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    Clinical Trial Results:
    A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects with Immune-Mediated Necrotizing Myopathy

    Summary
    EudraCT number
    		 2019-001497-29
    Trial protocol
    		 FR   NL  
    Global end of trial date
    14 Jun 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Jun 2022
    First version publication date
    19 Mar 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    RA101495-02.202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04025632
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCB Biosciences GmbH
    Sponsor organisation address
    Alfred-Nobel-Strasse 10, Monheim, Germany, 40789
    Public contact
    Clin Trial Reg & Results Disclosure, UCB Biosciences GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB Biosciences GmbH, clinicaltrials@ucb.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
    02 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of zilucoplan over placebo in creatine kinase (CK) levels in study participants with immune-mediated necrotizing myopathy (IMNM).
    Protection of trial subjects
    This study was conducted in accordance with the current version of the applicable regulatory and International Council for Harmonisation (ICH)-Good Clinical Practice requirements, the ethical principles that have their origin in the principles of the Declaration of Helsinki, and the local laws of the countries involved.
    Background therapy
    		 All standard of care therapy medications for IMNM were kept at the same doses throughout the study, including corticosteroids, immunosuppressive drugs, and intravenous immunoglobulin (IVIG).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2019
    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
    Netherlands: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    27
    EEA total number of subjects
    5
    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)
    21
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was performed in 4 countries (France, the Netherlands, the United Kingdom, and the United States of America) between 07 November 2019 and 14 June 2021.

    Pre-assignment
    Screening details
    		 Of the 37 participants who were screened, 27 participants with IMNM were randomized in a 1:1 ratio to receive zilucoplan 0.3 mg/kg or a matching placebo for the 8-week Treatment Period in the Main Portion. All eligible participants were given the option to receive daily subcutaneous (SC) zilucoplan 0.3 mg/kg in the Extension Portion.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were randomized to receive daily SC doses of matching placebo during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Daily SC injection over the 8-week study period.

    Arm title
    		 Zilucoplan 0.3 mg/kg
    Arm description
    		 Participants were randomized to receive daily SC doses of zilucoplan 0.3 mg/kg during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zilucoplan
    Investigational medicinal product code
    RA101495
    Other name
    ZLP
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Daily SC injection over the 8-week study period.

    Number of subjects in period 1
    		Placebo Zilucoplan 0.3 mg/kg
    Started
    15
    12
    Completed Main Portion
    15
    12
    Started Main Portion Safety Follow-up
    2
    0
    Completed Main Portion Safety Follow-up
    0
    0
    Started Extension Portion
    13
    12
    Completed
    0
    0
    Not completed
    15
    12
         Consent withdrawn by subject
    1
    1
         Physician decision
    3
    1
         Adverse event, non-fatal
    1
    1
         Study terminated by sponsor
    10
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive daily SC doses of matching placebo during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study.

    Reporting group title
    Zilucoplan 0.3 mg/kg
    Reporting group description
    		 Participants were randomized to receive daily SC doses of zilucoplan 0.3 mg/kg during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study.

    Reporting group values
    		 Placebo Zilucoplan 0.3 mg/kg Total
    Number of subjects
    		 15 12 27
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ± 13.6 56.9 ± 9.0 -
    Gender categorical
    Units: Subjects
        Female
    		 7 6 13
        Male
    		 8 6 14
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 5 9
        Not Hispanic or Latino
    		 8 5 13
        Unknown or Not Reported
    		 3 2 5
    Race
    Units: Subjects
        American Indian/ Alaska native
    		 0 0 0
        Asian
    		 0 0 0
        Black or African American
    		 1 3 4
        Native Hawaiian or other Pacific Islander
    		 0 0 0
        White
    		 10 7 17
        Other/Mixed
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1
        Missing
    		 3 2 5

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive daily SC doses of matching placebo during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study.

    Reporting group title
    Zilucoplan 0.3 mg/kg
    Reporting group description
    		 Participants were randomized to receive daily SC doses of zilucoplan 0.3 mg/kg during the 8-week Main Portion of the study. All eligible participants were given the option to receive daily SC zilucoplan 0.3 mg/kg in the Extension Portion of the study.

    Subject analysis set title
    Main Portion: Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive daily SC doses of matching placebo during the 8-week Main Portion of the study.

    Subject analysis set title
    Main Portion: Zilucoplan 0.3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive daily SC doses of zilucoplan 0.3 mg/kg during the 8-week Main Portion of the study.

    Subject analysis set title
    Extension Portion: Zilucoplan 0.3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daily SC doses of zilucoplan 0.3 mg/kg during the Extension Portion of the study.

    Primary: Percentage Change From Baseline to Week 8 in Serum CK Levels

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    End point title
    		 Percentage Change From Baseline to Week 8 in Serum CK Levels
    End point description
    All laboratory samples were obtained prior to administration of study drug at applicable visits. CK levels were measured by a central laboratory. The Intent-to-Treat (ITT) Population included all randomized study participants. The ITT population with no missing observations at Baseline and Week 8.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    14
    10
    Units: percentage change
        arithmetic mean (standard deviation)
    -20.72 ± 31.22
    -9.86 ± 26.06
    Statistical analysis title
    		 Placebo versus (vs) Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was calculated using a 2-sided Van Elteren test, which represents an extension of the Wilcoxon rank sum test for comparing 2 treatments in a stratified experiment using within-stratum ranks assigning greater weight to rank sums from smaller strata. The magnitude of association between treatment groups was expressed as in Wilcoxon-Mann-Whitney odds followed by the 95% confidence intervals.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.464
    Method
    		 2-sided Van Elteren test
    Parameter type
    		 Wilcoxon-Mann-Whitney odds
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 1.57

    Primary: Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) [1]
    End point description
    A TEAE was defined as: • An adverse event (AE) that occurred after study treatment start that was not present at the time of treatment start. • An AE that increased in severity after treatment start if the event was present at the time of treatment start. The Safety Population included all participants who have received at least 1 dose of study drug, with participants analyzed based on the actual study treatment received.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to end of Main Portion (Week 8)
    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 additional statistical analysis was pre-specified for this end point.
    End point values
    		 Main Portion: Placebo Main Portion: Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    15
    12
    Units: participants
    13
    9
    No statistical analyses for this end point

    Secondary: Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) Response Criteria Scale

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    End point title
    		 Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) Response Criteria Scale
    End point description
    The ACR/EULAR scale utilized a conjoint analysis-based continuous model using absolute percent change from Baseline in core set measures (physician, patient, and Myositis Disease Activity Assessment Tool (MDAAT); muscle strength; Health Assessment Questionnaire (HAQ); and muscle enzyme levels). A total improvement score (range 0-100) was determined by summing scores for each core set measure and comparing improvement in each respective core set measure. The threshold for minimal improvement was ≥20 in the total improvement score with higher scores indicating a better outcome. The ITT Population with no missing observations at Baseline and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    14
    11
    Units: participants
    7
    6
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value for the comparison of treatment groups was calculated using logistic regression with investigational medicinal product and strata as fixed factors.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.919
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.214
         upper limit
    		 5.535

    Secondary: Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time

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    End point title
    		 Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time
    End point description
    The 3TUG test involved the ambulatory participant getting up from a seated position in a chair, walking at their normal pace for 3 meters, turning around, walking back to the chair, and sitting down. This sequence was repeated 3 times without rest, and the 3TUG test time is the average of the 3 lap times. A negative change from baseline indicated a better outcome. The ITT Population with no missing observations at Baseline and Week 8. The test was also only performed in participants who were ambulatory.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    10
    10
    Units: seconds
        least squares mean (standard error)
    -0.712 ± 0.789
    -1.401 ± 0.788
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was based on a linear model with treatment and strata (anti-3-hydroxy-3-methyl-glutarylcoenzyme A reductase [HMGCR]+/anti-signal recognition particle [SRP]+) as fixed factors with Baseline 3TUG as a covariate. The difference presented is zilucoplan 0.3 mg/kg minus placebo.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.496
    Method
    		 Linear Mixed Effect Model
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    -0.688
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.781
         upper limit
    		 1.404

    Secondary: Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score

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    End point title
    		 Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score
    End point description
    The proximal MMT assessed muscle strength using manual muscle testing in 7 muscle groups (left and right sides assessed separately). The total MMT score for this study, inclusive of both sides, could range from 0-140, where 0 means no strength in any muscles and 140 means full strength in all the muscles examined. A negative change from Baseline indicated a worse outcome. The ITT Population with no missing observations at Baseline and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    14
    11
    Units: score on a scale
        least squares mean (standard error)
    -0.18 ± 3.44
    3.71 ± 3.81
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was based on a linear model with treatment and strata (anti-HMGCR+/anti-SRP+) as fixed factors with Baseline proximal MMT as a covariate. The difference presented is zilucoplan 0.3 mg/kg minus placebo.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.431
    Method
    		 Linear Mixed Effect Model
    Parameter type
    		 LS mean difference
    Point estimate
    3.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.18
         upper limit
    		 13.95

    Secondary: Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score

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    End point title
    		 Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score
    End point description
    The Physician Global Activity VAS Score measured the treating physician's global evaluation of the participant's overall disease activity using a 10 cm VAS labelled with "no activity" at the left end and "maximum activity" at the right end. The Physician Global Activity VAS Score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. The ITT Population with no missing observations at Baseline and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    15
    11
    Units: score on a scale
        least squares mean (standard error)
    -0.626 ± 0.557
    -0.830 ± 0.671
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was based on a linear model with treatment and strata (anti-HMGCR+/anti-SRP+) as fixed factors with Baseline Physician Global Activity VAS as a covariate. The difference presented is zilucoplan 0.3 mg/kg minus placebo.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Linear Mixed Effect Model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.204
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.855
         upper limit
    		 1.448

    Secondary: Change From Baseline to Week 8 in Patient Global Activity VAS Score

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    End point title
    		 Change From Baseline to Week 8 in Patient Global Activity VAS Score
    End point description
    The Patient Global Activity VAS Score measured the treating participant's global evaluation of their overall disease activity using a 10 cm VAS labelled with "no activity" at the left end and "maximum activity" at the right end. The Patient Global Activity VAS score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. The ITT Population with no missing observations at Baseline and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    15
    11
    Units: score on a scale
        least squares mean (standard error)
    -0.685 ± 0.707
    -1.966 ± 0.854
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was based on a linear model with treatment and strata (anti-HMGCR+/anti-SRP+) as fixed factors with Baseline Patient Global Activity VAS as a covariate. The difference presented is zilucoplan 0.3 mg/kg minus placebo.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.221
    Method
    		 Linear Mixed Effect Model
    Parameter type
    		 LS mean difference
    Point estimate
    -1.281
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.39
         upper limit
    		 0.829

    Secondary: Change From Baseline to Week 8 in HAQ Score

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    End point title
    		 Change From Baseline to Week 8 in HAQ Score
    End point description
    The HAQ had 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities with 2 to 3 questions for each section. Scoring within each section ranged from 0 (without any difficulty) to 3 (unable to do). The total HAQ score was then calculated by summing the scores and dividing by the number of categories answered. The total HAQ score for this study could range from 0-3, where 0 means no functional impairment and 3 means complete functional impairment. A negative change from Baseline indicated a better outcome. The ITT Population with no missing observations at Baseline and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    15
    11
    Units: score of a scale
        least squares mean (standard error)
    0.022 ± 0.151
    -0.125 ± 0.183
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was based on a linear model with treatment and strata (anti-HMGCR+/anti-SRP+) as fixed factors with Baseline HAQ as a covariate. The difference presented is zilucoplan 0.3 mg/kg minus placebo.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.508
    Method
    		 Linear Mixed Effect Model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.147
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.601
         upper limit
    		 0.307

    Secondary: Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score

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    End point title
    		 Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score
    End point description
    The MDAAT extramuscular disease activity VAS score measured the degree of disease activity of extramuscular organ systems and muscle. The scoring was performed by the physician and ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome. The ITT Population with no missing observations at Baseline and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    15
    11
    Units: score on a scale
        least squares mean (standard error)
    -0.144 ± 0.336
    -0.287 ± 0.398
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was based on a linear model with treatment and strata (anti-HMGCR+/anti-SRP+) as fixed factors with Baseline MDAAT as a covariate. The difference presented is zilucoplan 0.3 mg/kg minus placebo.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.765
    Method
    		 Linear Mixed Effect Model
    Parameter type
    		 LS mean difference
    Point estimate
    -0.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.123
         upper limit
    		 0.837

    Secondary: Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score

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    End point title
    		 Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score
    End point description
    The FACIT-Fatigue Scale is a 13-item tool which measured an individual’s level of fatigue during their usual daily activities over the past week. The level of fatigue was measured on a 4-point Likert scale. The total FACIT-Fatigue Scale score for this study could range from 0-52, where 0 means the participants were very much fatigued during their usual daily activities and 52 means the participants were not at all fatigued during their usual daily activities. A negative change from Baseline indicated a worse outcome. The ITT Population with no missing observations at Baseline and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and end of Main Portion (Week 8)
    End point values
    		 Placebo Zilucoplan 0.3 mg/kg
    Number of subjects analysed
    15
    11
    Units: score on a scale
        least squares mean (standard error)
    3.45 ± 3.41
    8.98 ± 4.08
    Statistical analysis title
    		 Placebo vs Zilucoplan 0.3 mg/kg
    Statistical analysis description
    The p-value was based on a linear model with treatment and strata (anti-HMGCR+/anti-SRP+) as fixed factors with Baseline FACIT-Fatigue Scale as a covariate. The difference presented is zilucoplan 0.3 mg/kg minus placebo.
    Comparison groups
    Placebo v Zilucoplan 0.3 mg/kg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.265
    Method
    		 Linear Mixed Effect Model
    Parameter type
    		 LS mean difference
    Point estimate
    5.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.49
         upper limit
    		 15.55

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) to End of Safety Follow-up (Week 83)
    Adverse event reporting additional description
    The Safety Population included all participants who have received at least 1 dose of study drug, with participants analyzed based on the actual study treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Main Portion: Placebo
    Reporting group description
    		 Participants were randomized to receive daily SC doses of matching placebo during the 8-week Main Portion of the study.

    Reporting group title
    Main Portion: Zilucoplan 0.3 mg/kg
    Reporting group description
    		 Participants were randomized to receive daily SC doses of zilucoplan 0.3 mg/kg during the 8-week Main Portion of the study.

    Reporting group title
    Extension Portion: Zilucoplan 0.3 mg/kg
    Reporting group description
    		 Participants received daily SC doses of zilucoplan 0.3 mg/kg during the Extension Portion of the study.

    Serious adverse events
    		 Main Portion: Placebo Main Portion: Zilucoplan 0.3 mg/kg Extension Portion: Zilucoplan 0.3 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 12 (0.00%)
    8 / 25 (32.00%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    1
    Investigations
    Liver function test increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Rhinovirus infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    3 / 25 (12.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinusitis bacterial
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Main Portion: Placebo Main Portion: Zilucoplan 0.3 mg/kg Extension Portion: Zilucoplan 0.3 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 15 (86.67%)
    9 / 12 (75.00%)
    15 / 25 (60.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Injection site pruritus
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Influenza like illness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    Injection site erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site bruising
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Vessel puncture site bruise
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Vaccination site pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    Investigations
    Lipase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Amylase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    3
    Skin procedural complication
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Contusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 15 (26.67%)
    4 / 12 (33.33%)
    2 / 25 (8.00%)
         occurrences all number
    5
    4
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    2
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 12 (25.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    3
    0
    Constipation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Faeces soft
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Tendonitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2021
    - The Extension Portion was included in the Objectives and Endpoints table. Notes were added into the global protocol amendment that the long-term safety, tolerability, and efficacy were evaluated during the open-label Extension Portion of the study. - Text regarding safety data review was updated. - For France only, the duration of study participation during the Extension Portion of this study was amended from 4 months to 18 months. - Added exclusion criterion 14 (hypersensitivity to investigational medicinal product [IMP]). - Footnote “a” was updated to state that if a study participant permanently discontinued IMP treatment prior to the Week 8 Visit for any reason, he/she was not eligible for the Extension Portion. For study participants who permanently discontinued treatment with IMP, a Safety Follow-up Visit was performed 40 days after the last dose to collect information on any ongoing AEs or new serious adverse events since the last study visit. - A new footnote “b” was added to the “Visits after Day Extension (E)117” to state that for France only, the duration of study participation during the Extension Portion included an open-label, single-arm, 18-month Treatment Period. - Revised information on contraception. - The objectives and endpoints were revised to reflect current UCB practices for the categorization and description of study objectives based on estimand definitions (to align with the updated ICH E9 [R1] addendum). - The efficacy analysis presented in the protocol was updated from the 2-sided Wilcoxon rank sum test to the Van Elteren test, and a sentence was added to state that the effect of ZLP on ACR/EULAR minimal response was investigated using a binary logistic regression model with treatment and stratification included as factors. - Provisions were included for the COVID-19 pandemic. - Administrative updates. - Changes were made to clarify that the snapshot was taken after the Week 8 Visit.

    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.
    The study was terminated based on the primary efficacy endpoint analysis after the first data lock.
    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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