Clincosm LogoSign in Get a demo

TRAFFIC: A Study of Lumacaftor in Combination With Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older Who Are Homozygous for the F508del-CFTR Mutation

Sponsor
Vertex Pharmaceuticals Incorporated (Industry)
Overall Status
Completed
CT.gov ID
NCT01807923
Collaborator
(none)
559
Enrollment
90
Locations
3
Arms
11
Duration (Months)
6.2
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of the study was to evaluate the efficacy of lumacaftor in combination with ivacaftor at Week 24 in participants aged 12 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.

Condition or Disease Intervention/Treatment Phase
  • Drug: Lumacaftor Plus Ivacaftor Combination
  • Drug: Ivacaftor
  • Drug: Placebo
 Phase 3

Detailed Description

This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group multicenter study of orally administered lumacaftor in combination with ivacaftor in participants aged 12 years and older with CF who are homozygous for the F508del-CFTR mutation.

The study included a Screening Period (Day -28 through Day -1), a Treatment Period (Day 1 [first dose of study drug] to Week 24 ± 5 days), and a Safety Follow-up Visit (4 weeks ± 7 days after the Week 24 Visit).

Study Design

Study Type:
Interventional
Actual Enrollment :
559 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del CFTR Mutation
Study Start Date :
May 1, 2013
Actual Primary Completion Date :
Apr 1, 2014
Actual Study Completion Date :
Apr 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo

Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.

Drug: Placebo
Matching placebo tablet
Experimental: LUM 600 mg qd/IVA 250 mg q12h

LUM 600 milligram (mg) plus IVA 250 mg fixed-dose combination (FDC) tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

Drug: Lumacaftor Plus Ivacaftor Combination
Fixed dose combination tablet
Other Names:
  • VX-809+VX-770, LUM+IVA

    • Drug: Ivacaftor
    Film-coated tablet
    Other Names:
  • VX-770, IVA

    		•
    Experimental: LUM 400 mg q12h/ IVA 250 mg q12h

    LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.

    Drug: Lumacaftor Plus Ivacaftor Combination
    Fixed dose combination tablet
    Other Names:
  • VX-809+VX-770, LUM+IVA

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24 [Baseline, Week 16 and 24]

      Absolute change from baseline at Week 24 was assessed as the average treatment effect at Week 16 and at Week 24. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.

    Secondary Outcome Measures

    1. Relative Change From Baseline in Percent Predicted FEV1 at Week 24 [Baseline, Week 16 and 24]

      Assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in Outcome Measure (OM) 1.

    2. Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 [Baseline, Week 24]

      BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).

    3. Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 [Baseline, Week 24]

      The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

    4. Percentage of Participants With Response Based on Percent Predicted FEV1 [Week 16 and 24]

      A participant was considered as a responder if the participant had >=5% increase from baseline in average percent predicted FEV1 at Week 16 and at Week 24 (relative change). FEV1 and percent predicted FEV1 are defined in OM 1. A participant with a missing average relative change from baseline in percent predicted FEV1 at Week 16 and at Week 24 was considered as a non-responder.

    5. Number of Pulmonary Exacerbation Events [through Week 24]

      The total number of days on study is equal to the Week 24 date or the last dose date (whichever occurred last) minus the first dose date plus 1. The total number of years (48 weeks) on study is equal to the number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.

    6. Absolute Change From Baseline in Weight at Week 24 [Baseline, Week 24]

    7. Absolute Change From Baseline in BMI-for-age Z-score at Week 24 [Baseline, Week 24]

      Z-Score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to + infinity; 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI-for-age z-score was calculated by using Centers for Disease Control and Prevention (CDC) growth charts for the pediatric population.

    8. Time-to-First Pulmonary Exacerbation [through Week 24]

      Time to first pulmonary exacerbation was assessed using Cox Regression. For participants who completed 24 weeks of treatment, participants without a pulmonary exacerbation before treatment completion were considered censored at the time of treatment completion or at the Week 24 Visit (whichever occurred last). For participants who prematurely discontinued study treatment, participants without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit.

    9. Percentage of Participants With At Least 1 Pulmonary Exacerbation Event [through Week 24]

    10. Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24 [Baseline, Week 24]

      EQ-5D-3L: participant rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). The 5 dimensional 3-level systems are converted into a single index utility score. Values for theoretically possible health states are calculated using a regression model and weighted according to the social preferences of the Unites States (US) general population. For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state.

    11. Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24 [Baseline, Week 24]

      The EQ-5D-3L VAS records the participant's self-rated health on a vertical, visual analogue scale where the best state a participant can imagine is marked 100 and the worst state a participant can imagine is marked 0, higher scores indicates a better health state.

    12. Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 [Baseline, Week 24]

      The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction.

    13. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Treatment-Emergent Adverse Events (SAEs) [up to Week 28]

      AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Nonserious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or that was newly developed at or after the initial dosing of study drug to 28 days after the last dose of study drug is considered treatment-emergent.

    14. Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) [For C3-6h: 3 to 6 hours after morning dose on Day 1 and 15, Week 4 and 8; For C3-6h,avg 3 to 6 hours after morning dose on Day 15, Week 4 and 8; For Ctrough and Ctrough,avg: before morning dose on Week 4, 8, and 16]

      Ctrough, Ctrough, avg, C3-6h, and C3-6h, avg for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. C3-6h,ave is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough, ave is average of individual pre-dose observed concentrations across Weeks 4, 8, and 16. This outcome was not planned to be assessed in Placebo arm.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Confirmed diagnosis of CF

    • Homozygous for the F508del CFTR mutation

    • Forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) and less than or equal to (=<) 90% of predicted normal for age, sex, and height

    • Willing to remain on a stable CF medication regimen through Week 24 or, if applicable, the Safety Follow up Visit

    Exclusion Criteria:

    • An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before first dose of study drug

    • History of solid organ or hematological transplantation

    • History of alcohol or drug abuse in the past year

    • Ongoing or prior participation in an investigational drug study (including studies investigating lumacaftor and/or ivacaftor) within 30 days of screening

    • Use of strong inhibitors, moderate inducers or strong inducers of Cytochrome P450 3A (CYP3A) within 14 days before Day 1 of dosing

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Birmingham Alabama United States
    2 Anchorage Alaska United States
    3 Tucson Arizona United States
    4 Little Rock Arkansas United States
    5 Fresno California United States
    6 La Jolla California United States
    7 Loma Linda California United States
    8 Long Beach California United States
    9 Los Angeles California United States
    10 Madera California United States
    11 Oakland California United States
    12 Palo Alto California United States
    13 Denver Colorado United States
    14 Gainsville Florida United States
    15 Hollywood Florida United States
    16 Orlando Florida United States
    17 Tampa Florida United States
    18 Atlanta Georgia United States
    19 Boise Idaho United States
    20 Chicago Illinois United States
    21 Park Ridge Illinois United States
    22 Peoria Illinois United States
    23 Baltimore Maryland United States
    24 Boston Massachusetts United States
    25 Ann Arbor Michigan United States
    26 Kansas City Missouri United States
    27 Bedford New Hampshire United States
    28 Lebanon New Hampshire United States
    29 Long Branch New Jersey United States
    30 Hawthorne New York United States
    31 New York New York United States
    32 Valhalla New York United States
    33 Chapel Hill North Carolina United States
    34 Durham North Carolina United States
    35 Akron Ohio United States
    36 Cincinnati Ohio United States
    37 Dayton Ohio United States
    38 Portland Oregon United States
    39 Hershey Pennsylvania United States
    40 Knoxville Tennessee United States
    41 Austin Texas United States
    42 Tyler Texas United States
    43 Colchester Vermont United States
    44 Charlottesville Virginia United States
    45 Norfolk Virginia United States
    46 Seattle Washington United States
    47 Morgantown West Virginia United States
    48 Madison Wisconsin United States
    49 Broadmeadow New South Wales Australia
    50 Westmead New South Wales Australia
    51 Adelaide South Australia Australia
    52 Halifax British Columbia Canada
    53 Vancouver British Columbia Canada
    54 Ottawa Ontario Canada
    55 Toronto Ontario Canada
    56 Brno Czech Republic
    57 Plzen-Bory Czech Republic
    58 Praha 5 Czech Republic
    59 Strasbourg Cedex 2 Bas Rhin France
    60 Roscoff Finistere France
    61 Paris Cedex 14 Paris France
    62 Paris Cedex 15 Paris France
    63 Bron Cedex Rhone France
    64 Pierre Benite Rhone France
    65 Tuebingen Baden Wuerttemberg Germany
    66 Erlangen Bayern Germany
    67 Wuerzburg Bayern Germany
    68 Koeln Nordrhein Westfalen Germany
    69 Leipzig Sachsen Germany
    70 Berlin Germany
    71 Tallaght Dublin Ireland
    72 Dublin Ireland
    73 Ancona Italy
    74 Firenze Italy
    75 Genova Italy
    76 Milano Italy
    77 Roma Italy
    78 Verona Italy
    79 Amsterdam Netherlands
    80 Den Haag Netherlands
    81 Nijmegen Netherlands
    82 Rotterdam Netherlands
    83 Goteborg Sweden
    84 Stockholm Sweden
    85 Uppsala Sweden
    86 Exeter Devon United Kingdom
    87 Southhampton Hampshire United Kingdom
    88 Nottingham Nottinghamshire United Kingdom
    89 Birmingham West Midlands United Kingdom
    90 Belfast United Kingdom

    Sponsors and Collaborators

    • Vertex Pharmaceuticals Incorporated

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Vertex Pharmaceuticals Incorporated
    ClinicalTrials.gov Identifier:
    NCT01807923
    Other Study ID Numbers:
    • VX12-809-103
    First Posted:
    Mar 8, 2013
    Last Update Posted:
    Aug 31, 2015
    Last Verified:
    Jun 1, 2015
    Additional relevant MeSH terms:
    Cystic Fibrosis
    Fibrosis
    Ivacaftor

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24. LUM 600 milligram (mg) plus IVA 250 mg fixed-dose combination (FDC) tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Period Title: Overall Study
    STARTED 187 185 187
    COMPLETED 182 179 176
    NOT COMPLETED 5 6 11

    Baseline Characteristics

    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h Total
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24. Total of all reporting groups
    Overall Participants 184 183 182 549
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    25.0
    (10.80)
    24.7
    (9.71)
    25.5
    (10.09)
    25.1
    (10.20)
    Sex: Female, Male (Count of Participants)
    Female
    84
    45.7%
    86
    47%
    84
    46.2%
    254
    46.3%
    Male
    100
    54.3%
    97
    53%
    98
    53.8%
    295
    53.7%

    Outcome Measures

    1. Primary Outcome
    Title Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24
    Description Absolute change from baseline at Week 24 was assessed as the average treatment effect at Week 16 and at Week 24. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
    Time Frame Baseline, Week 16 and 24

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) included all randomized participants who received any amount of study drug. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 180 176 172
    Least Squares Mean (Standard Error) [percent predicted of FEV1]
    -0.44
    (0.524)
    3.59
    (0.525)
    2.16
    (0.530)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using mixed-effects model for repeated measures (MMRM) model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (less than (<)18 versus greater than equal to (>=18) years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter Least Squares (LS) Mean Difference
    Estimated Value 4.03
    Confidence Interval (2-Sided) 95%
    2.62 to 5.44
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0003
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 2.60
    Confidence Interval (2-Sided) 95%
    1.18 to 4.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Relative Change From Baseline in Percent Predicted FEV1 at Week 24
    Description Assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in Outcome Measure (OM) 1.
    Time Frame Baseline, Week 16 and 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 180 176 172
    Least Squares Mean (Standard Error) [percent change]
    -0.34
    (0.913)
    6.39
    (0.914)
    3.99
    (0.923)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 6.73
    Confidence Interval (2-Sided) 95%
    4.27 to 9.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0006
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 4.33
    Confidence Interval (2-Sided) 95%
    1.86 to 6.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Absolute Change From Baseline in Body Mass Index (BMI) at Week 24
    Description BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 178 176
    Least Squares Mean (Standard Error) [kilogram per square meter (kg/m^2)]
    0.19
    (0.070)
    0.35
    (0.070)
    0.32
    (0.071)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline BMI.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1122
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.16
    Confidence Interval (2-Sided) 95%
    -0.04 to 0.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1938
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.13
    Confidence Interval (2-Sided) 95%
    -0.07 to 0.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24
    Description The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 176 172
    Least Squares Mean (Standard Error) [units on a scale]
    1.10
    (1.161)
    4.98
    (1.178)
    2.60
    (1.192)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline CFQ-R respiratory domain score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0168
    Comments This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 3.88
    Confidence Interval (2-Sided) 95%
    0.70 to 7.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed using MMRM model, as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3569
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 1.50
    Confidence Interval (2-Sided) 95%
    -1.69 to 4.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Percentage of Participants With Response Based on Percent Predicted FEV1
    Description A participant was considered as a responder if the participant had >=5% increase from baseline in average percent predicted FEV1 at Week 16 and at Week 24 (relative change). FEV1 and percent predicted FEV1 are defined in OM 1. A participant with a missing average relative change from baseline in percent predicted FEV1 at Week 16 and at Week 24 was considered as a non-responder.
    Time Frame Week 16 and 24

    Outcome Measure Data

    Analysis Population Description
    FAS.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 183 182
    Number [percentage of participants]
    22.3
    12.1%
    46.4
    25.4%
    36.8
    20.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Odds Ratio (OR) and 95% confidence intervals (Cis) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.9378
    Confidence Interval (2-Sided) 95%
    1.8786 to 4.5941
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0023
    Comments This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.0592
    Confidence Interval (2-Sided) 95%
    1.2920 to 3.2819
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Number of Pulmonary Exacerbation Events
    Description The total number of days on study is equal to the Week 24 date or the last dose date (whichever occurred last) minus the first dose date plus 1. The total number of years (48 weeks) on study is equal to the number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.
    Time Frame through Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 183 182
    Number [pulmonary exacerbation events per year]
    1.07
    0.77
    0.71
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using regression analysis for a negative binomial distribution with sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70) as covariates with the logarithm of time on study as the offset.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0491
    Comments
    Method Negative Binomial Regression
    Comments
    Method of Estimation Estimation Parameter Event Rate Ratio
    Estimated Value 0.7186
    Confidence Interval (2-Sided) 95%
    0.5170 to 0.9987
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0169
    Comments This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
    Method Negative Binomial Regression
    Comments
    Method of Estimation Estimation Parameter Event Rate Ratio
    Estimated Value 0.6643
    Confidence Interval (2-Sided) 95%
    0.4749 to 0.9291
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Absolute Change From Baseline in Weight at Week 24
    Description
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 178 176
    Least Squares Mean (Standard Error) [kilograms (kg)]
    0.93
    (0.202)
    1.34
    (0.205)
    1.23
    (0.205)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline weight.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1565
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.40
    Confidence Interval (2-Sided) 95%
    -0.16 to 0.96
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2992
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.30
    Confidence Interval (2-Sided) 95%
    -0.26 to 0.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Absolute Change From Baseline in BMI-for-age Z-score at Week 24
    Description Z-Score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to + infinity; 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI-for-age z-score was calculated by using Centers for Disease Control and Prevention (CDC) growth charts for the pediatric population.
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Only participants who were <20 years of age were analyzed.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 69 65 58
    Least Squares Mean (Standard Error) [z-score]
    0.0153
    (0.04886)
    0.1132
    (0.05081)
    0.0933
    (0.05431)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline BMI z-score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1539
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.0980
    Confidence Interval (2-Sided) 95%
    -0.0370 to 0.2330
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2713
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.0781
    Confidence Interval (2-Sided) 95%
    -0.0615 to 0.2176
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Time-to-First Pulmonary Exacerbation
    Description Time to first pulmonary exacerbation was assessed using Cox Regression. For participants who completed 24 weeks of treatment, participants without a pulmonary exacerbation before treatment completion were considered censored at the time of treatment completion or at the Week 24 Visit (whichever occurred last). For participants who prematurely discontinued study treatment, participants without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit.
    Time Frame through Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 183 182
    Median (Full Range) [days]
    NA
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using Cox proportional hazard regression, time is the time-to-first event or censoring, with adjustment for sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0396
    Comments
    Method Cox Proportional Hazard Regression
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.692
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0385
    Comments
    Method Cox Proportional Hazard Regression
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.691
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Percentage of Participants With At Least 1 Pulmonary Exacerbation Event
    Description
    Time Frame through Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 183 182
    Number [percentage of participants]
    39.7
    21.6%
    30.1
    16.4%
    30.2
    16.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments OR and 95% confidence intervals (CIs) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0552
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.6565
    Confidence Interval (2-Sided) 95%
    0.4266 to 1.0103
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0512
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.6438
    Confidence Interval (2-Sided) 95%
    0.4142 to 1.0005
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24
    Description EQ-5D-3L: participant rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). The 5 dimensional 3-level systems are converted into a single index utility score. Values for theoretically possible health states are calculated using a regression model and weighted according to the social preferences of the Unites States (US) general population. For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state.
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 179 175 170
    Least Squares Mean (Standard Error) [units on a scale]
    0.0006
    (0.00739)
    0.0066
    (0.00746)
    0.0100
    (0.00757)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline EQ-5D-3L index score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5604
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.0060
    Confidence Interval (2-Sided) 95%
    -0.0142 to 0.0262
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3613
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.0095
    Confidence Interval (2-Sided) 95%
    -0.0109 to 0.0298
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24
    Description The EQ-5D-3L VAS records the participant's self-rated health on a vertical, visual analogue scale where the best state a participant can imagine is marked 100 and the worst state a participant can imagine is marked 0, higher scores indicates a better health state.
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 180 173 171
    Least Squares Mean (Standard Error) [units on a scale]
    1.4
    (1.03)
    3.5
    (1.04)
    2.8
    (1.04)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline EQ-5D-3L VAS score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1342
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 2.1
    Confidence Interval (2-Sided) 95%
    -0.7 to 4.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3071
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 1.4
    Confidence Interval (2-Sided) 95%
    -1.3 to 4.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Secondary Outcome
    Title Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24
    Description The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction.
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    FAS. Here, "n" signifies participants who were evaluable for specified category for each arm, respectively.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 183 182
    Effectiveness (n = 163, 156, 144)
    -5.30
    (1.643)
    0.19
    (1.666)
    0.50
    (1.726)
    Side Effects (n = 162, 154, 143)
    2.23
    (1.119)
    -1.94
    (1.141)
    -2.51
    (1.179)
    Convenience (n = 163, 154, 144)
    4.37
    (1.504)
    4.98
    (1.540)
    7.45
    (1.579)
    Global Satisfaction (n= 163, 154, 144)
    -10.49
    (1.863)
    -5.00
    (1.906)
    -3.77
    (1.956)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Effectiveness: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM effectiveness score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0160
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 5.49
    Confidence Interval (2-Sided) 95%
    1.03 to 9.96
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Effectiveness: analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0126
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 5.80
    Confidence Interval (2-Sided) 95%
    1.25 to 10.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Side Effects: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM side effects score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0074
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -4.18
    Confidence Interval (2-Sided) 95%
    -7.23 to -1.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Side Effects: analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0029
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -4.74
    Confidence Interval (2-Sided) 95%
    -7.85 to -1.63
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Convenience: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM convenience score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.7721
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.61
    Confidence Interval (2-Sided) 95%
    -3.50 to 4.71
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Convenience: analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1472
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 3.08
    Confidence Interval (2-Sided) 95%
    -1.09 to 7.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 600 mg qd/IVA 250 mg q12h
    Comments Global Satisfaction: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM global satisfaction score.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0345
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 5.49
    Confidence Interval (2-Sided) 95%
    0.40 to 10.58
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
    Comments Global Satisfaction: analysis was performed as described in Statistical Analysis 1.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0109
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 6.72
    Confidence Interval (2-Sided) 95%
    1.55 to 11.89
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Treatment-Emergent Adverse Events (SAEs)
    Description AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Nonserious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or that was newly developed at or after the initial dosing of study drug to 28 days after the last dose of study drug is considered treatment-emergent.
    Time Frame up to Week 28

    Outcome Measure Data

    Analysis Population Description
    Safety Set (SS) included all randomized participants who received any amount of study drug.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 184 183 182
    Participants With Treatment-Emergent AEs
    174
    94.6%
    175
    95.6%
    174
    95.6%
    Participants With Treatment-Emergent SAEs
    49
    26.6%
    33
    18%
    33
    18.1%
    15. Secondary Outcome
    Title Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg)
    Description Ctrough, Ctrough, avg, C3-6h, and C3-6h, avg for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. C3-6h,ave is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough, ave is average of individual pre-dose observed concentrations across Weeks 4, 8, and 16. This outcome was not planned to be assessed in Placebo arm.
    Time Frame For C3-6h: 3 to 6 hours after morning dose on Day 1 and 15, Week 4 and 8; For C3-6h,avg 3 to 6 hours after morning dose on Day 15, Week 4 and 8; For Ctrough and Ctrough,avg: before morning dose on Week 4, 8, and 16

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) population included all randomized participants who received at least one dose of study drug and had a PK assessment. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and "n" signifies participants evaluable for specified category for each arm, respectively.
    Arm/Group Title LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    Measure Participants 180 181
    LUM, Day 1: C3-6h (n = 180, 175)
    27.5
    (12.5)
    18.4
    (8.55)
    LUM, Day 15: Ctrough (n = 172, 175)
    7.56
    (5.33)
    14.1
    (6.99)
    LUM, Day 15: C3-6 (n = 167, 171)
    26.1
    (11.5)
    23.6
    (8.54)
    LUM, Week 4: Ctrough (n = 172, 178)
    7.75
    (5.05)
    13.4
    (6.70)
    LUM, Week 4: C3-6 (n = 170, 171)
    28.4
    (11.2)
    24.2
    (8.66)
    LUM, Week 8: Ctrough (n = 173, 174)
    7.43
    (5.60)
    13.4
    (6.68)
    LUM, Week 8: C3-6 (n = 165, 171)
    28.2
    (11.2)
    24.4
    (8.80)
    LUM, Week 16: Ctrough (n = 165, 164)
    6.95
    (4.99)
    13.5
    (7.49)
    M-28 LUM, Day 1: C3-6h (n = 180, 175)
    0.220
    (0.107)
    0.179
    (0.0811)
    M-28 LUM, Day 15: Ctrough (n = 172, 175)
    1.25
    (0.614)
    1.48
    (0.590)
    M-28 LUM, Day 15: C3-6 (n = 167, 171)
    1.37
    (0.606)
    1.49
    (0.576)
    M-28 LUM, Week 4: Ctrough (n = 172, 178)
    1.31
    (0.646)
    1.48
    (0.642)
    M-28 LUM, Week 4: C3-6 (n = 170, 171)
    1.39
    (0.635)
    1.49
    (0.615)
    M-28 LUM, Week 8: Ctrough (n = 173, 174)
    1.32
    (0.684)
    1.53
    (0.674)
    M-28 LUM, Week 8: C3-6 (n = 165, 171)
    1.42
    (0.658)
    1.56
    (0.669)
    M-28 LUM, Week 16: Ctrough (n = 165, 164)
    1.30
    (0.769)
    1.57
    (0.757)
    IVA, Day 1: C3-6h (n = 180, 175)
    1.29
    (0.624)
    1.24
    (0.630)
    IVA, Day 15: Ctrough (n = 172, 176)
    0.151
    (0.123)
    0.115
    (0.123)
    IVA, Day 15: C3-6 (n = 167, 171)
    0.557
    (0.311)
    0.413
    (0.199)
    IVA, Week 4: Ctrough (n = 172, 178)
    0.142
    (0.107)
    0.105
    (0.083)
    IVA, Week 4: C3-6 (n = 170, 171)
    0.638
    (0.325)
    0.456
    (0.235)
    IVA, Week 8: Ctrough (n = 173, 174)
    0.130
    (0.101)
    0.0894
    (0.0726)
    IVA, Week 8: C3-6 (n = 165, 171)
    0.648
    (0.364)
    0.470
    (0.295)
    IVA, Week 16: Ctrough (n = 165, 164)
    0.133
    (0.131)
    0.0834
    (0.0622)
    M-1 IVA, Day 1: C3-6h (n = 180, 175)
    2.46
    (1.29)
    2.41
    (1.35)
    M-1 IVA, Day 15: Ctrough (n = 172, 176)
    0.665
    (0.578)
    0.511
    (0.530)
    M-1 IVA, Day 15: C3-6 (n = 167, 171)
    1.94
    (0.981)
    1.71
    (0.867)
    M-1 IVA, Week 4: Ctrough (n = 172, 178)
    0.628
    (0.492)
    0.450
    (0.345)
    M-1 IVA, Week 4: C3-6 (n = 170, 171)
    2.21
    (1.01)
    1.76
    (0.932)
    M-1 IVA, Week 8: Ctrough (n = 173, 174)
    0.584
    (0.451)
    0.404
    (0.381)
    M-1 IVA, Week 8: C3-6 (n = 165, 171)
    2.17
    (1.06)
    1.78
    (0.975)
    M-1 IVA, Week 16: Ctrough (n = 165, 164)
    0.589
    (0.519)
    0.396
    (0.319)
    M-6 IVA, Day 1: C3-6h (n = 180, 175)
    0.976
    (0.877)
    0.927
    (0.875)
    M-6 IVA, Day 15: Ctrough (n = 172, 176)
    1.68
    (1.31)
    1.67
    (1.40)
    M-6 IVA, Day 15: C3-6 (n = 167, 171)
    3.03
    (1.96)
    2.87
    (1.81)
    M-6 IVA, Week 4: Ctrough (n = 172, 178)
    1.66
    (1.36)
    1.46
    (0.938)
    M-6 IVA, Week 4: C3-6 (n = 170, 171)
    3.07
    (1.92)
    2.49
    (1.53)
    M-6 IVA, Week 8: Ctrough (n = 173, 174)
    1.52
    (1.12)
    1.31
    (0.946)
    M-6 IVA, Week 8: C3-6 (n = 165, 171)
    2.96
    (1.86)
    2.36
    (1.57)
    M-6 IVA, Week 16: Ctrough (n = 165, 164)
    1.40
    (1.11)
    1.33
    (1.02)
    LUM: Ctrough,ave (n = 179, 181)
    7.49
    (3.93)
    13.5
    (5.52)
    LUM: C3-6h,ave (n = 179, 181)
    27.7
    (8.63)
    24.0
    (7.29)
    M-28 LUM: Ctrough,ave (n = 179, 181)
    1.31
    (0.628)
    1.51
    (0.614)
    M-28 LUM: C3-6h,ave (n = 179, 181)
    1.39
    (0.596)
    1.51
    (0.585)
    IVA: Ctrough,ave (n = 179, 181)
    0.137
    (0.0773)
    0.0989
    (0.0644)
    IVA: C3-6h,ave (n = 179, 181)
    0.614
    (0.271)
    0.445
    (0.193)
    M1-IVA: Ctrough,ave (n = 179, 181)
    0.606
    (0.350)
    0.441
    (0.293)
    M1-IVA: C3-6h,ave (n = 179, 181)
    2.11
    (0.817)
    1.74
    (0.726)
    M6-IVA: Ctrough,ave (n = 179, 181)
    1.57
    (0.992)
    1.44
    (0.861)
    M6-IVA: C3-6h,ave (n = 179, 181)
    3.04
    (1.55)
    2.57
    (1.34)

    Adverse Events

    Time Frame Up to Week 28
    Adverse Event Reporting Description Participants were analyzed as per actual treatment received. Other adverse events includes only non-serious AEs.
    Arm/Group Title Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Arm/Group Description Placebo matched to LUM and IVA tablet q12h, up to Week 24. LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
    All Cause Mortality
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 49/184 (26.6%) 33/183 (18%) 33/182 (18.1%)
    Cardiac disorders
    Pericarditis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome 2/184 (1.1%) 2/183 (1.1%) 2/182 (1.1%)
    Constipation 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Abdominal adhesions 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Dysphagia 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Inguinal hernia 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Lower gastrointestinal haemorrhage 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Small intestinal obstruction 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Vomiting 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    General disorders
    Implant site thrombosis 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Device dislocation 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Hepatobiliary disorders
    Hepatitis cholestatic 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Immune system disorders
    Drug hypersensitivity 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis 41/184 (22.3%) 19/183 (10.4%) 17/182 (9.3%)
    Influenza 1/184 (0.5%) 2/183 (1.1%) 0/182 (0%)
    Tracheobronchitis 1/184 (0.5%) 1/183 (0.5%) 1/182 (0.5%)
    Pneumonia 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Appendicitis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Bronchopneumonia 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Catheter site cellulitis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Clostridium difficile infection 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Gastroenteritis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Infective exacerbation of bronchiectasis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Kidney infection 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Lung infection 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Pneumonia mycoplasmal 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Respiratory tract infection viral 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Urinary tract infection 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Injury, poisoning and procedural complications
    Post procedural haematoma 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Investigations
    Forced expiratory volume decreased 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Alanine aminotransferase increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Aspartate aminotransferase increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Blood alkaline phosphatase increased 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Gamma-glutamyltransferase increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer metastatic 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Renal cancer 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Seminoma 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Nervous system disorders
    Epilepsy 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Renal and urinary disorders
    Nephrolithiasis 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis 2/184 (1.1%) 0/183 (0%) 5/182 (2.7%)
    Cough 0/184 (0%) 2/183 (1.1%) 1/182 (0.5%)
    Bronchospasm 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Dyspnoea 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Lung disorder 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Pneumomediastinum 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Pneumothorax 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Skin and subcutaneous tissue disorders
    Rash 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Vascular disorders
    Deep vein thrombosis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Other (Not Including Serious) Adverse Events
    Placebo LUM 600 mg qd/IVA 250 mg q12h LUM 400 mg q12h/ IVA 250 mg q12h
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 173/184 (94%) 175/183 (95.6%) 172/182 (94.5%)
    Blood and lymphatic system disorders
    Eosinophilia 1/184 (0.5%) 2/183 (1.1%) 0/182 (0%)
    Lymphadenopathy 1/184 (0.5%) 2/183 (1.1%) 0/182 (0%)
    Lymph node pain 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Neutropenia 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Thrombocytosis 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Cardiac disorders
    Palpitations 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Atrial fibrillation 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Atrioventricular block second degree 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Defect conduction intraventricular 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Pericarditis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Tachycardia 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Ear and labyrinth disorders
    Vertigo 1/184 (0.5%) 4/183 (2.2%) 0/182 (0%)
    Ear pain 1/184 (0.5%) 2/183 (1.1%) 1/182 (0.5%)
    Cerumen impaction 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Tympanic membrane disorder 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Tympanic membrane hyperaemia 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Ear canal erythema 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Ear congestion 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Endocrine disorders
    Hypothyroidism 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Eye disorders
    Vision blurred 1/184 (0.5%) 1/183 (0.5%) 2/182 (1.1%)
    Asthenopia 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Blepharospasm 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Astigmatism 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Conjunctivitis allergic 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Eye disorder 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Eye pruritus 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Visual acuity reduced 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Gastrointestinal disorders
    Diarrhoea 13/184 (7.1%) 16/183 (8.7%) 24/182 (13.2%)
    Abdominal pain 12/184 (6.5%) 11/183 (6%) 23/182 (12.6%)
    Nausea 11/184 (6%) 9/183 (4.9%) 14/182 (7.7%)
    Constipation 11/184 (6%) 6/183 (3.3%) 7/182 (3.8%)
    Abdominal pain upper 10/184 (5.4%) 7/183 (3.8%) 5/182 (2.7%)
    Flatulence 1/184 (0.5%) 9/183 (4.9%) 11/182 (6%)
    Vomiting 2/184 (1.1%) 8/183 (4.4%) 7/182 (3.8%)
    Abdominal distension 4/184 (2.2%) 2/183 (1.1%) 5/182 (2.7%)
    Gastrooesophageal reflux disease 2/184 (1.1%) 3/183 (1.6%) 6/182 (3.3%)
    Dyspepsia 2/184 (1.1%) 3/183 (1.6%) 4/182 (2.2%)
    Abdominal discomfort 1/184 (0.5%) 3/183 (1.6%) 3/182 (1.6%)
    Enteritis 2/184 (1.1%) 0/183 (0%) 3/182 (1.6%)
    Steatorrhoea 0/184 (0%) 1/183 (0.5%) 3/182 (1.6%)
    Dry mouth 1/184 (0.5%) 1/183 (0.5%) 1/182 (0.5%)
    Frequent bowel movements 1/184 (0.5%) 1/183 (0.5%) 1/182 (0.5%)
    Toothache 1/184 (0.5%) 0/183 (0%) 2/182 (1.1%)
    Abdominal pain lower 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Distal intestinal obstruction syndrome 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Faeces soft 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Gastrointestinal motility disorder 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Malabsorption 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Abdominal tenderness 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Anal fissure 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Chapped lips 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Colonic haematoma 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Defaecation urgency 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Faecaloma 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Gastric dilatation 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Gastritis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Gastrointestinal pain 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Gastrointestinal sounds abnormal 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Gingival swelling 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Gingivitis ulcerative 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Haemorrhoids 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Oesophagitis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Rectal haemorrhage 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Rectal tenesmus 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Tongue coated 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    General disorders
    Fatigue 19/184 (10.3%) 17/183 (9.3%) 17/182 (9.3%)
    Pyrexia 12/184 (6.5%) 12/183 (6.6%) 17/182 (9.3%)
    Asthenia 3/184 (1.6%) 5/183 (2.7%) 3/182 (1.6%)
    Pain 2/184 (1.1%) 4/183 (2.2%) 3/182 (1.6%)
    Chest discomfort 1/184 (0.5%) 3/183 (1.6%) 3/182 (1.6%)
    Malaise 1/184 (0.5%) 2/183 (1.1%) 3/182 (1.6%)
    Chills 1/184 (0.5%) 0/183 (0%) 2/182 (1.1%)
    Drug intolerance 0/184 (0%) 0/183 (0%) 3/182 (1.6%)
    Chest pain 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Influenza like illness 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Drug interaction 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Exercise tolerance decreased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Feeling abnormal 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Feeling cold 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Feeling hot 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Hyperthermia 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Implant site thrombosis 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Local swelling 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Medical device pain 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Oedema peripheral 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Hepatobiliary disorders
    Cholelithiasis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Hepatitis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Immune system disorders
    Allergy to arthropod sting 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Seasonal allergy 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Anaphylactic reaction 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Hypersensitivity 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Milk allergy 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis 58/184 (31.5%) 57/183 (31.1%) 54/182 (29.7%)
    Nasopharyngitis 20/184 (10.9%) 9/183 (4.9%) 26/182 (14.3%)
    Upper respiratory tract infection 10/184 (5.4%) 16/183 (8.7%) 17/182 (9.3%)
    Viral upper respiratory tract infection 12/184 (6.5%) 15/183 (8.2%) 13/182 (7.1%)
    Rhinitis 12/184 (6.5%) 16/183 (8.7%) 8/182 (4.4%)
    Sinusitis 12/184 (6.5%) 7/183 (3.8%) 5/182 (2.7%)
    Influenza 3/184 (1.6%) 8/183 (4.4%) 8/182 (4.4%)
    Bronchitis 7/184 (3.8%) 9/183 (4.9%) 2/182 (1.1%)
    Respiratory tract infection 3/184 (1.6%) 2/183 (1.1%) 6/182 (3.3%)
    Pharyngitis 2/184 (1.1%) 4/183 (2.2%) 4/182 (2.2%)
    Vulvovaginal mycotic infection 4/184 (2.2%) 2/183 (1.1%) 3/182 (1.6%)
    Oral candidiasis 3/184 (1.6%) 2/183 (1.1%) 3/182 (1.6%)
    Urinary tract infection 3/184 (1.6%) 2/183 (1.1%) 3/182 (1.6%)
    Upper respiratory tract infection bacterial 2/184 (1.1%) 2/183 (1.1%) 3/182 (1.6%)
    Viral infection 4/184 (2.2%) 2/183 (1.1%) 1/182 (0.5%)
    Gastroenteritis viral 1/184 (0.5%) 2/183 (1.1%) 2/182 (1.1%)
    Lower respiratory tract infection bacterial 3/184 (1.6%) 1/183 (0.5%) 1/182 (0.5%)
    Respiratory tract infection viral 1/184 (0.5%) 2/183 (1.1%) 2/182 (1.1%)
    Gastroenteritis 0/184 (0%) 1/183 (0.5%) 3/182 (1.6%)
    H1N1 influenza 1/184 (0.5%) 1/183 (0.5%) 2/182 (1.1%)
    Oral herpes 1/184 (0.5%) 1/183 (0.5%) 2/182 (1.1%)
    Otitis media 0/184 (0%) 3/183 (1.6%) 1/182 (0.5%)
    Acute sinusitis 1/184 (0.5%) 1/183 (0.5%) 1/182 (0.5%)
    Bronchopulmonary aspergillosis allergic 1/184 (0.5%) 2/183 (1.1%) 0/182 (0%)
    Fungal skin infection 2/184 (1.1%) 1/183 (0.5%) 0/182 (0%)
    Laryngitis 1/184 (0.5%) 2/183 (1.1%) 0/182 (0%)
    Sputum purulent 0/184 (0%) 2/183 (1.1%) 1/182 (0.5%)
    Bacterial disease carrier 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Bronchitis bacterial 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Chronic sinusitis 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Clostridium difficile colitis 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Herpes zoster 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Lower respiratory tract infection viral 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Mycobacterium abscessus infection 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Pharyngitis streptococcal 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Tonsillitis 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Vulvovaginal candidiasis 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Acute tonsillitis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Body tinea 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Bronchopulmonary aspergillosis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Conjunctivitis bacterial 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Ear infection 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Eye infection 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Folliculitis 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Genital infection fungal 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Giardiasis 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Herpes dermatitis 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Herpes simplex 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Lower respiratory tract infection 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Lung infection 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Lung infection pseudomonal 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Oral fungal infection 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Oropharyngeal candidiasis 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Otitis externa 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Overgrowth bacterial 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Pseudomonas bronchitis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Soft tissue infection 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Stoma site infection 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Subcutaneous abscess 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Tinea pedis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Tinea versicolour 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Tooth infection 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Tracheitis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Vestibular neuronitis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Viral rhinitis 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Viral tonsillitis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Injury, poisoning and procedural complications
    Muscle strain 0/184 (0%) 3/183 (1.6%) 2/182 (1.1%)
    Joint injury 1/184 (0.5%) 1/183 (0.5%) 2/182 (1.1%)
    Ligament sprain 0/184 (0%) 1/183 (0.5%) 2/182 (1.1%)
    Procedural pain 1/184 (0.5%) 0/183 (0%) 2/182 (1.1%)
    Concussion 0/184 (0%) 0/183 (0%) 2/182 (1.1%)
    Excoriation 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Facial bones fracture 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Stoma site pain 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Sunburn 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Arthropod bite 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Back injury 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Contusion 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Fall 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Foot fracture 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Foreign body in eye 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Laceration 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Meniscus injury 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Muscle rupture 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Post procedural complication 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Radius fracture 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Respiratory fume inhalation disorder 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Skeletal injury 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Stoma site erythema 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Vaccination complication 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Vascular procedure complication 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Investigations
    Blood creatine phosphokinase increased 10/184 (5.4%) 10/183 (5.5%) 13/182 (7.1%)
    Bacterial test positive 9/184 (4.9%) 4/183 (2.2%) 7/182 (3.8%)
    Alanine aminotransferase increased 5/184 (2.7%) 4/183 (2.2%) 3/182 (1.6%)
    Forced expiratory volume decreased 7/184 (3.8%) 3/183 (1.6%) 1/182 (0.5%)
    Weight decreased 5/184 (2.7%) 2/183 (1.1%) 4/182 (2.2%)
    Liver function test abnormal 6/184 (3.3%) 3/183 (1.6%) 1/182 (0.5%)
    Pulmonary function test decreased 6/184 (3.3%) 4/183 (2.2%) 0/182 (0%)
    Aspartate aminotransferase increased 3/184 (1.6%) 3/183 (1.6%) 3/182 (1.6%)
    Blood creatinine increased 4/184 (2.2%) 3/183 (1.6%) 1/182 (0.5%)
    White blood cell count increased 1/184 (0.5%) 2/183 (1.1%) 2/182 (1.1%)
    Blood glucose decreased 3/184 (1.6%) 0/183 (0%) 1/182 (0.5%)
    Hepatic enzyme increased 0/184 (0%) 2/183 (1.1%) 2/182 (1.1%)
    Vitamin D decreased 1/184 (0.5%) 1/183 (0.5%) 2/182 (1.1%)
    Breath sounds abnormal 1/184 (0.5%) 2/183 (1.1%) 0/182 (0%)
    Fungal test positive 1/184 (0.5%) 1/183 (0.5%) 1/182 (0.5%)
    Staphylococcus test positive 0/184 (0%) 1/183 (0.5%) 2/182 (1.1%)
    Transaminases increased 1/184 (0.5%) 1/183 (0.5%) 1/182 (0.5%)
    Blood alkaline phosphatase increased 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Blood glucose increased 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Blood immunoglobulin E increased 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Blood phosphorus increased 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Body temperature increased 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Atypical mycobacterium test positive 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Blood bicarbonate decreased 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Blood calcium increased 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Blood lactate dehydrogenase increased 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Blood phosphorus abnormal 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Blood potassium increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Blood sodium decreased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Blood urea increased 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    C-reactive protein increased 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Chest X-ray abnormal 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Forced expiratory volume increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Gamma-glutamyltransferase increased 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Glucose tolerance test abnormal 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Glucose urine present 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Haemoglobin increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Heart rate increased 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Neutrophil count increased 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Platelet count decreased 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Pseudomonas test positive 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Red blood cell count increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Sputum abnormal 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Urine calcium increased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Vitamin E decreased 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    White blood cell count decreased 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    White blood cells urine positive 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 4/184 (2.2%) 6/183 (3.3%) 6/182 (3.3%)
    Hypoglycaemia 3/184 (1.6%) 6/183 (3.3%) 2/182 (1.1%)
    Dehydration 3/184 (1.6%) 0/183 (0%) 1/182 (0.5%)
    Hyperglycaemia 2/184 (1.1%) 1/183 (0.5%) 1/182 (0.5%)
    Gout 2/184 (1.1%) 1/183 (0.5%) 0/182 (0%)
    Diabetes mellitus 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Hyponatraemia 0/184 (0%) 0/183 (0%) 2/182 (1.1%)
    Glucose tolerance impaired 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Hyperkalaemia 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Hypokalaemia 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Iron deficiency 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Magnesium deficiency 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Vitamin K deficiency 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain 6/184 (3.3%) 7/183 (3.8%) 3/182 (1.6%)
    Myalgia 4/184 (2.2%) 3/183 (1.6%) 7/182 (3.8%)
    Back pain 5/184 (2.7%) 3/183 (1.6%) 5/182 (2.7%)
    Arthralgia 4/184 (2.2%) 1/183 (0.5%) 2/182 (1.1%)
    Pain in extremity 4/184 (2.2%) 0/183 (0%) 1/182 (0.5%)
    Musculoskeletal pain 0/184 (0%) 1/183 (0.5%) 3/182 (1.6%)
    Flank pain 0/184 (0%) 2/183 (1.1%) 1/182 (0.5%)
    Muscle spasms 2/184 (1.1%) 1/183 (0.5%) 0/182 (0%)
    Joint swelling 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Musculoskeletal stiffness 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Tendon pain 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Arthropathy 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Intervertebral disc protrusion 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Musculoskeletal discomfort 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Neck pain 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Tendon disorder 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Tendonitis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Nervous system disorders
    Headache 25/184 (13.6%) 28/183 (15.3%) 29/182 (15.9%)
    Dizziness 5/184 (2.7%) 5/183 (2.7%) 5/182 (2.7%)
    Sinus headache 2/184 (1.1%) 3/183 (1.6%) 3/182 (1.6%)
    Migraine 3/184 (1.6%) 0/183 (0%) 3/182 (1.6%)
    Lethargy 1/184 (0.5%) 2/183 (1.1%) 2/182 (1.1%)
    Dysgeusia 2/184 (1.1%) 0/183 (0%) 2/182 (1.1%)
    Poor quality sleep 0/184 (0%) 0/183 (0%) 3/182 (1.6%)
    Dysarthria 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Paraesthesia 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Syncope 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Tremor 0/184 (0%) 0/183 (0%) 2/182 (1.1%)
    Amnesia 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Ataxia 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Cognitive disorder 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Dysaesthesia 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Epilepsy 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Hypoaesthesia 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Memory impairment 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Neuropathy peripheral 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Presyncope 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Sciatica 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Somnolence 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Tension headache 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Psychiatric disorders
    Insomnia 6/184 (3.3%) 2/183 (1.1%) 3/182 (1.6%)
    Anxiety 2/184 (1.1%) 2/183 (1.1%) 2/182 (1.1%)
    Depression 4/184 (2.2%) 1/183 (0.5%) 1/182 (0.5%)
    Depressed mood 0/184 (0%) 0/183 (0%) 3/182 (1.6%)
    Irritability 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Attention deficit/hyperactivity disorder 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Bradyphrenia 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Depressive symptom 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Disorientation 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Disturbance in social behaviour 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Emotional disorder 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Libido decreased 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Middle insomnia 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Sleep disorder 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Suicidal ideation 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Renal and urinary disorders
    Nephrolithiasis 1/184 (0.5%) 2/183 (1.1%) 0/182 (0%)
    Urine odour abnormal 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Calculus urinary 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Haematuria 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Leukocyturia 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Nephropathy 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Nephropathy toxic 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Pollakiuria 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Renal failure acute 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Urine abnormality 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Reproductive system and breast disorders
    Dysmenorrhoea 2/184 (1.1%) 1/183 (0.5%) 2/182 (1.1%)
    Metrorrhagia 0/184 (0%) 2/183 (1.1%) 3/182 (1.6%)
    Amenorrhoea 0/184 (0%) 0/183 (0%) 3/182 (1.6%)
    Menorrhagia 0/184 (0%) 2/183 (1.1%) 1/182 (0.5%)
    Menstruation irregular 0/184 (0%) 2/183 (1.1%) 1/182 (0.5%)
    Polymenorrhoea 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Erectile dysfunction 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Gynaecomastia 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Penile erythema 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Testicular pain 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    Cough 66/184 (35.9%) 52/183 (28.4%) 47/182 (25.8%)
    Haemoptysis 23/184 (12.5%) 22/183 (12%) 26/182 (14.3%)
    Sputum increased 23/184 (12.5%) 15/183 (8.2%) 25/182 (13.7%)
    Dyspnoea 14/184 (7.6%) 21/183 (11.5%) 17/182 (9.3%)
    Respiration abnormal 9/184 (4.9%) 26/183 (14.2%) 14/182 (7.7%)
    Nasal congestion 25/184 (13.6%) 9/183 (4.9%) 11/182 (6%)
    Oropharyngeal pain 10/184 (5.4%) 24/183 (13.1%) 11/182 (6%)
    Rhinorrhoea 5/184 (2.7%) 6/183 (3.3%) 10/182 (5.5%)
    Wheezing 6/184 (3.3%) 5/183 (2.7%) 5/182 (2.7%)
    Rales 7/184 (3.8%) 4/183 (2.2%) 4/182 (2.2%)
    Productive cough 1/184 (0.5%) 6/183 (3.3%) 7/182 (3.8%)
    Respiratory tract congestion 5/184 (2.7%) 3/183 (1.6%) 4/182 (2.2%)
    Epistaxis 4/184 (2.2%) 4/183 (2.2%) 2/182 (1.1%)
    Asthma 3/184 (1.6%) 0/183 (0%) 6/182 (3.3%)
    Bronchospasm 1/184 (0.5%) 3/183 (1.6%) 5/182 (2.7%)
    Sinus congestion 1/184 (0.5%) 7/183 (3.8%) 1/182 (0.5%)
    Paranasal sinus hypersecretion 1/184 (0.5%) 4/183 (2.2%) 3/182 (1.6%)
    Sputum discoloured 3/184 (1.6%) 2/183 (1.1%) 1/182 (0.5%)
    Nasal inflammation 1/184 (0.5%) 3/183 (1.6%) 1/182 (0.5%)
    Rhinitis allergic 2/184 (1.1%) 1/183 (0.5%) 2/182 (1.1%)
    Rhonchi 2/184 (1.1%) 2/183 (1.1%) 1/182 (0.5%)
    Upper-airway cough syndrome 2/184 (1.1%) 1/183 (0.5%) 2/182 (1.1%)
    Dysphonia 2/184 (1.1%) 1/183 (0.5%) 1/182 (0.5%)
    Dyspnoea exertional 0/184 (0%) 3/183 (1.6%) 1/182 (0.5%)
    Increased upper airway secretion 1/184 (0.5%) 1/183 (0.5%) 2/182 (1.1%)
    Increased viscosity of bronchial secretion 2/184 (1.1%) 0/183 (0%) 2/182 (1.1%)
    Painful respiration 2/184 (1.1%) 1/183 (0.5%) 1/182 (0.5%)
    Pharyngeal erythema 1/184 (0.5%) 2/183 (1.1%) 1/182 (0.5%)
    Pleuritic pain 2/184 (1.1%) 0/183 (0%) 2/182 (1.1%)
    Lung hyperinflation 1/184 (0.5%) 1/183 (0.5%) 1/182 (0.5%)
    Throat irritation 2/184 (1.1%) 0/183 (0%) 1/182 (0.5%)
    Bronchial hyperreactivity 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Nasal polyps 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Obstructive airways disorder 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Paranasal cyst 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Pulmonary congestion 0/184 (0%) 2/183 (1.1%) 0/182 (0%)
    Allergic cough 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Bronchial obstruction 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Bronchiectasis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Hypoxia 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Nasal obstruction 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Nasal oedema 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Nasal septum deviation 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Nasal turbinate hypertrophy 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Pharyngeal exudate 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Prolonged expiration 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Pulmonary pain 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Respiratory failure 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Respiratory tract irritation 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Rhinalgia 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Sneezing 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Throat tightness 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Upper respiratory tract inflammation 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Skin and subcutaneous tissue disorders
    Rash 2/184 (1.1%) 8/183 (4.4%) 6/182 (3.3%)
    Pruritus 1/184 (0.5%) 5/183 (2.7%) 4/182 (2.2%)
    Acne 5/184 (2.7%) 1/183 (0.5%) 1/182 (0.5%)
    Hyperhidrosis 0/184 (0%) 1/183 (0.5%) 2/182 (1.1%)
    Night sweats 0/184 (0%) 2/183 (1.1%) 1/182 (0.5%)
    Urticaria 2/184 (1.1%) 1/183 (0.5%) 0/182 (0%)
    Alopecia 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Dermatitis allergic 2/184 (1.1%) 0/183 (0%) 0/182 (0%)
    Photosensitivity reaction 0/184 (0%) 0/183 (0%) 2/182 (1.1%)
    Pruritus allergic 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Pruritus generalised 1/184 (0.5%) 0/183 (0%) 1/182 (0.5%)
    Rash macular 1/184 (0.5%) 1/183 (0.5%) 0/182 (0%)
    Chloasma 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Cold sweat 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Dermatitis acneiform 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Drug eruption 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Dry skin 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Eczema 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Erythema 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Erythema nodosum 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Macule 0/184 (0%) 1/183 (0.5%) 0/182 (0%)
    Rash generalised 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Rash maculo-papular 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Red man syndrome 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Swelling face 0/184 (0%) 0/183 (0%) 1/182 (0.5%)
    Vascular disorders
    Hypertension 0/184 (0%) 2/183 (1.1%) 2/182 (1.1%)
    Flushing 0/184 (0%) 1/183 (0.5%) 1/182 (0.5%)
    Hot flush 0/184 (0%) 0/183 (0%) 2/182 (1.1%)
    Deep vein thrombosis 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Hypotension 1/184 (0.5%) 0/183 (0%) 0/182 (0%)
    Poor venous access 0/184 (0%) 0/183 (0%) 1/182 (0.5%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    PI is free to publish results of the study after (1) the first multi-center publication, (2) if the sponsor elects not to publish the results, or (3) 18 months after close of the study, whichever occurs first. Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 45 days (which may be extended under certain circumstances related to protection of intellectual property); the sponsor cannot require changes to the proposed publications.

    Results Point of Contact

    Name/Title Medical Monitor
    Organization Vertex Pharmaceuticals Incorporated
    Phone 617-341-6777
    Email medicalinfo@vrtx.com
    Responsible Party:
    Vertex Pharmaceuticals Incorporated
    ClinicalTrials.gov Identifier:
    NCT01807923
    Other Study ID Numbers:
    • VX12-809-103
    First Posted:
    Mar 8, 2013
    Last Update Posted:
    Aug 31, 2015
    Last Verified:
    Jun 1, 2015