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    Clinical Trial Results:
    A Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pegcetacoplan in subjects with amyotrophic lateral sclerosis (ALS)

    Summary
    EudraCT number
    2019-003797-10
    Trial protocol
    IE   FR   BE   DE   CZ   NL   IT  
    Global end of trial date
    13 Jul 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Feb 2025
    First version publication date
    27 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APL2-ALS-206
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04579666
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Apellis Pharmaceuticals Inc.
    Sponsor organisation address
    100 5th Avenue, Waltham, Massachusetts, United States, 02451
    Public contact
    Apellis Clinical Trial Information Line, Apellis Pharmaceuticals Inc., +1 833-284-6361, clinicaltrials@apellis.com
    Scientific contact
    Apellis Clinical Trial Information Line, Apellis Pharmaceuticals Inc., +1 833-284-6361, clinicaltrials@apellis.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
    13 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jul 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of twice per week subcutaneous (SC) doses of pegcetacoplan 1080 milligram (mg) compared to placebo in subjects with sporadic amyotrophic lateral sclerosis (ALS) as measured by the Combined Assessment of Function and Survival (CAFS) rank score (joint-rank score)
    Protection of trial subjects
    This research was carried out in accordance with the protocol, applicable regulations, the ethical principles set forth in the Declaration of Helsinki, and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Harmonised Guideline for Good Clinical Practice E6 Revision 2. An external, independent data monitoring committee assessed the safety, tolerability and efficacy data of the study periodically.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Sep 2020
    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
    Argentina: 24
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Czechia: 19
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Japan: 20
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    Ukraine: 13
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    249
    EEA total number of subjects
    154
    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)
    171
    From 65 to 84 years
    77
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This Phase 2, placebo-controlled study was conducted in subjects diagnosed with ALS. A total of 249 subjects were randomized in a 2:1 ratio to either receive pegcetacoplan or placebo.

    Pre-assignment
    Screening details
    Study consists of 5 periods: 6-week screening period, 52-week randomized treatment period (RTP), 52-week open-label treatment period (OLP), 52-week long-term extension treatment period and a 6-week off-treatment follow-up period. Study was terminated early during OLP due to lack of efficacy as determined by the Week 52 data and no safety concerns.

    Period 1
    Period 1 title
    RTP (Up to Week 52)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RTP: Pegcetacoplan
    Arm description
    Subjects received pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL-2
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan 1080 mg was administered as an SC injection/infusion twice per week for 52 weeks in the RTP.

    Arm title
    RTP: Placebo
    Arm description
    Subjects received placebo matching pegcetacoplan as SC injection/infusion twice per week for 52 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching pegcetacoplan was administered as SC injection/infusion twice per week for 52 weeks in the RTP.

    Number of subjects in period 1
    RTP: Pegcetacoplan RTP: Placebo
    Started
    169
    80
    Completed
    99
    51
    Not completed
    70
    29
         Physician decision
    4
    1
         Consent withdrawn by subject
    25
    11
         Adverse event, non-fatal
    4
    3
         Death
    24
    9
         Site terminated by sponsor
    7
    5
         Study terminated by sponsor
    2
    -
         Unspecified
    2
    -
         Lost to follow-up
    1
    -
         Progressive disease
    1
    -
    Period 2
    Period 2 title
    OLP (From Week 52 up to Week 104)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OLP: Pegcetacoplan/Pegcetacoplan
    Arm description
    Eligible subjects who had received pegcetacoplan in RTP entered OLP and continued to receive pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL-2
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan 1080 mg was administered as an SC injection/infusion twice per week for 52 weeks in the OLP.

    Arm title
    OLP: Placebo/Pegcetacoplan
    Arm description
    Eligible subjects who had received placebo matching pegcetacoplan in RTP entered OLP to receive pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Pegcetacoplan
    Investigational medicinal product code
    APL-2
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegcetacoplan 1080 mg was administered as an SC injection/infusion twice per week for 52 weeks in the OLP.

    Number of subjects in period 2 [1]
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Started
    97
    50
    Completed
    0
    0
    Not completed
    97
    50
         Consent withdrawn by subject
    19
    12
         Physician decision
    3
    1
         Adverse event, non-fatal
    2
    -
         Death
    10
    6
         Sponsor request
    63
    31
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 2 subjects in RTP: Pegcetacoplan arm and 1 subject in RTP: Placebo arm withdrew after completing the RTP and before entering the OLP period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RTP: Pegcetacoplan
    Reporting group description
    Subjects received pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.

    Reporting group title
    RTP: Placebo
    Reporting group description
    Subjects received placebo matching pegcetacoplan as SC injection/infusion twice per week for 52 weeks.

    Reporting group values
    RTP: Pegcetacoplan RTP: Placebo Total
    Number of subjects
    169 80 249
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.0 ( 12.47 ) 57.7 ( 11.02 ) -
    Gender categorical
    Units: Subjects
        Female
    64 25 89
        Male
    105 55 160
    Race
    Units: Subjects
        Caucasian
    130 67 197
        Black or African American
    0 0 0
        North East Asian
    14 6 20
        South East Asian
    0 0 0
        Other
    13 5 18
        Unknown
    12 2 14
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    27 15 42
        Not Hispanic or Latino
    124 62 186
        Unknown or Not Reported
    18 3 21

    End points

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    End points reporting groups
    Reporting group title
    RTP: Pegcetacoplan
    Reporting group description
    Subjects received pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.

    Reporting group title
    RTP: Placebo
    Reporting group description
    Subjects received placebo matching pegcetacoplan as SC injection/infusion twice per week for 52 weeks.
    Reporting group title
    OLP: Pegcetacoplan/Pegcetacoplan
    Reporting group description
    Eligible subjects who had received pegcetacoplan in RTP entered OLP and continued to receive pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.

    Reporting group title
    OLP: Placebo/Pegcetacoplan
    Reporting group description
    Eligible subjects who had received placebo matching pegcetacoplan in RTP entered OLP to receive pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.

    Primary: RTP: Combined Assessment of Function and Survival (CAFS) Rank Score (Joint-Rank Score) at Week 52

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    End point title
    RTP: Combined Assessment of Function and Survival (CAFS) Rank Score (Joint-Rank Score) at Week 52
    End point description
    CAFS scale is combined endpoint ranking subjects’ clinical outcomes based on ALS Functional Rating Scale-Revised (ALSFRS-R) and survival time.For ALSFRS-R,12 functions were rated on 5-point ordinal rating scales (0 to 4);total score 0-48 (sum of all 12 items);higher score indicated better functioning.For survival time, longer the subject survives indicated better outcome.Each subject’s outcome was compared to every other subject outcome in trial in series of pairwise comparisons,summed scores (sum of comparisons [+1 {better}, 0 {tie}, -1 {worse}]) were ranked and ranged from 001-247 (number of subjects in modified [m]ITT population).Reported values:mean rank scores in each group for composite endpoint.Higher rank indicated better outcome. mITT set:all randomized subjects who received at least 1 dose of randomized treatment (pegcetacoplan or placebo) and who died or had postbaseline assessment of endpoint that was used in CAFS.Only subjects with data collected at Week 52 are reported.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    168
    79
    Units: score on a scale
        least squares mean (standard error)
    123.0 ( 4.17 )
    126.0 ( 6.89 )
    Statistical analysis title
    Difference in LS means for CAFS
    Statistical analysis description
    Analysis of covariance (ANCOVA) was used to analyze the ranks of the CAFS score with treatment as a fixed effect, adjusted for baseline ALSFRS-R total score, time from symptom onset, baseline Log neurofilament light chain (NfL), and the randomization stratification factors (location of first muscle weakness and use of riluzole and edaravone).
    Comparison groups
    RTP: Pegcetacoplan v RTP: Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7205
    Method
    ANCOVA
    Parameter type
    Difference in LS mean
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.5
         upper limit
    13.5

    Primary: RTP: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    RTP: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [1]
    End point description
    An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An SAE was any AE or suspected adverse reaction that, in the view of the investigator, resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or was a congenital anomaly or birth defect. TEAEs were AEs that started on or after first dose of study drug or started before first dose of study drug but increased in severity on or after the first dose of study drug up to 56 days post last dose of study drug. The safety set for RTP included all subjects who received at least 1 dose of study drug: pegcetacoplan or placebo.
    End point type
    Primary
    End point timeframe
    From first dose of study drug (Day 1) up to 56 days post last dose of study drug, approximately 60 weeks
    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: As the endpoint is descriptive in nature, statistical analysis is not provided.
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    169
    80
    Units: subjects
        TEAEs
    137
    61
        TESAEs
    57
    27
    No statistical analyses for this end point

    Primary: OLP: Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events

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    End point title
    OLP: Number of Subjects With Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events [2]
    End point description
    An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An SAE was any AE or suspected adverse reaction that, in the view of the investigator, resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or was a congenital anomaly or birth defect. TEAEs were AEs that started on or after first dose of study drug or started before first dose of study drug but increased in severity on or after the first dose of study drug up to 56 days post last dose of study drug. The safety set for the OLP included only those subjects who received at least 1 dose of the open-label treatment.
    End point type
    Primary
    End point timeframe
    From first dose of study drug (Week 52) up to 56 days post last dose of study drug, approximately 60 weeks
    Notes
    [2] - 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: As the endpoint is descriptive in nature, statistical analysis is not provided.
    End point values
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    97
    50
    Units: subjects
        TEAEs
    54
    33
        TESAEs
    24
    14
    No statistical analyses for this end point

    Primary: RTP: Number of Subjects With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS) up to Week 52

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    End point title
    RTP: Number of Subjects With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS) up to Week 52 [3]
    End point description
    C-SSRS is a measure used to identify and assess individuals at risk for suicide and included "yes" or "no" responses for assessment of SI and SB. SI items classified on 5-item scale:1 (wish to be dead),2 (non-specific active suicidal thoughts),3 (active SI with any methods without intent to act),4 (active SI with some intent to act, without specific plan) and 5 (active SI with a specific plan and intent).SB items classified on 5-item scale:0 (preparatory acts or behavior),1 (aborted attempt),2 (interrupted attempt),3 (actual attempt [non-fatal]) and 4 (completed suicide).Numeric ratings provided for SI: total score 0 to 25, for SB: total score 0 to 16; higher scores for both indicate more severity. Baseline was defined as last available, non-missing observation prior to first study drug administration. The safety set for RTP included all subjects who received at least 1 dose of study drug: pegcetacoplan or placebo.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) up to Week 52
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, statistical analysis is not provided.
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    169
    80
    Units: subjects
        SI only
    16
    6
        SB only
    0
    0
        SI and SB
    1
    0
    No statistical analyses for this end point

    Primary: OLP: Number of Subjects With Positive Response to Columbia-Suicide Severity Rating Scale up to Week 104

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    End point title
    OLP: Number of Subjects With Positive Response to Columbia-Suicide Severity Rating Scale up to Week 104 [4]
    End point description
    C-SSRS is a measure used to identify and assess individuals at risk for suicide and included "yes" or "no" responses for assessment of suicidal ideation (SI) and suicidal behavior (SB).SI items classified on 5-item scale:1 (wish to be dead),2 (non-specific active suicidal thoughts),3 (active SI with any methods without intent to act),4 (active SI with some intent to act, without specific plan) and 5 (active SI with a specific plan and intent).SB items classified on 5-item scale:0 (preparatory acts or behavior),1 (aborted attempt),2 (interrupted attempt),3 (actual attempt [non-fatal]) and 4 (completed suicide).Numeric ratings provided for SI: total score 0 to 25, for SB: total score 0 to 16; higher scores for both indicate more severity. Baseline was defined as last available, non-missing observation prior to first study drug administration. The safety set for the OLP included only those subjects who received at least 1 dose of the open-label treatment.
    End point type
    Primary
    End point timeframe
    From Baseline (Week 52) up to Week 104
    Notes
    [4] - 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: As the endpoint is descriptive in nature, statistical analysis is not provided.
    End point values
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    97
    50
    Units: subjects
        SI only
    11
    3
        SB only
    0
    0
        SI and SB
    1
    0
    No statistical analyses for this end point

    Secondary: RTP: Change From Baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Score at Week 52

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    End point title
    RTP: Change From Baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Score at Week 52
    End point description
    The ALSFRS-R included 12 items for assessment of functional status: speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency. Each item ranged from 0 (no ability) to 4 (normal ability). Individual item scores were summed to produce a total score between 0 (worst) and 48 (best) with higher scores meaning better outcome. Least squares mean is presented here. Baseline was defined as the last available, non-missing observation prior to first study drug administration. The ITT set for RTP included all randomized subjects who received at least 1 dose of randomized treatment (pegcetacoplan or placebo). Only those subjects with data collected at Baseline and Week 52 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    168
    79
    Units: score on a scale
        least squares mean (standard error)
    -16.5 ( 0.81 )
    -15.8 ( 1.20 )
    Statistical analysis title
    Difference in LS means for ALSFRS-R at Week 52
    Statistical analysis description
    The mixed-effect model for repeated measures (MMRM) included fixed categorical effects for treatment, week, and the week-by-treatment interaction, as well as the continuous, fixed covariate of the baseline value of the endpoint, and the week-by-baseline interaction, baseline log NfL, time from symptoms onset to the first dose of study drug, and randomization stratification factors location of first muscle weakness and use of riluzole and/or edaravone).
    Comparison groups
    RTP: Pegcetacoplan v RTP: Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6447
    Method
    MMRM
    Parameter type
    Difference in LS mean
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    2.2

    Secondary: RTP: Change From Baseline in Percent Predicted Slow Vital Capacity (%SVC) at Week 52

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    End point title
    RTP: Change From Baseline in Percent Predicted Slow Vital Capacity (%SVC) at Week 52
    End point description
    SVC is a pulmonary function test and predictor of functional loss in ALS. It was conducted at clinic visits with the clinic spirometer which reflected the maximum amount of air that could be exhaled slowly. %SVC is the actual volume exhaled in the first 1 second, divided by the normal value for that actual value for a person of that age, gender, height and weight. Baseline was defined as the last available, non-missing observation prior to first study drug administration. Analysis was performed on the ITT population. Only those subjects with data collected at baseline and Week 52 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    167
    75
    Units: percentage of predicted SVC
        least squares mean (standard error)
    -39.2 ( 2.30 )
    -32.6 ( 3.17 )
    Statistical analysis title
    Difference in LS means for %SVC at Week 52
    Statistical analysis description
    The MMRM included fixed categorical effects for treatment, week, and the week-by-treatment interaction, as well as the continuous, fixed covariate of the baseline value of the endpoint, and the week-by-baseline interaction, baseline log NfL, time from symptoms onset to the first dose of study drug, and randomization stratification factors (location of first muscle weakness and use of riluzole and/or edaravone).
    Comparison groups
    RTP: Pegcetacoplan v RTP: Placebo
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0949
    Method
    MMRM
    Parameter type
    Difference in LS mean
    Point estimate
    -6.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.3
         upper limit
    1.2

    Secondary: RTP: Change From Baseline in Muscle Strength at Week 52

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    End point title
    RTP: Change From Baseline in Muscle Strength at Week 52
    End point description
    Muscle strength was measured using handheld dynamometry (HHD) and assessed the following muscles: first dorsal interosseous, wrist extension, elbow extension, elbow flexion, shoulder flexion, knee extension, knee flexion, and ankle dorsiflexion, on both sides of the body. Baseline was defined as the last available, non-missing observation prior to first study drug administration. Analysis was performed on the ITT population. Only those subjects with data collected at baseline and Week 52 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    166
    75
    Units: pounds
        least squares mean (standard error)
    -0.78 ( 0.06 )
    -0.59 ( 0.10 )
    Statistical analysis title
    Difference in LS means for muscle strength-Week 52
    Statistical analysis description
    The MMRM included fixed categorical effects for treatment, week, and the week-by-treatment interaction, as well as the continuous, fixed covariate of the baseline value of the endpoint, and the week-by-baseline interaction, baseline log NfL, time from symptoms onset to the first dose of study drug, and randomization stratification factors (location of first muscle weakness and use of riluzole and/or edaravone).
    Comparison groups
    RTP: Pegcetacoplan v RTP: Placebo
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0935
    Method
    MMRM
    Parameter type
    Difference in LS mean
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.42
         upper limit
    0.03

    Secondary: RTP: Number of Subjects With an Event of Death or Permanent Tracheostomy or Permanent Assisted Ventilation at Week 52

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    End point title
    RTP: Number of Subjects With an Event of Death or Permanent Tracheostomy or Permanent Assisted Ventilation at Week 52
    End point description
    Subjects with an event (that is, either death or permanent tracheostomy or permanent assisted ventilation) in RTP are reported. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 52
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    169
    80
    Units: subjects
    42
    27
    No statistical analyses for this end point

    Secondary: RTP: Change From Baseline in ALS Assessment Questionnaire (ALSAQ)- 40 at Week 52

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    End point title
    RTP: Change From Baseline in ALS Assessment Questionnaire (ALSAQ)- 40 at Week 52
    End point description
    The ALSAQ-40 was a 40-item validated questionnaire designed to assess health related quality of life (QoL) over the previous 2 weeks in subjects with ALS. It represented 5 dimensions of health status; each scored from 0 (never, or best) to 4 (always, or worst). 5 dimensions evaluated were: physical mobility (10 items: 1-10; possible score of 0-40); activities of daily living/independence (10 items: 11-20; possible score of 0-40); eating and drinking (3 items: 21-23; possible score of 0-12); communication (7 items: 24-30; possible score: 0-28) and emotional functioning (10 items: 31-40; possible score: 0-40). The total score 0 (no impairment) to 160 (severe impairment) was calculated by adding the 5 dimension scores; least squares mean is presented here. Higher scores indicated worse QoL. Analysis was performed on the ITT population. Only those subjects with data collected at baseline and Week 52 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    RTP: Pegcetacoplan RTP: Placebo
    Number of subjects analysed
    168
    79
    Units: score on a scale
        least squares mean (standard error)
    31.3 ( 1.35 )
    24.8 ( 1.94 )
    Statistical analysis title
    Difference in LS means for ALSAQ-40 at Week 52
    Statistical analysis description
    The MMRM included fixed categorical effects for treatment, week, and the week-by-treatment interaction, as well as the continuous, fixed covariate of the baseline value of the endpoint, and the week-by-baseline interaction, baseline log NfL, time from symptoms onset to the first dose of study drug, and randomization stratification factors (location of first muscle weakness and use of riluzole and/or edaravone).
    Comparison groups
    RTP: Pegcetacoplan v RTP: Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0069
    Method
    MMRM
    Parameter type
    Difference in LS mean
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.8
         upper limit
    11.1

    Secondary: OLP: Change From Baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Score at Week 104

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    End point title
    OLP: Change From Baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Score at Week 104
    End point description
    The ALSFRS-R included 12 items for assessment of functional status: speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency. Each item ranged from 0 (no ability) to 4 (normal ability). Individual item scores were summed to produce a total score between 0 (worst) and 48 (best) with higher scores meaning better outcome. Mean is presented here. Baseline was defined as the last observed value for the efficacy assessment prior to taking the first dose of study drug in OLP. The ITT set for OLP included all randomized subjects who received at least 1 dose of open label treatment. Only those subjects with data collected at specified timepoints are reported. Here, 99999=Standard deviation cannot be calculated when only 1 subject analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 52) and Week 104
    End point values
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    3
    1
    Units: score on a scale
        arithmetic mean (standard deviation)
    -19.0 ( 10.82 )
    -28.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: OLP: Change From Baseline in Percent Predicted Slow Vital Capacity at Week 104

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    End point title
    OLP: Change From Baseline in Percent Predicted Slow Vital Capacity at Week 104
    End point description
    SVC is a pulmonary function test and predictor of functional loss in ALS. It was planned to be conducted at clinic visits with the clinic spirometer which reflected the maximum amount of air that could be exhaled slowly. %SVC is the actual volume exhaled in the first 1 second, divided by the normal value for that actual value for a person of that age, gender, height and weight. Baseline was defined as the last available, non-missing observation prior to first study drug administration. Analysis was planned to be performed on the ITT population. Data was not collected as the study was terminated early.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 52) and Week 104
    End point values
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: percentage of predicted normal
        least squares mean (standard error)
    ( )
    ( )
    Notes
    [5] - Data was not collected as the study was terminated early.
    [6] - Data was not collected as the study was terminated early.
    No statistical analyses for this end point

    Secondary: OLP: Change From Baseline in Muscle Strength at Week 104

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    End point title
    OLP: Change From Baseline in Muscle Strength at Week 104
    End point description
    Muscle strength was planned to be measured using HHD and assessed the following muscles: first dorsal interosseous, wrist extension, elbow extension, elbow flexion, shoulder flexion, knee extension, knee flexion, and ankle dorsiflexion, on both sides of the body. Baseline was defined as the last available, non-missing observation prior to first study drug administration. Analysis was planned to be performed on the ITT population. Data was not collected as the study was terminated early.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 52) and Week 104
    End point values
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: pounds
        least squares mean (standard error)
    ( )
    ( )
    Notes
    [7] - Data was not collected as the study was terminated early.
    [8] - Data was not collected as the study was terminated early.
    No statistical analyses for this end point

    Secondary: OLP: Number of Subjects With an Event of Death or Permanent Tracheostomy or Permanent Assisted Ventilation at Week 104

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    End point title
    OLP: Number of Subjects With an Event of Death or Permanent Tracheostomy or Permanent Assisted Ventilation at Week 104
    End point description
    Subjects with an event of death are reported. Subjects were planned to be assessed for permanent tracheostomy or permanent assisted ventilation) in OLP; however, that data was not collected as study was terminated early. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 52) and Week 104
    End point values
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    97
    50
    Units: subjects
    10
    6
    No statistical analyses for this end point

    Secondary: OLP: Change From Baseline in ALS Assessment Questionnaire-40 at Week 104

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    End point title
    OLP: Change From Baseline in ALS Assessment Questionnaire-40 at Week 104
    End point description
    The ALSAQ-40 was a 40-item validated questionnaire designed to assess health related QoL over the previous 2 weeks in subjects with ALS. It represented 5 dimensions of health status; each scored from 0 (never, or best) to 4 (always, or worst). 5 dimensions evaluated were: physical mobility (10 items: 1-10; possible score of 0-40); activities of daily living/independence (10 items: 11- 20; possible score of 0-40); eating and drinking (3 items: 21-23; possible score of 0-12); communication (7 items: 24-30; possible score: 0-28) and emotional functioning (10 items: 31-40; possible score: 0-40). The total score 0 (no impairment) to 160 (severe impairment) was planned to be calculated by adding the 5 dimension scores. Higher scores would have indicated worse QoL. Analysis was planned to be performed on the ITT population. Data was not collected as the study was terminated early.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 52) and Week 104
    End point values
    OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: score on a scale
        least squares mean (standard error)
    ( )
    ( )
    Notes
    [9] - Data was not collected as the study was terminated early.
    [10] - Data was not collected as the study was terminated early.
    No statistical analyses for this end point

    Secondary: Number of Subjects with an Event of Death During the Study

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    End point title
    Number of Subjects with an Event of Death During the Study
    End point description
    Total number of subjects who died in the study are reported. Analysis was performed on the ITT population.
    End point type
    Secondary
    End point timeframe
    RTP: Baseline (Day 1) up to Week 52; OLP: Baseline (Week 52) up to Week 104
    End point values
    RTP: Pegcetacoplan RTP: Placebo OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Number of subjects analysed
    169
    80
    97
    50
    Units: subjects
    26
    11
    10
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs, TESAEs and deaths were collected from first dose of study drug (RTP: Day 1/OLP: Week 52) up to 56 days post last dose of study drug, approximately 60 weeks each for RTP and OLP.
    Adverse event reporting additional description
    RTP: Safety set included all subjects who received at least 1 dose of study treatment, pegcetacoplan or placebo. OLP: Safety set included only subjects who received at least 1 dose of the open-label treatment. RTP reporting groups: MedDRA 23.0.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    RTP: Pegcetacoplan
    Reporting group description
    Subjects received pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.

    Reporting group title
    RTP: Placebo
    Reporting group description
    Subjects received placebo matching pegcetacoplan as SC injection/infusion twice per week for 52 weeks.

    Reporting group title
    OLP: Pegcetacoplan/Pegcetacoplan
    Reporting group description
    Eligible subjects who had received pegcetacoplan in RTP entered OLP and continued to receive pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.

    Reporting group title
    OLP: Placebo/Pegcetacoplan
    Reporting group description
    Eligible subjects who had received placebo matching pegcetacoplan in RTP entered OLP to receive pegcetacoplan 1080 mg SC injection/infusion twice per week for 52 weeks.

    Serious adverse events
    RTP: Pegcetacoplan RTP: Placebo OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    57 / 169 (33.73%)
    27 / 80 (33.75%)
    24 / 97 (24.74%)
    14 / 50 (28.00%)
         number of deaths (all causes)
    26
    11
    10
    6
         number of deaths resulting from adverse events
    26
    11
    9
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic uterine cancer
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 80 (2.50%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrostomy
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory Failure
         subjects affected / exposed
    13 / 169 (7.69%)
    7 / 80 (8.75%)
    4 / 97 (4.12%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 13
    1 / 7
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 9
    0 / 4
    0 / 1
    0 / 2
    Pneumonia aspiration
         subjects affected / exposed
    7 / 169 (4.14%)
    2 / 80 (2.50%)
    4 / 97 (4.12%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    0 / 1
    Dyspnoea
         subjects affected / exposed
    5 / 169 (2.96%)
    2 / 80 (2.50%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 80 (1.25%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    2 / 97 (2.06%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep Apnoea Syndrome
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Symptom
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute Stress Disorder
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight Decreased
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic Lateral Sclerosis
         subjects affected / exposed
    6 / 169 (3.55%)
    3 / 80 (3.75%)
    0 / 97 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
    0 / 2
    Headache
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bulbar Palsy
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 80 (2.50%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic Atrophy
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    3 / 169 (1.78%)
    3 / 80 (3.75%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Ischaemic skin ulcer
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    7 / 169 (4.14%)
    2 / 80 (2.50%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 169 (1.18%)
    2 / 80 (2.50%)
    2 / 97 (2.06%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 80 (1.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia moraxella
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    3 / 97 (3.09%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Stoma site infection
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Rash
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food refusal
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    0 / 97 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    RTP: Pegcetacoplan RTP: Placebo OLP: Pegcetacoplan/Pegcetacoplan OLP: Placebo/Pegcetacoplan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    124 / 169 (73.37%)
    55 / 80 (68.75%)
    31 / 97 (31.96%)
    20 / 50 (40.00%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    37 / 169 (21.89%)
    14 / 80 (17.50%)
    6 / 97 (6.19%)
    1 / 50 (2.00%)
         occurrences all number
    57
    23
    10
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 169 (1.78%)
    5 / 80 (6.25%)
    1 / 97 (1.03%)
    4 / 50 (8.00%)
         occurrences all number
    3
    5
    1
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 169 (7.10%)
    7 / 80 (8.75%)
    5 / 97 (5.15%)
    1 / 50 (2.00%)
         occurrences all number
    12
    7
    5
    1
    Diarrhoea
         subjects affected / exposed
    10 / 169 (5.92%)
    5 / 80 (6.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    10
    5
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 169 (4.14%)
    5 / 80 (6.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    7
    5
    0
    0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    2 / 97 (2.06%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    2
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 169 (4.73%)
    5 / 80 (6.25%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    8
    5
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    1 / 97 (1.03%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    1
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    28 / 169 (16.57%)
    13 / 80 (16.25%)
    6 / 97 (6.19%)
    1 / 50 (2.00%)
         occurrences all number
    28
    14
    6
    1
    Nasopharyngitis
         subjects affected / exposed
    10 / 169 (5.92%)
    4 / 80 (5.00%)
    0 / 97 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    12
    4
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 169 (5.92%)
    4 / 80 (5.00%)
    5 / 97 (5.15%)
    0 / 50 (0.00%)
         occurrences all number
    13
    4
    5
    0
    Urinary tract infection
         subjects affected / exposed
    6 / 169 (3.55%)
    5 / 80 (6.25%)
    1 / 97 (1.03%)
    3 / 50 (6.00%)
         occurrences all number
    7
    5
    1
    3
    Pneumonia
         subjects affected / exposed
    0 / 169 (0.00%)
    0 / 80 (0.00%)
    4 / 97 (4.12%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    4
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2020
    Added an exploratory endpoint and associated language. Updated the exclusion criteria and language in the immunogenicity section. Added benefit/risk information and Coronavirus Disease 2019 (COVID-19) risk mitigation measures. Removed interim analysis and analysis information related to population pharmacokinetic and exposure-response modeling.
    25 Jun 2020
    Updated information related to serious adverse events and pregnancy. Added a new section to describe drug abuse, misuse, overdose, and medication error.
    27 Jul 2020
    The language regarding use of riluzole and edaravone was updated to allow for dose alterations or discontinuation should the investigator have any safety concerns. Added a new section for COVID-19 testing. Updated the information regarding adverse events, disease progression and pregnancy.
    05 Apr 2021
    Clarified the language regarding subject transition to the open-label portion of the study. Updated exclusion criteria. Language updated for: time period for resting prior to ECG and pregnancy testing, the definitions of AEs and SAEs for clarity, the relationships to study drug and to reflect that the mITT set will be used for the primary efficacy analysis of CAFS. Added a new section for Severity of Event. Additional details added regarding the ethical conduct of the study to incorporate national laws and regulation.
    09 Feb 2022
    Modified secondary and exploratory endpoints. Language was added to provide guidance in the event that direct-to-subject shipment is required during the course of the study, where approved. The at-home assessment of SVC was changed to an exploratory endpoint.
    04 Jan 2023
    Added an open-label long-term extension period. Updated a few exploratory endpoints. Clarified that long-term extension was no longer planned, it will be Part 4 of the study. Updated the exclusion criteria, blinding description and statistical methodology for the secondary efficacy endpoints. Added the newly approved medication (Relyvrio) for the treatment of ALS. Updated the language regarding vaccinations to provide further clarity and regarding anti-pegcetacoplan peptide antibody and anti-polyethylene glycol antibody collection.

    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 early, during the OLP, due to lack of efficacy as determined by the Week 52 data and no safety concerns.
    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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