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    Clinical Trial Results:
    A 12-month prospective, randomized, interventional, global, multi-center, active-controlled study comparing sustained benefit of two treatment paradigms (erenumab qm vs. oral prophylactics) in adult episodic migraine patients

    Summary
    EudraCT number
    		 2018-001228-20
    Trial protocol
    		 BE   DE   CZ   FI   GB   SK   PT   GR   PL   ES   IT  
    Global end of trial date
    30 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2023
    First version publication date
    21 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAMG334A2401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03927144
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    30 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the superiority of subcutaneous AMG334 compared to oral prophylactics on sustained benefit defined as % subjects completing one-year on the randomized treatment and achieving at least a 50% reduction from baseline in monthly migraine days at month 12.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 May 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
    Argentina: 15
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 60
    Country: Number of subjects enrolled
    Czechia: 105
    Country: Number of subjects enrolled
    Finland: 18
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Greece: 32
    Country: Number of subjects enrolled
    Israel: 32
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Poland: 80
    Country: Number of subjects enrolled
    Portugal: 37
    Country: Number of subjects enrolled
    Slovakia: 39
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    621
    EEA total number of subjects
    541
    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)
    615
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 84 investigative sites in 17 countries.

    Pre-assignment
    Screening details
    		 The screening period began once patients had signed the study informed consent. Screening evaluations were performed during 2 weeks. After the Screening Period there was a Baseline Period of 4 weeks.

    Period 1
    Period 1 title
    Core Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AMG334 70mg / 140mg (Core Phase)
    Arm description
    		 Participants randomized to erenumab in the Core Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    erenumab
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pre-filled 1mL syringes (PFS) containing 70 mg/1mL of erenumab (AMG334) for subcutaneous administration for 70 mg or 140 mg dose were supplied to the investigators. Participants randomized to erenumab were dosed every 4 weeks from Day 1 up to Week 48. The investigator could treat the subject with either 70 mg or 140 mg. Dose modification/escalation was allowed as per the approved label.

    Arm title
    		 Oral SOC prophylactics (Core Phase)
    Arm description
    		 Participants randomized to oral SOC prophylactics in the Core Phase
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oral SOC prophylactics
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral standard of care (SOC) prophylactics was locally approved oral prophylactic migraine medication. Participants randomized to oral SOC prophylactics continued to be dosed through Week 52 as per label.

    Number of subjects in period 1
    		AMG334 70mg / 140mg (Core Phase) Oral SOC prophylactics (Core Phase)
    Started
    413
    208
    Completed
    377
    146
    Not completed
    36
    62
         Physician decision
    2
    8
         Subject decision
    16
    40
         Protocol deviation
    2
    2
         Adverse event
    9
    5
         No longer clinically benefiting
    4
    4
         Lost to follow-up
    3
    2
         New therapy for study indication
    -
    1
    Period 2
    Period 2 title
    PTA (Extension) Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AMG334 70mg / 140mg (PTA Phase)
    Arm description
    		 Subjects who continued with erenumab treatment in the PTA (extension) Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    erenumab
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Erenumab (70 mg or 140 mg) monthly from Week 52 up to Week 100.

    Arm title
    		 From oral SOC prophylactics to AMG334 (PTA Phase)
    Arm description
    		 Subjects who switched from oral SOC to erenumab treatment in the PTA (extension) Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    erenumab
    Investigational medicinal product code
    AMG334
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Erenumab (70 mg or 140 mg) monthly from Week 52 up to Week 100.

    Number of subjects in period 2 [1]
    		AMG334 70mg / 140mg (PTA Phase) From oral SOC prophylactics to AMG334 (PTA Phase)
    Started
    343
    118
    Completed
    328
    108
    Not completed
    15
    10
         Subject decision
    8
    3
         Protocol deviation
    -
    1
         Pregnancy
    1
    -
         Adverse event
    2
    1
         No longer clinically benefiting
    4
    5
    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: Not all subjects who completed the Core Phase started the PTA (Extension) Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AMG334 70mg / 140mg (Core Phase)
    Reporting group description
    		 Participants randomized to erenumab in the Core Phase

    Reporting group title
    Oral SOC prophylactics (Core Phase)
    Reporting group description
    		 Participants randomized to oral SOC prophylactics in the Core Phase

    Reporting group values
    		 AMG334 70mg / 140mg (Core Phase) Oral SOC prophylactics (Core Phase) Total
    Number of subjects
    		 413 208 621
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 407 208 615
        From 65-84 years
    		 6 0 6
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.1 ( 11.5 ) 41.5 ( 10.4 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 363 182 545
        Male
    		 50 26 76
    Race
    Units: Subjects
        White
    		 406 206 612
        Black or African American
    		 2 0 2
        Asian
    		 0 1 1
        Native Hawaiian or other Pacific Islander
    		 0 0 0
        American Indian or Alaska Native
    		 1 0 1
        Multiple
    		 2 0 2
        Unknown
    		 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    AMG334 70mg / 140mg (Core Phase)
    Reporting group description
    		 Participants randomized to erenumab in the Core Phase

    Reporting group title
    Oral SOC prophylactics (Core Phase)
    Reporting group description
    		 Participants randomized to oral SOC prophylactics in the Core Phase
    Reporting group title
    AMG334 70mg / 140mg (PTA Phase)
    Reporting group description
    		 Subjects who continued with erenumab treatment in the PTA (extension) Phase

    Reporting group title
    From oral SOC prophylactics to AMG334 (PTA Phase)
    Reporting group description
    		 Subjects who switched from oral SOC to erenumab treatment in the PTA (extension) Phase

    Primary: Proportion of subjects who complete initially assigned treatment and achieve at least 50% reduction from baseline in monthly migraine days at Month 12

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    End point title
    		 Proportion of subjects who complete initially assigned treatment and achieve at least 50% reduction from baseline in monthly migraine days at Month 12
    End point description
    Responder is defined as subject completing one year on the initially assigned treatment and achieving at least 50% reduction from baseline in monthly migraine days at Week 52. A migraine day was defined as any calendar day in which the subject experiences a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined as a migraine with or without aura, lasting for ≥ 30 minutes, and meeting specific criteria defined in the protocol. Missing data are imputed as non-response (NRI).
    End point type
    Primary
    End point timeframe
    Month 12 (Week 52)
    End point values
    		 AMG334 70mg / 140mg (Core Phase) Oral SOC prophylactics (Core Phase)
    Number of subjects analysed
    413
    208
    Units: participants
    232
    35
    Statistical analysis title
    		 AMG334 vs oral SOC prophylactics
    Statistical analysis description
    Null hypothesis for primary analysis: In subjects with episodic migraine, AMG334 treatment group had the same effect as oral prophylactics group (net benefit OR =1). Alternative hypothesis: In subjects with episodic migraine, AMG334 treatment group was different from oral prophylactics group (net benefit OR ≠1). Statistical analysis utilizes a Cochran-Mantel-Haenszel test adjusting for stratification factor (no. of prior prophylactic migraine treatment failures=1 vs 2) after NRI for missing data
    Comparison groups
    AMG334 70mg / 140mg (Core Phase) v Oral SOC prophylactics (Core Phase)
    Number of subjects included in analysis
    621
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.28
         upper limit
    		 9.82

    Secondary: Proportion of subjects completing the treatment period at Month 12 on the initially assigned treatment

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    End point title
    		 Proportion of subjects completing the treatment period at Month 12 on the initially assigned treatment
    End point description
    Subjects who completed one year on the initially assigned treatment were considered as responders for the analysis of this secondary endpoint. A subject was considered as a non-responder if a subject did not complete one year on the initially assigned treatment. This included (a) subjects who discontinued initially assigned treatment permanently (b) subjects who switched to oral prophylactics other than initially assigned treatment. Missing data are imputed as non-response (NRI).
    End point type
    Secondary
    End point timeframe
    Month 12 (Week 52)
    End point values
    		 AMG334 70mg / 140mg (Core Phase) Oral SOC prophylactics (Core Phase)
    Number of subjects analysed
    413
    208
    Units: participants
    359
    78
    Statistical analysis title
    		 AMG334 vs Oral SOC prophylactics
    Statistical analysis description
    Statistical analysis utilizes a Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor (no. of prior prophylactic migraine treatment failures=1 vs 2) after NRI for missing data.
    Comparison groups
    AMG334 70mg / 140mg (Core Phase) v Oral SOC prophylactics (Core Phase)
    Number of subjects included in analysis
    621
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.53
         upper limit
    		 16.87

    Secondary: Cumulative average change from baseline on the monthly migraine days during the treatment period for subjects on the initially assigned treatment (Months 1-12)

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    End point title
    		 Cumulative average change from baseline on the monthly migraine days during the treatment period for subjects on the initially assigned treatment (Months 1-12)
    End point description
    The average of monthly migraine days was obtained cumulatively every 4 weeks across 52 weeks (e.g. at Week 8 the average was based on data from Week 1 to Week 8; at Week 12 the average was based on Week 1 to Week 12 and so on). The cumulative average change from baseline in monthly migraine days was derived using difference between cumulative average of each month and baseline monthly migraine days. The change from baseline was analyzed using a linear mixed effects repeated measures model including treatment group, baseline value, stratification factor(s), scheduled visit, and the interaction of treatment group with scheduled visit.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 AMG334 70mg / 140mg (Core Phase) Oral SOC prophylactics (Core Phase)
    Number of subjects analysed
    413
    208
    Units: monthly migraine days
    least squares mean (standard error)
        Week 4
    -2.55 ( 0.17 )
    -0.55 ( 0.25 )
        Week 8
    -3.00 ( 0.17 )
    -1.01 ( 0.25 )
        Week 12
    -3.27 ( 0.17 )
    -1.05 ( 0.26 )
        Week 16
    -3.45 ( 0.17 )
    -1.22 ( 0.26 )
        Week 20
    -3.63 ( 0.17 )
    -1.35 ( 0.26 )
        Week 24
    -3.75 ( 0.17 )
    -1.56 ( 0.26 )
        Week 28
    -3.84 ( 0.17 )
    -1.73 ( 0.26 )
        Week 32
    -3.93 ( 0.17 )
    -1.91 ( 0.27 )
        Week 36
    -3.99 ( 0.17 )
    -1.99 ( 0.27 )
        Week 40
    -4.05 ( 0.17 )
    -2.06 ( 0.27 )
        Week 44
    -4.12 ( 0.17 )
    -2.11 ( 0.27 )
        Week 48
    -4.18 ( 0.17 )
    -2.07 ( 0.27 )
        Week 52
    -4.24 ( 0.17 )
    -2.11 ( 0.27 )
    Statistical analysis title
    		 AMG334 vs Oral SOC prophylactics - Week 52
    Statistical analysis description
    A linear mixed effects model includes treatment group, baseline value, stratification factor, scheduled visit, and the interaction of treatment group with scheduled visit. Unstructured covariance matrix assumed. Comparison of adjusted means (Test - Ref.)
    Comparison groups
    AMG334 70mg / 140mg (Core Phase) v Oral SOC prophylactics (Core Phase)
    Number of subjects included in analysis
    621
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Linear mixed effects model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 -1.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31

    Secondary: Proportion of responders (PGI-I score ≥5) as measured by PGIC at Month 12 for subjects completing the treatment period at Month 12 on initially assigned treatment

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    End point title
    		 Proportion of responders (PGI-I score ≥5) as measured by PGIC at Month 12 for subjects completing the treatment period at Month 12 on initially assigned treatment
    End point description
    The Patients' Global Impression of Change (PGIC) is a global assessment by the subject of the change in clinical status since the start of treatment. The PGIC is assessed periodically through the treatment period and at the end of the treatment period. The PGIC was rated with a 7-point scale, from 1 (no change or condition is worse) to 7 (a great deal better). Subjects were considered as responder if PGIC score was 5, 6, or 7 at Month 12 on initially assigned treatment. Subject was considered as non-responder if subject did not complete 12 months on initially assigned treatment or if subject did not have score 5, 6 or 7 at Month 12. Missing data are imputed as non-response (NRI). The PGIC scores 5 to 7 are as follows: 5 = Moderately better, and a slight noticeable change 6 = Better, and a definite improvement that has made a real and worthwhile difference 7 = A great deal better, and a considerable difference that has made all the difference
    End point type
    Secondary
    End point timeframe
    Month 12 (Week 52)
    End point values
    		 AMG334 70mg / 140mg (Core Phase) Oral SOC prophylactics (Core Phase)
    Number of subjects analysed
    413
    208
    Units: participants
    314
    39
    Statistical analysis title
    		 AMG334 vs Oral SOC prophylactics
    Statistical analysis description
    Statistical analysis utilizes a Cochran-Mantel-Haenszel (CMH) test adjusting for stratification factor (no. of prior prophylactic migraine treatment failures=1 vs 2) after NRI for missing data.
    Comparison groups
    AMG334 70mg / 140mg (Core Phase) v Oral SOC prophylactics (Core Phase)
    Number of subjects included in analysis
    621
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    13.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.08
         upper limit
    		 20.83

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Core Phase: From first dose of study medication (Day 1) up to 30 days after last dose (Week 52). PTA (extension) Phase: From first dose of study medication (Week 52) up to 30 days after last dose (Week 104).
    Adverse event reporting additional description
    In the core phase, for the patients who switched from AMG334 to oral SOC prophylactics, safety data collected before the switch is summarized in the AMG334 arm and safety data collected after the switch is summarized in the oral SOC prophylactics arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Core Phase: AMG334 70mg / 140mg
    Reporting group description
    		 Subjects randomized to erenumab in the Core Phase (Day 1 to Week 52)

    Reporting group title
    PTA (extension) Phase: From oral SOC prophylactics to AMG334
    Reporting group description
    		 Subjects who switched from oral SOC to erenumab treatment in the PTA (extension) Phase

    Reporting group title
    PTA (extension) Phase: AMG334 70mg / 140mg
    Reporting group description
    		 Subjects who continued with erenumab treatment in the PTA (extension) Phase (Week 52 to Week 104)

    Reporting group title
    Core Phase: Oral SOC prophylactics
    Reporting group description
    		 Subjects randomized to oral SOC prophylactics in the Core Phase (Day 1 to Week 52). Includes 9 subjects switched from AMG334 to SOC prophylactics during the core phase.

    Serious adverse events
    		 Core Phase: AMG334 70mg / 140mg PTA (extension) Phase: From oral SOC prophylactics to AMG334 PTA (extension) Phase: AMG334 70mg / 140mg Core Phase: Oral SOC prophylactics
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 408 (3.68%)
    4 / 118 (3.39%)
    9 / 343 (2.62%)
    9 / 206 (4.37%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Thyroid cancer
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Salivary gland neoplasm
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Medical device pain
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Anaphylactic reaction
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Reproductive system and breast disorders
    Menometrorrhagia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Endometriosis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Breast fibrosis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Ovarian cyst
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 118 (0.85%)
    0 / 343 (0.00%)
    0 / 206 (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
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Mood altered
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 118 (0.85%)
    0 / 343 (0.00%)
    0 / 206 (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
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Radius fracture
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Procedural pain
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Muscle hernia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Meniscus injury
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Ligament sprain
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Hip fracture
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Hand fracture
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Ankle fracture
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Headache
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 118 (0.85%)
    0 / 343 (0.00%)
    0 / 206 (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
    Eye disorders
    Ulcerative keratitis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Gastrointestinal disorders
    Umbilical hernia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Skin and subcutaneous tissue disorders
    Skin laxity
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 118 (0.85%)
    0 / 343 (0.00%)
    0 / 206 (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 and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Hydronephrosis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Ureteric rupture
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    Musculoskeletal and connective tissue disorders
    Diastasis recti abdominis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 118 (0.85%)
    0 / 343 (0.00%)
    0 / 206 (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
    Femoroacetabular impingement
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Joint stiffness
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Metatarsalgia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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 pneumonia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Diverticulitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    0 / 206 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    0 / 343 (0.00%)
    1 / 206 (0.49%)
         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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 118 (0.00%)
    1 / 343 (0.29%)
    0 / 206 (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
    		 Core Phase: AMG334 70mg / 140mg PTA (extension) Phase: From oral SOC prophylactics to AMG334 PTA (extension) Phase: AMG334 70mg / 140mg Core Phase: Oral SOC prophylactics
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    131 / 408 (32.11%)
    47 / 118 (39.83%)
    106 / 343 (30.90%)
    91 / 206 (44.17%)
    Investigations
    Weight increased
         subjects affected / exposed
    12 / 408 (2.94%)
    2 / 118 (1.69%)
    0 / 343 (0.00%)
    22 / 206 (10.68%)
         occurrences all number
    12
    2
    0
    22
    Injury, poisoning and procedural complications
    Vaccination complication
         subjects affected / exposed
    9 / 408 (2.21%)
    8 / 118 (6.78%)
    16 / 343 (4.66%)
    2 / 206 (0.97%)
         occurrences all number
    14
    16
    27
    4
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    5 / 408 (1.23%)
    1 / 118 (0.85%)
    3 / 343 (0.87%)
    15 / 206 (7.28%)
         occurrences all number
    6
    1
    3
    15
    Dizziness
         subjects affected / exposed
    7 / 408 (1.72%)
    1 / 118 (0.85%)
    6 / 343 (1.75%)
    18 / 206 (8.74%)
         occurrences all number
    7
    1
    6
    22
    Somnolence
         subjects affected / exposed
    5 / 408 (1.23%)
    2 / 118 (1.69%)
    0 / 343 (0.00%)
    15 / 206 (7.28%)
         occurrences all number
    6
    2
    0
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 408 (4.41%)
    2 / 118 (1.69%)
    4 / 343 (1.17%)
    33 / 206 (16.02%)
         occurrences all number
    27
    2
    5
    38
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    53 / 408 (12.99%)
    16 / 118 (13.56%)
    10 / 343 (2.92%)
    2 / 206 (0.97%)
         occurrences all number
    71
    17
    10
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    36 / 408 (8.82%)
    10 / 118 (8.47%)
    28 / 343 (8.16%)
    15 / 206 (7.28%)
         occurrences all number
    46
    18
    34
    19
    COVID-19
         subjects affected / exposed
    20 / 408 (4.90%)
    18 / 118 (15.25%)
    61 / 343 (17.78%)
    12 / 206 (5.83%)
         occurrences all number
    20
    18
    69
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2019
    The purpose of this global amendment was to update the protocol language to reflect feedback received from Health Authorities on contraception/pregnancy language and on standard of care practices globally from participating investigators.
    15 Jun 2020
    The purpose of this amendment was to provide post trial access (PTA) to AMG334 for eligible subjects completing visits through Week 52 of the Core phase. PTA to AMG334 was provided for up to 52 Weeks (based on continued benefit of AMG334 treatment) in all eligible subjects for the PTA (extension) phase. In addition, details for potential trial conduct changes due to the COVID-19 pandemic were incorporated in this protocol amendment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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