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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Effects of Fasinumab on Peripheral Nerve Function in Patients with Pain Due to Osteoarthritis of the Hip or Knee

    Summary
    EudraCT number
    		 2017-004921-33
    Trial protocol
    		 GB   PL  
    Global end of trial date
    07 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jan 2022
    First version publication date
    22 Jan 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    R475-OA-1758
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03691974
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, NY, United States, 10591
    Public contact
    Clinical Trial Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.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
    07 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of fasinumab compared to placebo on peripheral nerves in subjects with pain due to Osteoarthritis (OA) of the hip or knee. The secondary objectives of the study were to: - Evaluate the efficacy of fasinumab compared to placebo in subjects with pain due to OA of the hip or knee - Evaluate the safety and tolerability of fasinumab compared to placebo in subjects with pain due to OA of the hip or knee - Characterize the concentrations of fasinumab in serum in subjects with pain due to OA of the hip or knee - Evaluate the immunogenicity of fasinumab in subjects with pain due to OA of the hip or knee
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2018
    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
    United Kingdom: 63
    Country: Number of subjects enrolled
    United States: 55
    Country: Number of subjects enrolled
    Poland: 62
    Worldwide total number of subjects
    180
    EEA total number of subjects
    62
    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)
    102
    From 65 to 84 years
    78
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1604 subjects were screened, out of which 180 were randomized into the study.

    Pre-assignment
    Screening details
    		 Subjects who met the eligibility criteria were randomized in a 1:1 ratio to receive either fasinumab or fasinumab-matching placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fasinumab-matching Placebo
    Arm description
    		 Subjects received Fasinumab-matching placebo subcutaneously (SC) every 4 weeks (Q4W) from Day 1 through Week 12 of the 16-week treatment period.
    Arm type
    		 Placebo

    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 SC injection of Fasinumab-matching placebo in the abdomen, thigh, or upper arm.

    Arm title
    		 Fasinumab 1 mg SC Q4W
    Arm description
    		 Subjects received Fasinumab 1 milligram (mg) SC Q4W from Day 1 through Week 12 of the 16-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fasinumab
    Investigational medicinal product code
    REGN475
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of Fasinumab in the abdomen, thigh, or upper arm.

    Number of subjects in period 1
    		Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Started
    89
    91
    Completed
    67
    75
    Not completed
    22
    16
         Physician decision
    1
    -
         Consent withdrawn by subject
    11
    9
         Noncompliance with protocol by subject
    1
    -
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    8
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fasinumab-matching Placebo
    Reporting group description
    		 Subjects received Fasinumab-matching placebo subcutaneously (SC) every 4 weeks (Q4W) from Day 1 through Week 12 of the 16-week treatment period.

    Reporting group title
    Fasinumab 1 mg SC Q4W
    Reporting group description
    		 Subjects received Fasinumab 1 milligram (mg) SC Q4W from Day 1 through Week 12 of the 16-week treatment period.

    Reporting group values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W Total
    Number of subjects
    		 89 91 180
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.4 ( 7.9 ) 62.9 ( 9.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 63 59 122
        Male
    		 26 32 58
    Peroneal Motor Nerve Conduction Velocity
    Peroneal motor nerve conduction velocity was evaluated by electrical stimulation of the nerve and recorded the compound muscle action potential from surface electrodes overlying a muscle supplied by the nerve. The safety analysis set (SAF) included all randomized subjects who received any study drug and was based on the treatment received (as treated). In the SAF, 'N' = 88 in the placebo group as one subject did not meet eligibility criteria but was randomized. The subject did not receive study drug and was therefore excluded from the placebo group in the SAF.
    Units: Meters per Second (m/s)
        arithmetic mean (standard deviation)
    		 46.864 ( 4.174 ) 46.803 ( 3.880 ) -
    Peroneal Motor Nerve Action Potential Amplitude - Ankle
    Peroneal motor nerve action potential amplitude was evaluated at ankle by electrical stimulation of the nerve and recorded the compound muscle action potential from surface electrodes overlying a muscle supplied by the nerve. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated). In the SAF, 'N' = 88 in the placebo group as one subject did not meet eligibility criteria but was randomized. The subject did not receive study drug and was therefore excluded from the placebo group in the SAF.
    Units: Millivolts (mV)
        arithmetic mean (standard deviation)
    		 4.75 ( 2.01 ) 4.67 ( 1.70 ) -
    Sural Sensory Nerve Conduction Velocity
    Sural sensory nerve conduction velocity was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated). In the SAF, 'N' = 88 in the placebo group as one subject did not meet eligibility criteria but was randomized. The subject did not receive study drug and was therefore excluded from the placebo group in the SAF.
    Units: Meters per Second (m/s)
        arithmetic mean (standard deviation)
    		 52.349 ( 8.519 ) 52.488 ( 8.276 ) -
    Sural Sensory Nerve Action Potential Amplitude
    Sural sensory nerve action potential amplitude was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated). In the SAF, 'N' = 88 in the placebo group as one subject did not meet eligibility criteria but was randomized. The subject did not receive study drug and was therefore excluded from the placebo group in the SAF.
    Units: Microvolts (μV)
        arithmetic mean (standard deviation)
    		 9.67 ( 4.79 ) 9.95 ( 5.67 ) -
    Ulnar Sensory Nerve Conduction Velocity
    Ulnar sensory nerve conduction velocity was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated). In the SAF, 'N' = 88 in the placebo group as one subject did not meet eligibility criteria but was randomized. The subject did not receive study drug and was therefore excluded from the placebo group in the SAF.
    Units: Meters per Second (m/s)
        arithmetic mean (standard deviation)
    		 56.033 ( 6.584 ) 56.238 ( 7.452 ) -
    Ulnar Sensory Nerve Action Potential Amplitude
    Ulnar sensory nerve action potential amplitude was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated). In the SAF, 'N' = 88 in the placebo group as one subject did not meet eligibility criteria but was randomized. The subject did not receive study drug and was therefore excluded from the placebo group in the SAF.
    Units: Microvolts (μV)
        arithmetic mean (standard deviation)
    		 19.18 ( 9.68 ) 18.47 ( 10.20 ) -

    End points

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    End points reporting groups
    Reporting group title
    Fasinumab-matching Placebo
    Reporting group description
    		 Subjects received Fasinumab-matching placebo subcutaneously (SC) every 4 weeks (Q4W) from Day 1 through Week 12 of the 16-week treatment period.

    Reporting group title
    Fasinumab 1 mg SC Q4W
    Reporting group description
    		 Subjects received Fasinumab 1 milligram (mg) SC Q4W from Day 1 through Week 12 of the 16-week treatment period.

    Primary: Change From Baseline in Peroneal Motor Nerve Conduction Velocity at Week 16

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    End point title
    		 Change From Baseline in Peroneal Motor Nerve Conduction Velocity at Week 16
    End point description
    Peroneal motor nerve conduction velocity was evaluated by electrical stimulation of the nerve and recorded the compound muscle action potential from surface electrodes overlying a muscle supplied by the nerve. Change from baseline in peroneal motor nerve conduction velocity at Week 16 was reported. Safety analysis set (SAF) included all randomized subjects who received any study drug and was based on the treatment received (as treated).
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    69
    84
    Units: Meters per Second (m/s)
        least squares mean (standard error)
    -0.2 ( 0.46 )
    0.2 ( 0.42 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab 1 mg SC Q4W v Fasinumab-matching Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4192 [1]
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 1.32
    Notes
    [1] - Analyses are based on Mixed Model for Repeated Measures (MMRM) model with terms for baseline nerve conduction test score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction.

    Primary: Change From Baseline in Peroneal Motor Nerve Action Potential Amplitude at Week 16

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    End point title
    		 Change From Baseline in Peroneal Motor Nerve Action Potential Amplitude at Week 16
    End point description
    Peroneal motor nerve action potential amplitude was evaluated at ankle by electrical stimulation of the nerve and recorded the compound muscle action potential from surface electrodes overlying a muscle supplied by the nerve. Change from baseline in peroneal motor nerve action potential amplitude at Week 16 was reported. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated).
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    69
    84
    Units: Millivolts (mV)
        least squares mean (standard error)
    -0.2 ( 0.20 )
    0.2 ( 0.19 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab 1 mg SC Q4W v Fasinumab-matching Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0521 [2]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.8
    Notes
    [2] - Analyses are based on MMRM model with terms for baseline nerve conduction test score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction.

    Primary: Change From Baseline in Sural Sensory Nerve Conduction Velocity at Week 16

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    End point title
    		 Change From Baseline in Sural Sensory Nerve Conduction Velocity at Week 16
    End point description
    Sural sensory nerve conduction velocity was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline in sural sensory nerve conduction velocity at Week 16 was reported. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated).
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    69
    84
    Units: Meters per Second (m/s)
        least squares mean (standard error)
    -2.9 ( 0.90 )
    -1.6 ( 0.83 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab-matching Placebo v Fasinumab 1 mg SC Q4W
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1593
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 3.15
    Notes
    [3] - Analyses are based on MMRM model with terms for baseline nerve conduction test score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction.

    Primary: Change From Baseline in Sural Sensory Nerve Action Potential Amplitude at Week 16

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    End point title
    		 Change From Baseline in Sural Sensory Nerve Action Potential Amplitude at Week 16
    End point description
    Sural sensory nerve action potential amplitude was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline in sural sensory nerve action potential amplitude at Week 16 was reported. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated).
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    69
    84
    Units: Microvolts (µV)
        least squares mean (standard error)
    0.5 ( 0.69 )
    0.3 ( 0.64 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab-matching Placebo v Fasinumab 1 mg SC Q4W
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7757 [4]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.59
         upper limit
    		 1.19
    Notes
    [4] - Analyses are based on MMRM model with terms for baseline nerve conduction test score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction

    Primary: Change From Baseline in Ulnar Sensory Nerve Conduction Velocity at Week 16

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    End point title
    		 Change From Baseline in Ulnar Sensory Nerve Conduction Velocity at Week 16
    End point description
    Ulnar sensory nerve conduction velocity was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline in ulnar sensory nerve conduction velocity at Week 16 was reported. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated).
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    69
    84
    Units: Meters per Second (m/s)
        least squares mean (standard error)
    -0.7 ( 0.74 )
    -1.1 ( 0.68 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab-matching Placebo v Fasinumab 1 mg SC Q4W
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6063 [5]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 1.09
    Notes
    [5] - Analyses are based on MMRM model with terms for baseline nerve conduction test score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction.

    Primary: Change From Baseline in Ulnar Sensory Nerve Action Potential Amplitude at Week 16

    		 Close Top of page
    End point title
    		 Change From Baseline in Ulnar Sensory Nerve Action Potential Amplitude at Week 16
    End point description
    Ulnar sensory nerve action potential amplitude was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline ulnar sensory nerve action potential amplitude at Week 16 was reported. SAF included all randomized subjects who received any study drug and was based on the treatment received (as treated).
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    69
    84
    Units: Microvolts (µV)
        least squares mean (standard error)
    2.4 ( 1.21 )
    1.4 ( 1.12 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab-matching Placebo v Fasinumab 1 mg SC Q4W
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4203 [6]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 1.39
    Notes
    [6] - Analyses are based on MMRM model with terms for baseline nerve conduction test score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction.

    Secondary: Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score at Week 16

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    End point title
    		 Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score at Week 16
    End point description
    WOMAC pain subscale was a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index joint (knee or hip) in past 48 hours. It was calculated as the mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (higher pain), where higher scores indicated higher pain. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicate higher pain. A negative change from baseline indicated improvement. The FAS included all randomized subjects and was based on the treatment allocated (as randomized). Change from Baseline in WOMAC Pain subscale score at Week 16 was reported.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    54
    67
    Units: Score on a Scale
        least squares mean (standard error)
    -1.19 ( 0.359 )
    -2.52 ( 0.335 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab-matching Placebo v Fasinumab 1 mg SC Q4W
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [7]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.123
         upper limit
    		 -0.538
    Notes
    [7] - Analyses are based on multiple imputation with MMRM model with terms for baseline WOMAC subscale score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction.

    Secondary: Change From Baseline in WOMAC Physical Function Subscale Score at Week 16

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    End point title
    		 Change From Baseline in WOMAC Physical Function Subscale Score at Week 16
    End point description
    Physical function referred to subject's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale was a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint (knee or hip) during past 48 hours. It was calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (no difficulty) to 10 (extreme difficulty), where higher scores indicated worse function. Total score range for WOMAC physical function subscale score is 0 (no difficulty) to 10 (extreme difficulty), where higher scores indicate worse function. A negative change from baseline indicated improvement. FAS included all randomized subjects and was based on the treatment allocated (as randomized). Change from Baseline in WOMAC physical function subscale score at Week 16 was reported.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    54
    66
    Units: Score on a Scale
        least squares mean (standard error)
    -0.83 ( 0.366 )
    -2.24 ( 0.341 )
    Statistical analysis title
    		 Placebo vs Fasinumab 1 mg SC Q4W
    Comparison groups
    Fasinumab-matching Placebo v Fasinumab 1 mg SC Q4W
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [8]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.212
         upper limit
    		 -0.625
    Notes
    [8] - Analyses are based on multiple imputation with MMRM model with terms for baseline WOMAC subscale score, treatment, screening Kellgren-Lawrence score, index joint, visit, and treatment by visit interaction.

    Secondary: Serum Concentration of Functional Fasinumab

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    End point title
    		 Serum Concentration of Functional Fasinumab [9]
    End point description
    Serum concentrations of functional Fasinumab were reported. The Pharmacokinetic (PK) Analysis Set included all treated subjects who received any study drug and who had at least 1 non-missing drug concentration result following the first dose of study drug. Here, 'n' signifies those subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, 2, 4, 8, 12, 16, and 36
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint applies to Fasinumab 1 mg SC Q4W arm only.
    End point values
    		 Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    91
    Units: Milligrams per Liter (mg/L)
    arithmetic mean (standard deviation)
        Baseline: n = 91
    0 ( 0 )
        Week 1: n = 84
    0.0864 ( 0.0299 )
        Week 2: n = 87
    0.0820 ( 0.0252 )
        Week 4: n = 85
    0.0525 ( 0.0181 )
        Week 8: n = 84
    0.0780 ( 0.0326 )
        Week 12: n = 81
    0.0802 ( 0.0400 )
        Week 16: n = 76
    0.0824 ( 0.0497 )
        Week 36: n = 11
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With At-least One Positive Anti-Drug Antibody (ADA)

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    End point title
    		 Number of Subjects With At-least One Positive Anti-Drug Antibody (ADA)
    End point description
    ADA analysis set included all treated subjects who received any amount of study drug (active or placebo [safety analysis set]) and had at least one non-missing anti-fasinumab antibody result following the first dose of study drug or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 36
    End point values
    		 Fasinumab-matching Placebo Fasinumab 1 mg SC Q4W
    Number of subjects analysed
    80
    87
    Units: Subjects
        Negative
    79
    87
        Pre-Existing Immunoreactivity
    1
    0
        Treatment-Boosted Response
    0
    0
        Treatment-Emergent Response
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to 24 weeks post the last dose of study drug (up to Week 36)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Fasinumab 1 mg SC Q4W
    Reporting group description
    		 Subjects received Fasinumab 1 milligram (mg) SC Q4W from Day 1 through Week 12 of the 16-week treatment period.

    Reporting group title
    Fasinumab-matching Placebo
    Reporting group description
    		 Subjects received Fasinumab-matching placebo subcutaneously (SC) every 4 weeks (Q4W) from Day 1 through Week 12 of the 16-week treatment period.

    Serious adverse events
    		 Fasinumab 1 mg SC Q4W Fasinumab-matching Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 91 (3.30%)
    6 / 88 (6.82%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple injuries
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 88 (1.14%)
         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
    Arthralgia
         subjects affected / exposed
    1 / 91 (1.10%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rapidly progressive osteoarthritis
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 88 (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
    		 Fasinumab 1 mg SC Q4W Fasinumab-matching Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 91 (60.44%)
    49 / 88 (55.68%)
    Investigations
    Nerve conduction studies abnormal
         subjects affected / exposed
    10 / 91 (10.99%)
    17 / 88 (19.32%)
         occurrences all number
    13
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 91 (14.29%)
    15 / 88 (17.05%)
         occurrences all number
    22
    26
    Dizziness
         subjects affected / exposed
    5 / 91 (5.49%)
    3 / 88 (3.41%)
         occurrences all number
    5
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 91 (5.49%)
    3 / 88 (3.41%)
         occurrences all number
    6
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 91 (26.37%)
    19 / 88 (21.59%)
         occurrences all number
    44
    27
    Myalgia
         subjects affected / exposed
    0 / 91 (0.00%)
    5 / 88 (5.68%)
         occurrences all number
    0
    5
    Pain in extremity
         subjects affected / exposed
    6 / 91 (6.59%)
    5 / 88 (5.68%)
         occurrences all number
    7
    8
    Back pain
         subjects affected / exposed
    5 / 91 (5.49%)
    5 / 88 (5.68%)
         occurrences all number
    5
    5
    Osteoarthritis
         subjects affected / exposed
    5 / 91 (5.49%)
    1 / 88 (1.14%)
         occurrences all number
    6
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 91 (8.79%)
    6 / 88 (6.82%)
         occurrences all number
    10
    8
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 91 (5.49%)
    5 / 88 (5.68%)
         occurrences all number
    5
    6
    Urinary tract infection
         subjects affected / exposed
    7 / 91 (7.69%)
    4 / 88 (4.55%)
         occurrences all number
    8
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2018
    The purpose of this amendment was to change the fasinumab 3 mg Q4W dose regimen to a 1 mg Q4W dose regimen because the 3 mg Q4W dose regimen is no longer being evaluated in the osteoarthritis (OA) pain program. The 1 mg Q4W dose regimen is now the highest dose being evaluated in this patient population.
    19 Feb 2019
    The purpose of this amendment was to revise the criterion for detecting a change in nerve conduction velocity that would be considered not to be within established parameters, in order to reduce false-positive findings.

    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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