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    Clinical Trial Results:
    LIBERTY 1: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered with and without Low-Dose Estradiol and Norethindrone Acetate in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids

    Summary
    EudraCT number
    		 2016-003727-27
    Trial protocol
    		 GB   DE   PL   IT  
    Global end of trial date
    29 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jun 2020
    First version publication date
    12 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MVT-601-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03049735
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Myovant Sciences GmbH
    Sponsor organisation address
    Viaduktstrasse 8, Basel, Switzerland, 4051
    Public contact
    Clinical Trials at Myovant, Myovant Sciences GmbH, +1 650 238 0250, clinicaltrials@myovant.com
    Scientific contact
    Senior VP of Clinical Development, Myovant Sciences GmbH, +1 650 238 0250, LIBERTY@myovant.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
    31 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the benefit of relugolix 40 milligrams (mg) once a day co-administered with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 298
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Poland: 50
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    United Kingdom: 2
    Worldwide total number of subjects
    388
    EEA total number of subjects
    72
    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)
    388
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 80 study centers globally were initiated in this study, including centers in the United States, Brazil, Italy, Poland, South Africa, and the United Kingdom.

    Pre-assignment
    Screening details
    		 A total of 388 premenopausal women aged 18 to 50 years with heavy menstrual bleeding (≥ 80 mL per cycle for two cycles or ≥ 160 milliliters (mL) during one cycle documented by the alkaline hematin method) associated with uterine fibroids were randomized. One placebo participant was randomized and not treated due to a serious adverse event.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Relugolix plus E2/NETA (Group A)
    Arm description
    		 Relugolix co-administered with E2/NETA for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Relugolix
    Investigational medicinal product code
    Other name
    TAK-385, MVT-601
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Relugolix (40 mg) tablet administered orally once daily for 24 weeks.

    Investigational medicinal product name
    Estradiol/Norethindrone Acetate
    Investigational medicinal product code
    Other name
    E2/NETA, low-dose hormonal add-back
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily for 24 weeks.

    Arm title
    		 Relugolix plus Delayed E2/NETA (Group B)
    Arm description
    		 Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Relugolix
    Investigational medicinal product code
    Other name
    TAK-385, MVT-601
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Relugolix (40 mg) tablet co-administered with E2 (0 mg)/NETA (0 mg) placebo capsule for 12 weeks followed by relugolix (40 mg) tablet co-administered with E2 (1.0 mg)/NETA (0.5 mg) capsule for 12 weeks.

    Investigational medicinal product name
    Estradiol/Norethindrone Acetate
    Investigational medicinal product code
    Other name
    E2/NETA, low-dose hormonal add-back
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily for 12 weeks.

    Investigational medicinal product name
    Estradiol/Norethindrone Acetate Placebo
    Investigational medicinal product code
    Other name
    E2/NETA, low-dose hormonal add-back placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily for 12 weeks.

    Arm title
    		 Placebo (Group C)
    Arm description
    		 Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Relugolix Placebo
    Investigational medicinal product code
    Other name
    TAK-385 Placebo, MVT-601 Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Relugolix (0 mg) placebo tablet administered orally once daily for 24 weeks.

    Investigational medicinal product name
    Estradiol/Norethindrone Acetate Placebo
    Investigational medicinal product code
    Other name
    E2/NETA, low-dose hormonal add-back placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily for 24 weeks.

    Number of subjects in period 1
    		Relugolix plus E2/NETA (Group A) Relugolix plus Delayed E2/NETA (Group B) Placebo (Group C)
    Started
    128
    132
    128
    Received at Least 1 Dose of Study Drug
    128
    132
    127
    Completed
    100
    103
    105
    Not completed
    28
    29
    23
         Consent withdrawn by subject
    10
    3
    7
         Did not receive any study drug
    -
    -
    1
         Adverse event, non-fatal
    7
    18
    5
         Other
    5
    3
    1
         Pregnancy
    -
    -
    1
         Lost to follow-up
    1
    5
    5
         Protocol deviation
    1
    -
    -
         Lack of efficacy
    4
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Relugolix plus E2/NETA (Group A)
    Reporting group description
    		 Relugolix co-administered with E2/NETA for 24 weeks.

    Reporting group title
    Relugolix plus Delayed E2/NETA (Group B)
    Reporting group description
    		 Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks.

    Reporting group title
    Placebo (Group C)
    Reporting group description
    		 Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.

    Reporting group values
    		 Relugolix plus E2/NETA (Group A) Relugolix plus Delayed E2/NETA (Group B) Placebo (Group C) Total
    Number of subjects
    		 128 132 128 388
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.5 ( 4.99 ) 41.3 ( 5.39 ) 42.2 ( 5.70 ) -
    Gender categorical
    Units: Subjects
        Female
    		 128 132 128 388
        Male
    		 0 0 0 0
    Geographic Region
    Units: Subjects
        North America
    		 98 101 99 298
        Rest of World
    		 30 31 29 90
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 5 1 8
        Asian
    		 0 2 2 4
        Black or African American
    		 59 67 66 192
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        White
    		 64 53 56 173
        Other
    		 2 1 1 4
        Multiple
    		 1 4 2 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Not Hispanic or Latino
    		 92 99 104 295
        Hispanic or Latino
    		 34 33 23 90
        Not reported
    		 2 0 1 3
    Mean MBL volume
    Units: mL
        arithmetic mean (standard deviation)
    		 239.44 ( 180.292 ) 228.89 ( 159.623 ) 218.76 ( 125.039 ) -
    Subject analysis sets

    Subject analysis set title
    Baseline Analysis Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All participants who were randomized to treatment and who received at least 1 dose of study drug.

    Subject analysis sets values
    		 Baseline Analysis Population
    Number of subjects
    387
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.0 ( 5.38 )
    Gender categorical
    Units: Subjects
        Female
    387
        Male
    0
    Geographic Region
    Units: Subjects
        North America
    297
        Rest of World
    90
    Race
    Units: Subjects
        American Indian or Alaska Native
    8
        Asian
    4
        Black or African American
    191
        Native Hawaiian or Other Pacific Islander
    0
        White
    173
        Other
    4
        Multiple
    7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Not Hispanic or Latino
    294
        Hispanic or Latino
    90
        Not reported
    3
    Mean MBL volume
    Units: mL
        arithmetic mean (standard deviation)
    229.05 ( 156.576 )

    End points

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    End points reporting groups
    Reporting group title
    Relugolix plus E2/NETA (Group A)
    Reporting group description
    		 Relugolix co-administered with E2/NETA for 24 weeks.

    Reporting group title
    Relugolix plus Delayed E2/NETA (Group B)
    Reporting group description
    		 Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks.

    Reporting group title
    Placebo (Group C)
    Reporting group description
    		 Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.

    Subject analysis set title
    Baseline Analysis Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All participants who were randomized to treatment and who received at least 1 dose of study drug.

    Primary: Percentage Of Participants Who Achieved A Menstrual Blood Loss (MBL) Volume Of < 80 mL And A ≥ 50% Reduction From Baseline MBL Volume With Relugolix Plus E2/NETA

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    End point title
    		 Percentage Of Participants Who Achieved A Menstrual Blood Loss (MBL) Volume Of < 80 mL And A ≥ 50% Reduction From Baseline MBL Volume With Relugolix Plus E2/NETA [1]
    End point description
    A responder was a participant who had MBL volume of < 80 mL and at least a 50% reduction from baseline MBL volume over the last 35 days of treatment (up to Week 24). All returned feminine products collected at each clinical visit were analyzed by the alkaline hematin method to obtain the MBL volume. MBL volume was measured over the Week 24/early termination feminine product collection interval (up to 35 days prior to the last dose of treatment). The percentage of participants who were responders are presented.
    End point type
    Primary
    End point timeframe
    From Baseline up to last 35 days of treatment (up to Week 24)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified primary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    128 [2]
    127 [3]
    Units: percentage of participants
        number (confidence interval 95%)
    73.4 (64.91 to 80.85)
    18.9 (12.50 to 26.80)
    Notes
    [2] - Modified Intention-to-Treat Population
    [3] - Modified Intention-to-Treat Population
    Statistical analysis title
    		 Number of responders at Week 24
    Statistical analysis description
    The primary efficacy analysis was the comparison of the relugolix + E2/NETA group with the placebo group with respect to responder rate.
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    54.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 44.3
         upper limit
    		 64.78
    Notes
    [4] - Treatment difference is relugolix + E2/NETA minus placebo.
    [5] - P-value was stratified by baseline MBL volume (< 225 mL or ≥ 225 mL) and geographic region (North America or Rest of World). Assessed at a two-sided α = 0.05 significance level.

    Secondary: Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment

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    End point title
    		 Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment [6]
    End point description
    Amenorrhea was defined as meeting one of the following criteria for two consecutive visits: 1. No feminine product returned due to reported amenorrhea; 2. No feminine product returned due to reports of spotting/negligible bleeding coupled with eDiary data indicating infrequent non-cyclic bleeding/spotting; 3. Feminine product collection with a negligible observed MBL volume coupled with eDiary data indicating infrequent non-cyclic bleeding/spotting.
    End point type
    Secondary
    End point timeframe
    From Baseline up to last 35 days of treatment (up to Week 24)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    128 [7]
    127 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    52.34 (43.34 to 61.24)
    5.51 (2.24 to 11.03)
    Notes
    [7] - mITT Population
    [8] - mITT Population
    Statistical analysis title
    		 Achieved Amenorrhea with Relugolix+E2/NETA
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    46.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 37.31
         upper limit
    		 56.35
    Notes
    [9] - Treatment difference was Relugolix + E2/NETA minus Placebo. 95% CI for difference is based on the normal approximation.
    [10] - P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, >= 225 mL) and geographic region (North America or Rest of World). Assessed at a two-sided α = 0.05 significance level.

    Secondary: Percent Change From Baseline At Week 24 In MBL Volume

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    End point title
    		 Percent Change From Baseline At Week 24 In MBL Volume [11]
    End point description
    MBL volume was measured using the alkaline hematin method. Least square (LS) means for test of difference is Relugolix + E2/NETA minus Placebo based on mixed-effect model with treatment, visit, region, Baseline MBL and treatment by visit interaction included as fixed effects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    89
    95
    Units: percent change
        least squares mean (confidence interval 95%)
    -84.3 (-93.5 to -75.0)
    -23.2 (-32.2 to -14.1)
    Statistical analysis title
    		 MBL Volume Percent Change with Relugolix + E2/NETA
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -61.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -73.5
         upper limit
    		 -48.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.32
    Notes
    [12] - p-value for test of difference was Relugolix + E2/NETA minus placebo based on mixed-effect model with treatment, visit, region, Baseline MBL and treatment by visit interaction included as fixed effects. Assessed at a two-sided α = 0.05 significance.

    Secondary: Percentage Of Participants With A Hemoglobin Level ≤ 10.5 g/dL At Baseline Who Achieved An Increase Of > 2 g/dL From Baseline At Week 24

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    End point title
    		 Percentage Of Participants With A Hemoglobin Level ≤ 10.5 g/dL At Baseline Who Achieved An Increase Of > 2 g/dL From Baseline At Week 24 [13]
    End point description
    Blood samples were collected from participants for hemoglobin measurements .Percentages are based on number of participants with hemoglobin ≤ 10.5 gram (g)/deciliter (dL) at Baseline and reported at Week 24.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 24
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA with placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    30
    23
    Units: percentage of participants
        number (confidence interval 95%)
    50.0 (31.30 to 68.70)
    21.74 (7.46 to 43.70)
    Statistical analysis title
    		 Change in Hemoglobin with Relugolix+E2/NETA
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.0377 [15]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    28.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.68
         upper limit
    		 52.84
    Notes
    [14] - Treatment difference is Relugolix + E2/NETA minus Placebo. 95% CI for difference is based on the normal approximation.
    [15] - P-value is based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, >= 225 mL). Assessed at a two-sided α = 0.05 significance level.

    Secondary: Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment

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    End point title
    		 Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment [16]
    End point description
    Uterine fibroid-associated pain was assessed by a pain numerical rating scale (NRS). The pain NRS is a validated, single-item, self-reported measure, which asks respondents to rank their pain on an 11-point scale as follows: 0 (no pain), 1 to 3 (mild pain), 4 to 6 (moderate pain), and 7 to 10 (severe pain). Participants were asked to document, in an electronic diary, the worst pain associated with their uterine fibroids that they experienced during the last 24 hours, every day until the end of study drug administration. Pain evaluable participants, defined as those who had maximum NRS score >=4 at baseline and had at least 28 days (80% of the last 35 days of treatment) of pain scores recorded in the e-Diary, were analyzed.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 24
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    58
    69
    Units: Percentage of Participants
        number (confidence interval 95%)
    43.10 (30.16 to 56.77)
    10.14 (4.18 to 19.79)
    Statistical analysis title
    		 Pain Assessment with Relugolix+E2/NETA
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    32.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.36
         upper limit
    		 47.56
    Notes
    [17] - Treatment difference is Relugolix + E2/NETA minus Placebo. 95% CI for difference is based on the normal approximation.
    [18] - P-value is based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, >= 225 mL). Assessed at a two-sided α = 0.05 significance level.

    Secondary: Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume

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    End point title
    		 Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume [19]
    End point description
    The volume of the primary uterine fibroid was measured by transvaginal or transabdominal ultrasound. LS Means based on analysis of covariance model including treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, >= 225 mL) and geographic region (North America, Rest of World), and Baseline values as covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    94
    102
    Units: percent change
        least squares mean (confidence interval 95%)
    -12.4 (-23.5 to -1.4)
    -0.3 (-10.9 to 10.4)
    Statistical analysis title
    		 Uterine Fibroid Volume with Relugolix+E2/NETA
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0921 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.3
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.19
    Notes
    [20] - Based on analysis of covariance model with treatment, randomization stratification factors, Baseline MBL volume, geographic region (North America, Rest of World), and Baseline values as covariate. Assessed at a two-sided α = 0.05 significance level.

    Secondary: Percent Change From Baseline At Week 24 In Uterine Volume

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    End point title
    		 Percent Change From Baseline At Week 24 In Uterine Volume [21]
    End point description
    The volume of the uterus was measured by transvaginal or transabdominal ultrasound. LS means for test of difference is Relugolix + E2/NETA minus Placebo at Week 24 is based on analysis of covariance model including treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, >= 225 mL) and geographic region (North America, Rest of World), and Baseline values as covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    97
    102
    Units: percent change
        least squares mean (confidence interval 95%)
    -12.9 (-19.0 to -6.9)
    2.2 (-3.7 to 8.1)
    Statistical analysis title
    		 Uterine Volume with Relugolix+E2/NETA
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -15.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23
         upper limit
    		 -7.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.98
    Notes
    [22] - Based on analysis of covariance model with treatment, randomization stratification factors, Baseline MBL volume, geographic region (North America, Rest of World), and Baseline values as covariate. Assessed at a two-sided α = 0.05 significance level.

    Secondary: Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)

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    End point title
    		 Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5) [23]
    End point description
    The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) Bleeding and Pelvic Discomfort Scale has been derived from the UFS-QoL Symptoms Scale. The scale consists of the following three symptoms proximal to uterine fibroids: Heavy bleeding during your menstrual period (Question [Q] 1), passing blood clots during your menstrual period (Q2), and feeling tightness or pressure in your pelvic area (Q5). The lowest possible raw score is 3 and the highest possible raw score is 15. The possible raw score range is 12. The following formula was used to transform the raw score to a normalized score: Transformed Score = [(Actual raw score – lowest possible raw score)/(Possible raw score range)] * 100 Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Lower score indicates minimal symptom severity and higher score indicates maximum symptom severity.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    97
    103
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -45.0 (-50.7 to -39.3)
    -16.1 (-21.6 to -10.5)
    Statistical analysis title
    		 UFS-QoL BPD Score with Relugolix +E2/NETA
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Placebo (Group C)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.0001 [25]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -28.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.3
         upper limit
    		 -21.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.75
    Notes
    [24] - Treatment difference is Relugolix + E2/NETA minus Placebo based on mixed-effect model with treatment, visit, region, Baseline MBL and treatment by visit interaction included as fixed effects. The multiple visits for each participant were the repeated measures as random effect within each participant and an unstructured covariance.
    [25] - Assessed at a two-sided α = 0.05 significance level.

    Other pre-specified: Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 - L4), As Assessed By DXA

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    End point title
    		 Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 - L4), As Assessed By DXA [26]
    End point description
    Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA) at the lumbar spine (L1, L2, L3, and L4) at Baseline and at Week 12. The scans were read by the central radiology laboratory in accordance with the imaging charter. The same DXA machine was used at the local imaging center at each site and operated in the same scan mode for all images procured for an individual participant. All images were submitted for central reading. The central radiology laboratory collected and evaluated all DXA scans for acceptability and measured BMD. The LS means were based on a mixed-effect model with visit, region, Baseline menstrual blood loss volume, age at Baseline, body mass index at Baseline, bone mineral density at Baseline, race, and treatment by visit interaction included as fixed effects.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary analyses compared relugolix plus E2/NETA with relugolix plus delayed E2/NETA at Week 12. Therefore, only the relugolix plus E2/NETA and relugolix plus delayed E2/NETA arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Relugolix plus Delayed E2/NETA (Group B)
    Number of subjects analysed
    101
    103
    Units: percent change
    least squares mean (standard error)
        Lumbar Spine (L1-L4): Week 12
    -0.470 ( 0.2915 )
    -1.995 ( 0.2848 )
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 - L4), Total Hip, And Femoral Neck

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    End point title
    		 Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 - L4), Total Hip, And Femoral Neck [27]
    End point description
    BMD was assessed by DXA at the lumbar spine (L1, L2, L3, and L4), total hip, and femoral neck at Baseline and at Week 24. The scans were read by the central radiology laboratory in accordance with the imaging charter. The same DXA machine was used at the local imaging center at each site and operated in the same scan mode for all images procured for an individual participant. All images were submitted for central reading. The central radiology laboratory collected and evaluated all DXA scans for acceptability and measured BMD. The LS means were based on a mixed-effect model with visit, region, Baseline menstrual blood loss volume, age at Baseline, body mass index at Baseline, bone mineral density at Baseline, race, and treatment by visit interaction included as fixed effects.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 24
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    101
    103
    Units: percent change
    least squares mean (standard error)
        Lumbar Spine (L1-L4)
    -0.356 ( 0.2929 )
    0.052 ( 0.2896 )
        Total Hip
    0.023 ( 0.2461 )
    0.549 ( 0.2407 )
        Femoral Neck
    -0.262 ( 0.4466 )
    0.307 ( 0.4395 )
    No statistical analyses for this end point

    Other pre-specified: Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12

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    End point title
    		 Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12 [28]
    End point description
    An adverse event was defined as an unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The preferred terms of hyperhidrosis, feeling hot, hot flush, night sweats, and flushing were combined to describe vasomotor symptoms. Participants with multiple events for a given preferred term were counted only once for each preferred term. Reported CI based on exact binomial 95% CI (Clopper-Pearson).
    End point type
    Other pre-specified
    End point timeframe
    Baseline through Week 12
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the secondary analysis compared relugolix plus E2/NETA with relugolix plus delayed E2/NETA at Week 12. Therefore, only the relugolix plus E2/NETA and relugolix plus delayed E2/NETA arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Relugolix plus Delayed E2/NETA (Group B)
    Number of subjects analysed
    128
    129
    Units: percentage of participants
        number (confidence interval 95%)
    10.94 (6.11 to 17.67)
    36.36 (28.17 to 45.18)
    Statistical analysis title
    		 Vasomotor Symptoms Through Week 12
    Comparison groups
    Relugolix plus E2/NETA (Group A) v Relugolix plus Delayed E2/NETA (Group B)
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.52
    Notes
    [29] - Relative risk ratio is relugolix plus E2/NETA over relugolix plus delayed E2/NETA.

    Other pre-specified: Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24

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    End point title
    		 Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24 [30]
    End point description
    An adverse event was defined as an unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The preferred terms of hyperhidrosis, feeling hot, hot flush, night sweats, and flushing were combined to describe vasomotor symptoms. Participants with multiple events for a given preferred term were counted only once for each preferred term. Reported percentages based on the total number of patients in each treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Baseline through Week 24
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, the pre-specified secondary analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A) Placebo (Group C)
    Number of subjects analysed
    128
    127
    Units: percentage of participants
        number (not applicable)
    14.8
    9.4
    No statistical analyses for this end point

    Other pre-specified: Predose Trough Concentrations Of Relugolix And Norethindrone In The Relugolix Plus E2/NETA Group At Week 24

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    End point title
    		 Predose Trough Concentrations Of Relugolix And Norethindrone In The Relugolix Plus E2/NETA Group At Week 24 [31]
    End point description
    Blood samples for determination of relugolix and Norethindrone (NET) plasma concentrations were collected predose at Week 24. On clinic visit days, participants were instructed to hold their dose of study drug until blood samples for determination of plasma drug concentrations were collected at the clinic and to record the time of their previous dose (that is, the time they took their dose on the day before the clinic visit). Relugolix and NET plasma concentrations were determined using validated bioanalytical methodology. The lower limit of quantification for relugolix and NET plasma concentrations were both 0.05 nanograms/milliliter (ng/mL). Concentrations below the quantification limit (BQL) were set to 0 for analysis of summary statistics.
    End point type
    Other pre-specified
    End point timeframe
    Week 24
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, only relugolix plus E2/NETA concentrations are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A)
    Number of subjects analysed
    92
    Units: ng/mL
    arithmetic mean (standard deviation)
        Relugolix (n=92)
    2.13 ( 2.144 )
        NET (n=91)
    0.33 ( 0.369 )
    No statistical analyses for this end point

    Other pre-specified: Predose Trough Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group At Week 24

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    End point title
    		 Predose Trough Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group At Week 24 [32]
    End point description
    Blood samples for determination of estradiol serum concentrations were collected predose at Baseline and Week 24. On clinic visit days, participants were instructed to hold their dose of study drug until blood samples for determination of serum concentrations were collected at the clinic and to record the time of their previous dose (that is, the time they took their dose on the day before the clinic visit). Summary data for estradiol trough serum concentrations are descriptive only and values were not baseline-adjusted, which is an approach that has been employed for assessment of endogenously- produced substances upon exogenous administration. Estradiol serum concentrations were determined using validated bioanalytical methodology. The lower limit of quantification for estradiol serum concentration was 2.5 picograms (pg)/mL. Concentrations BQL were set to 0 for analysis of summary statistics.
    End point type
    Other pre-specified
    End point timeframe
    Week 24
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, only relugolix plus E2/NETA concentrations are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A)
    Number of subjects analysed
    91
    Units: pg/mL
        arithmetic mean (standard deviation)
    48.34 ( 59.660 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group

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    End point title
    		 Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group [33]
    End point description
    Blood samples for determination of estradiol concentrations were collected predose at Baseline and at Weeks 4, 12, and 24 and were analyzed at a central laboratory using a standard, validated clinical methodology. For pharmacokinetic analysis of estradiol, a separate pharmacokinetic sample was obtained to be analyzed at the bioanalytical laboratory. The lower limit of quantification for estradiol was 19 pg/mL. Concentrations BQL were set to 0 for analysis of summary statistics. Data reported as pg/mL.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 24
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per the objective of the study, only relugolix plus E2/NETA concentrations were are presented.
    End point values
    		 Relugolix plus E2/NETA (Group A)
    Number of subjects analysed
    91
    Units: pg/mL
        arithmetic mean (standard deviation)
    -22.95 ( 84.005 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to End of Study (24 Weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Relugolix plus E2/NETA (Group A)
    Reporting group description
    		 Relugolix co-administered with E2/NETA for 24 weeks.

    Reporting group title
    Relugolix plus Delayed E2/NETA (Group B)
    Reporting group description
    		 Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks.

    Reporting group title
    Placebo (Group C)
    Reporting group description
    		 Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.

    Serious adverse events
    		 Relugolix plus E2/NETA (Group A) Relugolix plus Delayed E2/NETA (Group B) Placebo (Group C)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 128 (5.47%)
    3 / 132 (2.27%)
    2 / 127 (1.57%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine myoma expulsion
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Avulsion fracture
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 132 (0.76%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vitreous detachment
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 132 (0.76%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    0 / 128 (0.00%)
    0 / 132 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 132 (0.76%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 128 (0.00%)
    0 / 132 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Relugolix plus E2/NETA (Group A) Relugolix plus Delayed E2/NETA (Group B) Placebo (Group C)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 128 (60.16%)
    95 / 132 (71.97%)
    84 / 127 (66.14%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    14 / 128 (10.94%)
    47 / 132 (35.61%)
    10 / 127 (7.87%)
         occurrences all number
    14
    48
    10
    Hypertension
         subjects affected / exposed
    7 / 128 (5.47%)
    3 / 132 (2.27%)
    0 / 127 (0.00%)
         occurrences all number
    8
    5
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 128 (10.94%)
    14 / 132 (10.61%)
    19 / 127 (14.96%)
         occurrences all number
    15
    18
    20
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 132 (0.00%)
    7 / 127 (5.51%)
         occurrences all number
    1
    0
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 128 (3.13%)
    7 / 132 (5.30%)
    4 / 127 (3.15%)
         occurrences all number
    6
    8
    5
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 128 (0.78%)
    7 / 132 (5.30%)
    3 / 127 (2.36%)
         occurrences all number
    1
    7
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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