description
    Use of rescue medication (acetaminophen/paracetamol) and other OA pain medication was recorded weekly during the study. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline through double-blind Phase
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Units on Scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [2] - Subjects were neither analyzed nor listed in the Clinical Study Report (CSR) for this end point.
    [3] - Subjects were neither analyzed nor listed in the CSR for this end point.
    [4] - Subjects were neither analyzed nor listed in the CSR for this end point.
    No statistical analyses for this end point

    Secondary: Change from Baseline Through Double-blind Phase in Medical Outcomes Study (MOS) Sleep Subscale Scores

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    End point title
    		 Change from Baseline Through Double-blind Phase in Medical Outcomes Study (MOS) Sleep Subscale Scores
    End point description
    The MOS Sleep Scale (acute version) contains 12 items that address aspects of sleep. Six subscale scores may be calculated including: daytime somnolence, sleep disturbances, snoring, shortness of breath or headache upon awaking, adequacy of sleep and amount of sleep plus a summary index of sleep disturbances. A higher score indicates worse sleep in most domains, but the amount of sleep and adequacy of sleep are scored in the opposite direction. The primary subscale of interest in this study is daytime somnolence. The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline through double-Blind Phase
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: Units on Scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [5] - Subjects were neither analyzed nor listed in the CSR for this end point.
    [6] - Subjects were neither analyzed nor listed in the CSR for this end point.
    [7] - Subjects were neither analyzed nor listed in the CSR for this end point.
    No statistical analyses for this end point

    Secondary: Change From Baseline Through Double Blind Phase in Short-Form-36 Health Survey (SF-36) Subscale Score

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    End point title
    		 Change From Baseline Through Double Blind Phase in Short-Form-36 Health Survey (SF-36) Subscale Score
    End point description
    The Short Form-36 (SF-36) is a self-administered, generic, 36-item questionnaire designed to evaluate 8 domains of functional health and well being: physical and social functioning, physical and emotional role (role-physical, role-emotional) limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). The ITT analysis set was defined as all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline through double-blind Phase
    End point values
    		 Placebo Fulranumab 1 mg Fulranumab 3 mg
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Units on Scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [8] - Subjects were neither analyzed nor listed in the CSR for this end point.
    [9] - Subjects were neither analyzed nor listed in the CSR for this end point.
    [10] - Subjects were neither analyzed nor listed in the CSR for this end point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 67 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    FUL 1mg
    Reporting group description
    		 Subjects received fulranumab 1 mg injection every 4 weeks for 16 weeks during double-blind treatment phase and were followed up for 24 weeks in follow up phase (Period 2).Subjects who received Fulranumab 1mg and discontinued from the double-blind phase and did not enter the post-treatment follow-up phase were followed up for 24 weeks in LSFU phase (Period 3). Subjects who discontinued from the post-treatment follow-up phase were also followed up for 24 weeks in LSFU (Period 3).‌

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received 4 placebo subcutaneous (SC) injection (one injection every 4 week) for 16 weeks during double blind treatment phase (Period 1) and were followed up for 24 weeks in follow up phase (Period 2).Subjects who received placebo and discontinued from the double-blind phase and did not enter the post-treatment follow-up phase were followed up for 24 weeks in LSFU phase (Period 3). Subjects who discontinued from the post-treatment follow-up phase were also followed up for 24 weeks in LSFU (Period 3).

    Reporting group title
    FUL 3mg
    Reporting group description
    		 Subjects received fulranumab 1 mg injection every 4 weeks for 16 weeks during double-blind treatment phase and were followed up for 24 weeks in follow up phase (Period 2).Subjects who received Fulranumab 3 mg and discontinued from the double-blind phase and did not enter the post-treatment follow-up phase were followed up for 24 weeks in LSFU phase (Period 3). Subjects who discontinued from the post-treatment follow-up phase were also followed up for 24 weeks in LSFU (Period 3).‌‌

    Serious adverse events
    		 FUL 1mg Placebo FUL 3mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Skin Bacterial Infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 FUL 1mg Placebo FUL 3mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 25 (72.00%)
    15 / 26 (57.69%)
    19 / 27 (70.37%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Orthostatic Hypotension
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Productive Cough
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Sleep Disorder
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood Pressure Diastolic Decreased
         subjects affected / exposed
    5 / 25 (20.00%)
    4 / 26 (15.38%)
    4 / 27 (14.81%)
         occurrences all number
    6
    5
    6
    Heart Rate Decreased
         subjects affected / exposed
    6 / 25 (24.00%)
    6 / 26 (23.08%)
    10 / 27 (37.04%)
         occurrences all number
    6
    7
    16
    Blood Pressure Systolic Decreased
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 26 (15.38%)
    2 / 27 (7.41%)
         occurrences all number
    3
    4
    2
    Hepatic Enzyme Increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Ligament Sprain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Meniscus Injury
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Procedural Pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Palpitations
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness Exertional
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Dizziness Postural
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    Hyporeflexia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
         occurrences all number
    0
    5
    0
    Headache
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    5
    Sciatica
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    0
    0
    5
    Constipation
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermal Cyst
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Eczema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Urticaria
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertonic Bladder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    2
    Back Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Bone Cyst
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Bursitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    2
    Joint Effusion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Joint Swelling
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    1
    Joint Stiffness
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle Spasms
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    2
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    3
    0
    Neck Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in Extremity
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Osteoarthritis
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 26 (7.69%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    0
    Rapidly Progressive Osteoarthritis
    Additional description: After review by the blinded Adjudication Committee both cases of rapidly progressive Osteoarthritis (OA) were determined to be normal OA.
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    1
    Synovial Cyst
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Epididymitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    2
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    1
    Oral Herpes
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea Pedis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 26 (3.85%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 26 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    2
    Vitamin D Deficiency
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Decreased Appetite
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 26 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2015
    Amendment INT-1 included the following changes: Addition of criteria to be used to alert the Independent Data Monitoring Committee (IDMC) to review events of interest (neurologic) and reference to criteria to be used by the IDMC for decisions related to the further conduct of the study based on prespecified safety based criteria (for joint replacement, neurologic, sympathetic, hepatic and renal events of interest, that is stopping criteria).
    18 Feb 2015
    Amendment INT-2 included the following changes: Addition of criteria to be used to alert the IDMC to review events of interest (neurologic) and reference to criteria to be used by the IDMC for decisions related to the further conduct of the study based on prespecified safety based criteria (for joint replacement, neurologic, sympathetic, hepatic and renal events of interest, ie, stopping criteria); clarification to improve performance of assessments and conduct of study and minor errors were noted.
    16 Jul 2015
    Amendment INT-3 included the following changes: Changes requested by ethics committees and health authorities to clarify study conduct and/or subject safety; and changes to clarify study conduct.
    14 Dec 2015
    Amendment INT-4 included the following changes: Respond to regulatory authority request to prohibit resumption of dosing for subjects who develop joint events of interest; respond to regulatory authority requests to include an assessment for carpal tunnel syndrome (CTS), at each clinic visit during the treatment periods, and at dedicated clinic visits during the safety follow-up period; clarification of what is acceptable as opioid failure in U.S. and Canada as per FDA request. clarification that a medication that is contraindicated will qualify as a failure due to intolerability; and clarify that fasting serum and urine samples are preferred for biomarker analysis; and minor errors were noted.

    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.
    Due to discontinuation of fulranumab program by sponsor for strategic reasons, the study was closed to enrollment before being fully enrolled. Hence, the study results are limited to descriptive summaries of all safety data and select efficacy data.
    For support, Contact us.
    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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