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Study of VX-809 Alone and in Combination With VX-770 in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01225211
Recruitment Status : Completed
First Posted : October 20, 2010
Results First Posted : October 5, 2015
Last Update Posted : October 5, 2015
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Factorial Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Cystic Fibrosis
Interventions Drug: Lumacaftor
Drug: Ivacaftor
Drug: Lumacaftor Placebo
Drug: Ivacaftor Placebo
Enrollment 312
Recruitment Details Participants in each cohort are mutually exclusive. A total of 312 participants were randomized of which one participant did not receive any treatment and a total of 311 participants were treated.
Pre-assignment Details Study included 4 cohorts which were studied in sequential manner. For results reporting, combined placebo arm was reported for Cohort 2 and 3 and results for these 2 cohorts are reported collectively.
Arm/Group Title Cohort 1: Placebo Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h Cohort 2 and 3: Placebo (HO and HE) Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description Participants homozygous (HO) for the F508del-CF transmembrane conductance regulator gene (CFTR) mutation received lumacaftor matched placebo once daily (qd) (Day 1 through Day 14), followed by lumacaftor matched placebo qd in combination with ivacaftor matched placebo every 12 hours (q12h) (Day 15 through Day 21). Participants homozygous for the F508del-CFTR mutation received 200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor (IVA) q12h (Day 15 through Day 21). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21). Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56). Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Period Title: Overall Study
Started 21 20 21 27 23 21 42 11 63 62
Completed 21 20 20 27 23 21 41 11 62 57
Not Completed 0 0 1 0 0 0 1 0 1 5
Reason Not Completed
Adverse Event             0             0             1             0             0             0             0             0             0             1
Withdrawal by Subject             0             0             0             0             0             0             1             0             1             3
Other             0             0             0             0             0             0             0             0             0             1
Arm/Group Title Cohort 1: Placebo Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h Cohort 2 and 3: Placebo (HO and HE) Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h Total
Hide Arm/Group Description Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 14), followed by lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21). Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56). Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56). Total of all reporting groups
Overall Number of Baseline Participants 21 20 21 27 23 21 42 11 63 62 311
Hide Baseline Analysis Population Description
Full Analysis Set (FAS) for Cohort 1, 2, and 3 included all randomized participants who received at least 1 dose of study drug and FAS for Cohort 4 included all randomized participants who received any amount of study drug.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 20 participants 21 participants 27 participants 23 participants 21 participants 42 participants 11 participants 63 participants 62 participants 311 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
21
 100.0%
20
 100.0%
21
 100.0%
27
 100.0%
23
 100.0%
21
 100.0%
42
 100.0%
11
 100.0%
63
 100.0%
62
 100.0%
311
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 20 participants 21 participants 27 participants 23 participants 21 participants 42 participants 11 participants 63 participants 62 participants 311 participants
Female
10
  47.6%
8
  40.0%
13
  61.9%
9
  33.3%
11
  47.8%
9
  42.9%
19
  45.2%
5
  45.5%
31
  49.2%
29
  46.8%
144
  46.3%
Male
11
  52.4%
12
  60.0%
8
  38.1%
18
  66.7%
12
  52.2%
12
  57.1%
23
  54.8%
6
  54.5%
32
  50.8%
33
  53.2%
167
  53.7%
1.Primary Outcome
Title Cohort 1: Safety and Tolerability Based on Adverse Events (AEs)
Hide Description AE: any untoward medical occurrence in a participant during study; irrespective of relationship with treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after informed consent. AE includes serious AEs (SAEs) as well as Non-SAEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to 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. Number of participants with AEs and SAEs are reported. AE that started at/after initial dosing of study drug, or increased in severity after initial dosing of study drug is considered treatment-emergent. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 14) and combination therapy period (Period 2: Day 15 to Day 21).
Time Frame Cohort 1: Day 1 up to 28 days after last dose (Last dose = Day 21)
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 Safety Set included all participants who received at least 1 dose of study drug in Cohort 1. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 1: Placebo - Period 1 Cohort 1: LUM 200 mg qd - Period 1 Cohort 1: Placebo - Period 2 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 14).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14).
Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).
Overall Number of Participants Analyzed 21 41 21 20 20
Measure Type: Number
Unit of Measure: participants
Participants with any AEs 12 29 15 14 12
Participants with SAEs 0 0 0 0 0
2.Primary Outcome
Title Cohort 2 and 3: Safety and Tolerability Based on Adverse Events (AEs)
Hide Description Detailed description is provided in Outcome Measure 1. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 28) and combination therapy period (Period 2: Day 29 to Day 56).
Time Frame Cohort 2 and 3: Day 1 up to 28 days after last dose (Last dose = Day 56)
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Safety Set included all participants who received at least 1 dose of study drug in Cohort 2 or 3. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2 and 3: Placebo (HO and HE) - Period 1 Cohort 2: LUM 200 mg qd - Period 1 Cohort 2: LUM 400 mg qd - Period 1 Cohort 2: LUM 600 mg qd - Period 1 Cohort 3: LUM 400 mg q12h - Period 1 Cohort 2 and 3: Placebo (HO and HE) - Period 2 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2
Hide Arm/Group Description:
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28).
Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Overall Number of Participants Analyzed 27 23 21 42 11 27 21 20 38 11
Measure Type: Number
Unit of Measure: participants
Participants with any AEs 23 18 18 37 7 20 12 15 26 10
Participants with SAEs 1 2 0 3 2 4 0 1 4 1
3.Primary Outcome
Title Cohort 4: Safety and Tolerability Assessed by Number of Participants With AEs and SAEs
Hide Description AEs and SAEs are defined in Outcome Measure 1.
Time Frame Cohort 4: Day 1 up to 28 days after last dose (Last dose = Day 56)
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 4 Safety Set included all participants who received at least 1 dose of study drug in Cohort 4.
Arm/Group Title Cohort 4: Placebo Cohort 4: Active Study Drug
Hide Arm/Group Description:
Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Overall Number of Participants Analyzed 63 62
Measure Type: Number
Unit of Measure: participants
Participants with any AEs 53 52
Participants with SAEs 5 9
4.Primary Outcome
Title Cohort 1: Absolute Change From Day 14 in Sweat Chloride at Day 21
Hide Description [Not Specified]
Time Frame Cohort 1: Day 14, Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 1. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2 Cohort 1: Placebo - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21).
Overall Number of Participants Analyzed 19 14 17
Least Squares Mean (95% Confidence Interval)
Unit of Measure: millimole per liter (mmol/L)
-2.131
(-5.381 to 1.119)
-9.128
(-12.893 to -5.362)
0.548
(-2.955 to 4.052)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2, Cohort 1: Placebo - Period 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.267
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -2.679
Confidence Interval (2-Sided) 95%
-7.484 to 2.125
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2, Cohort 1: Placebo - Period 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -9.676
Confidence Interval (2-Sided) 95%
-14.801 to -4.551
Estimation Comments [Not Specified]
5.Primary Outcome
Title Cohort 2 And 3: Absolute Change From Day 28 in Sweat Chloride at Day 56
Hide Description [Not Specified]
Time Frame Cohort 2 and 3: Day 28, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
Overall Number of Participants Analyzed 21 19 20 17 9 24
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mmol/L
0.321
(-4.208 to 4.849)
-1.043
(-5.800 to 3.714)
-2.900
(-7.542 to 1.743)
-1.240
(-6.287 to 3.807)
-2.154
(-9.177 to 4.870)
1.627
(-2.661 to 5.915)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2, Cohort 2 and 3: Placebo (HO and HE) - Period 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.680
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -1.306
Confidence Interval (2-Sided) 95%
-7.565 to 4.953
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2, Cohort 2 and 3: Placebo (HO and HE) - Period 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.409
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -2.670
Confidence Interval (2-Sided) 95%
-9.053 to 3.712
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) - Period 2, Cohort 2 and 3: Placebo (HO and HE) - Period 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.161
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -4.526
Confidence Interval (2-Sided) 95%
-10.888 to 1.835
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) - Period 2, Cohort 2 and 3: Placebo (HO and HE) - Period 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.396
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -2.867
Confidence Interval (2-Sided) 95%
-9.543 to 3.810
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2, Cohort 2 and 3: Placebo (HO and HE) - Period 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.365
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -3.780
Confidence Interval (2-Sided) 95%
-12.028 to 4.467
Estimation Comments [Not Specified]
6.Primary Outcome
Title Cohort 4: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 56
Hide Description FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Hankinson method.
Time Frame Cohort 4: Baseline, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 4 Full Analysis Set included all randomized participants who received any amount of study drug in Cohort 4. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description:
Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Overall Number of Participants Analyzed 60 55
Least Squares Mean (Standard Error)
Unit of Measure: percent predicted of FEV1
-1.23  (0.801) -0.62  (0.829)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cohort 4: Placebo, Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5978
Comments [Not Specified]
Method Mixed Model Repeated Measure (MMRM)
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
-1.66 to 2.86
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Cohort 1: Absolute Change From Baseline in Sweat Chloride at Day 14
Hide Description [Not Specified]
Time Frame Cohort 1: Baseline, Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 1. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 1: LUM 200 mg qd - Period 1 Cohort 1: Placebo - Period 1
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14).
Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 14).
Overall Number of Participants Analyzed 36 17
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mmol/L
-4.442
(-7.141 to -1.742)
-1.668
(-5.606 to 2.271)
8.Secondary Outcome
Title Cohort 2 And 3: Absolute Change From Baseline in Sweat Chloride at Day 14
Hide Description [Not Specified]
Time Frame Cohort 2: Baseline, Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2: LUM 200 mg qd - Period 1 Cohort 2: LUM 400 mg qd - Period 1 Cohort 2: LUM 600 mg qd (HO) - Period 1 Cohort 2: LUM 600 mg qd (HE) - Period 1 Cohort 3: LUM 400 mg q12h - Period 1 Cohort 2 and 3: Placebo (HO and HE) - Period 1
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28).
Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28).
Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28).
Overall Number of Participants Analyzed 19 17 21 17 11 25
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mmol/L
-6.490
(-11.226 to -1.755)
-5.901
(-10.910 to -0.892)
-9.442
(-13.953 to -4.931)
-3.137
(-8.167 to 1.893)
-9.179
(-15.470 to -2.888)
0.048
(-4.162 to 4.258)
9.Secondary Outcome
Title Cohort 4: Absolute Change From Baseline in Sweat Chloride at Day 56
Hide Description [Not Specified]
Time Frame Cohort 4: Baseline, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 4 Full Analysis Set included all randomized participants who received any amount of study drug in Cohort 4. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description:
Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Overall Number of Participants Analyzed 59 54
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
-0.78  (1.230) -11.82  (1.281)
10.Secondary Outcome
Title Cohort 1: Absolute Change From Day 14 in FEV1 at Day 21
Hide Description FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame Cohort 1: Day 14, Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 1. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2 Cohort 1: Placebo - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21).
Overall Number of Participants Analyzed 20 18 21
Least Squares Mean (95% Confidence Interval)
Unit of Measure: liters
0.128
(0.030 to 0.225)
0.015
(-0.094 to 0.124)
-0.046
(-0.138 to 0.047)
11.Secondary Outcome
Title Cohort 1: Absolute Change From Day 14 in ppFEV1 at Day 21
Hide Description FEV1 and ppFEV1 are defined in Outcome Measure 6.
Time Frame Cohort 1: Day 14, Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 1 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 1. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2 Cohort 1: Placebo - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).
Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21).
Overall Number of Participants Analyzed 20 18 21
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent predicted of FEV1
3.46
(0.87 to 6.05)
0.63
(-2.20 to 3.46)
-1.44
(-3.89 to 1.01)
12.Secondary Outcome
Title Cohort 2 and 3: Absolute Change From Day 28 in ppFEV1 at Day 56
Hide Description FEV1 and ppFEV1 are defined in Outcome Measure 6.
Time Frame Cohort 2 and 3: Day 28, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
Overall Number of Participants Analyzed 21 20 20 17 10 27
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent predicted of FEV1
1.96
(-0.84 to 4.76)
1.99
(-0.87 to 4.84)
6.15
(3.27 to 9.02)
2.29
(-0.82 to 5.39)
6.09
(2.02 to 10.16)
-1.57
(-4.24 to 1.09)
13.Secondary Outcome
Title Cohort 2 and 3: Relative Change From Day 28 in ppFEV1 at Day 56
Hide Description FEV1 and ppFEV1 are defined in Outcome Measure 6.
Time Frame Cohort 2 and 3: Day 28, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
Overall Number of Participants Analyzed 21 20 20 17 10 24
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
3.13
(-1.29 to 7.54)
2.98
(-1.52 to 7.48)
9.70
(5.17 to 14.23)
4.30
(-0.59 to 9.19)
8.24
(1.83 to 14.65)
-2.05
(-6.25 to 2.15)
14.Secondary Outcome
Title Cohort 2 and 3: Absolute Change From Baseline in ppFEV1 at Day 28 and 56
Hide Description FEV1 and ppFEV1 are defined in Outcome Measure 6.
Time Frame Cohort 2 and 3: Baseline, Day 28 and 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Here, n = participants evaluable for specified category for each arm, respectively. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HE) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 2 and 3: Placebo (HO and HE)
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants heterozygous (HE) for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
Overall Number of Participants Analyzed 23 21 21 21 11 27
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent predicted of FEV1
Day 28: (n= 21, 20, 20, 18, 11, 27)
0.21
(-2.77 to 3.19)
-1.35
(-4.39 to 1.69)
-2.62
(-5.67 to 0.42)
-3.82
(-7.03 to -0.61)
-4.52
(-8.65 to -0.39)
-0.03
(-2.68 to 2.62)
Day 56: (n= 21, 20, 20, 17, 10, 24)
1.82
(-1.28 to 4.91)
0.64
(-2.52 to 3.80)
3.59
(0.41 to 6.77)
-1.68
(-5.12 to 1.75)
2.16
(-2.34 to 6.66)
-2.02
(-4.97 to 0.93)
15.Secondary Outcome
Title Cohort 2 and 3: Relative Change From Baseline in FEV1 at Day 28 and 56
Hide Description FEV1 and ppFEV1 are defined in Outcome Measure 6.
Time Frame Cohort 2 and 3: Baseline, Day 28 and 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Here, n = participants evaluable for specified category for each arm, respectively. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO) Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HE) Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO) Cohort 2 and 3: Placebo (HO and HE)
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants heterozygous (HE) for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
Overall Number of Participants Analyzed 23 21 21 21 11 27
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent change
Day 28: (n= 21, 20, 20, 18, 11, 27)
0.24
(-4.27 to 4.75)
-1.15
(-5.75 to 3.45)
-3.13
(-7.74 to 1.48)
-5.46
(-10.32 to -0.60)
-6.39
(-12.65 to -0.14)
1.89
(-2.12 to 5.90)
Day 56: (n= 21, 20, 20, 17, 10, 24)
2.51
(-2.21 to 7.23)
1.72
(-3.09 to 6.53)
5.55
(0.70 to 10.39)
-2.34
(-7.57 to 2.89)
2.96
(-3.90 to 9.81)
-2.42
(-6.91 to 2.08)
16.Secondary Outcome
Title Cohort 4: Relative Change From Baseline in Percent Predicted FEV1 at Day 56
Hide Description FEV1 and ppFEV1 are defined in Outcome Measure 6.
Time Frame Cohort 4: Baseline, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 4 Full Analysis Set included all randomized participants who received any amount of study drug in Cohort 4. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description:
Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Overall Number of Participants Analyzed 60 55
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-2.20  (1.373) -0.69  (1.423)
17.Secondary Outcome
Title Cohort 2 and 3: Absolute Change From Day 28 in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Day 56
Hide Description The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time Frame Cohort 2 and 3: Day 28, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 2 and 3 Full Analysis Set included all randomized participants who received at least 1 dose of study drug in Cohort 2 or 3. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2
Hide Arm/Group Description:
Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
Overall Number of Participants Analyzed 21 20 20 17 10 25
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
3.3
(-3.6 to 10.1)
7.9
(0.8 to 14.9)
8.9
(1.9 to 15.9)
5.5
(-2.1 to 13.1)
11.2
(1.3 to 21.1)
-8.6
(-14.9 to -2.2)
18.Secondary Outcome
Title Cohort 4: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 56
Hide Description CFQ-R respiratory domain is defined in Outcome Measure 17.
Time Frame Cohort 4: Baseline, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 4 Full Analysis Set included all randomized participants who received any amount of study drug in Cohort 4. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description:
Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Overall Number of Participants Analyzed 60 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.82  (1.802) 5.66  (1.864)
19.Secondary Outcome
Title Cohort 4: Absolute Change From Baseline in Body Mass Index (BMI) at Day 56
Hide Description BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).
Time Frame Cohort 4: Baseline, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 4 Full Analysis Set included all randomized participants who received any amount of study drug in Cohort 4. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description:
Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Overall Number of Participants Analyzed 60 56
Least Squares Mean (Standard Error)
Unit of Measure: kg/m^2
0.08  (0.075) -0.04  (0.077)
20.Secondary Outcome
Title Cohort 4: Absolute Change From Baseline in Weight at Day 56
Hide Description [Not Specified]
Time Frame Cohort 4: Baseline, Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Cohort 4 Full Analysis Set included all randomized participants who received any amount of study drug in Cohort 4. Number of participants analysed signifies participants evaluable for this outcome.
Arm/Group Title Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description:
Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
Overall Number of Participants Analyzed 60 56
Least Squares Mean (Standard Error)
Unit of Measure: kg
0.16  (0.211) -0.11  (0.216)
Time Frame Cohort 1: Day 1 up to 28 days after last dose (Last dose = Day 21); Cohort 2 and 3: Day 1 up to 28 days after last dose (Last dose = Day 56); Cohort 4: Day 1 up to 28 days after last dose (Last dose = Day 56)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cohort 1: LUM 200 mg qd - Period 1 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2 Cohort 1: Placebo - Period 1 Cohort 1: Placebo - Period 2 Cohort 2: LUM 200 mg qd - Period 1 Cohort 2: LUM 400 mg qd - Period 1 Cohort 2: LUM 600 mg qd - Period 1 Cohort 3: LUM 400 mg q12h - Period 1 Cohort 2 and 3: Placebo (HO and HE) - Period 1 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2 Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Hide Arm/Group Description Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor q12h (Day 15 through Day 21). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21). Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 14). Participants homozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd in combination with ivacaftor matched placebo q12h (Day 15 through Day 21). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28). Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28). Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28). Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56). Participants heterozygous for the F508del-CFTR mutation received lumacaftor in combination with ivacaftor matched placebo q12h (Day 1 through Day 56). Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
All-Cause Mortality
Cohort 1: LUM 200 mg qd - Period 1 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2 Cohort 1: Placebo - Period 1 Cohort 1: Placebo - Period 2 Cohort 2: LUM 200 mg qd - Period 1 Cohort 2: LUM 400 mg qd - Period 1 Cohort 2: LUM 600 mg qd - Period 1 Cohort 3: LUM 400 mg q12h - Period 1 Cohort 2 and 3: Placebo (HO and HE) - Period 1 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2 Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
Cohort 1: LUM 200 mg qd - Period 1 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2 Cohort 1: Placebo - Period 1 Cohort 1: Placebo - Period 2 Cohort 2: LUM 200 mg qd - Period 1 Cohort 2: LUM 400 mg qd - Period 1 Cohort 2: LUM 600 mg qd - Period 1 Cohort 3: LUM 400 mg q12h - Period 1 Cohort 2 and 3: Placebo (HO and HE) - Period 1 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2 Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/41 (0.00%)      0/20 (0.00%)      0/20 (0.00%)      0/21 (0.00%)      0/21 (0.00%)      2/23 (8.70%)      0/21 (0.00%)      3/42 (7.14%)      2/11 (18.18%)      1/27 (3.70%)      0/21 (0.00%)      1/20 (5.00%)      4/38 (10.53%)      1/11 (9.09%)      4/27 (14.81%)      5/63 (7.94%)      9/62 (14.52%)    
Congenital, familial and genetic disorders                                   
CYSTIC FIBROSIS LUNG † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/23 (4.35%)  1 0/21 (0.00%)  0 1/42 (2.38%)  1 1/11 (9.09%)  1 1/27 (3.70%)  1 0/21 (0.00%)  0 1/20 (5.00%)  1 3/38 (7.89%)  3 1/11 (9.09%)  1 4/27 (14.81%)  4 0/63 (0.00%)  0 0/62 (0.00%)  0
Immune system disorders                                   
HYPERSENSITIVITY † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/23 (4.35%)  1 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Infections and infestations                                   
Infective pulmonary exacerbation of cystic fibrosis † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 3/63 (4.76%)  4 7/62 (11.29%)  7
PNEUMONIA † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Investigations                                   
Spirometry abnormal † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
BLOOD CREATINE PHOSPHOKINASE INCREASED † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Renal and urinary disorders                                   
Nephrolithiasis † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 1/63 (1.59%)  1 0/62 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                                   
Haemoptysis † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 1/27 (3.70%)  1 1/63 (1.59%)  1 1/62 (1.61%)  1
DYSPNOEA † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 1/11 (9.09%)  1 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
RESPIRATION ABNORMAL † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 1/11 (9.09%)  1 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (12.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cohort 1: LUM 200 mg qd - Period 1 Cohort 1: LUM 200 mg qd+IVA 150 mg q12h - Period 2 Cohort 1: LUM 200 mg qd+IVA 250 mg q12h - Period 2 Cohort 1: Placebo - Period 1 Cohort 1: Placebo - Period 2 Cohort 2: LUM 200 mg qd - Period 1 Cohort 2: LUM 400 mg qd - Period 1 Cohort 2: LUM 600 mg qd - Period 1 Cohort 3: LUM 400 mg q12h - Period 1 Cohort 2 and 3: Placebo (HO and HE) - Period 1 Cohort 2: LUM 200 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 400 mg qd+IVA 250 mg q12h (HO) - Period 2 Cohort 2: LUM 600 mg qd+IVA 250 mg q12h (HO&HE) - Period 2 Cohort 3: LUM 400 mg q12h+IVA 250 mg q12h (HO) - Period 2 Cohort 2 and 3: Placebo (HO and HE) - Period 2 Cohort 4: Placebo Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   29/41 (70.73%)      14/20 (70.00%)      12/20 (60.00%)      12/21 (57.14%)      15/21 (71.43%)      17/23 (73.91%)      18/21 (85.71%)      37/42 (88.10%)      6/11 (54.55%)      23/27 (85.19%)      12/21 (57.14%)      15/20 (75.00%)      26/38 (68.42%)      10/11 (90.91%)      20/27 (74.07%)      53/63 (84.13%)      51/62 (82.26%)    
Blood and lymphatic system disorders                                   
LYMPHADENOPATHY † 1  0/41 (0.00%)  0 1/20 (5.00%)  1 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Eosinophilia † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
Increased tendency to bruise † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
Leukopenia † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Cardiac disorders                                   
SINUS BRADYCARDIA † 1  0/41 (0.00%)  0 1/20 (5.00%)  1 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Tachycardia † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Congenital, familial and genetic disorders                                   
CYSTIC FIBROSIS LUNG † 1  2/41 (4.88%)  2 2/20 (10.00%)  2 1/20 (5.00%)  1 0/21 (0.00%)  0 1/21 (4.76%)  1 0/23 (0.00%)  0 2/21 (9.52%)  2 7/42 (16.67%)  7 1/11 (9.09%)  1 2/27 (7.41%)  2 1/21 (4.76%)  1 1/20 (5.00%)  1 3/38 (7.89%)  3 1/11 (9.09%)  1 4/27 (14.81%)  4 1/63 (1.59%)  1 0/62 (0.00%)  0
Cystic fibrosis related diabetes † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Ear and labyrinth disorders                                   
EAR PAIN † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 1/27 (3.70%)  1 0/63 (0.00%)  0 0/62 (0.00%)  0
EAR DISCOMFORT † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/63 (0.00%)  0 0/62 (0.00%)  0
EAR DISORDER † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
TINNITUS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 1/20 (5.00%)  2 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%) 
Vertigo † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  3 0/62 (0.00%)  0
Eye disorders                                   
EYELID OEDEMA † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
CONJUNCTIVITIS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Vision Blurred † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Gastrointestinal disorders                                   
DIARRHOEA † 1  1/41 (2.44%)  1 1/20 (5.00%)  1 1/20 (5.00%)  1 0/21 (0.00%)  0 2/21 (9.52%)  2 1/23 (4.35%)  1 3/21 (14.29%)  3 5/42 (11.90%)  5 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 2/20 (10.00%)  2 0/38 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 5/63 (7.94%)  9 7/62 (11.29%)  7
ABDOMINAL PAIN UPPER † 1  3/41 (7.32%)  3 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 2/23 (8.70%)  2 1/21 (4.76%)  1 0/42 (0.00%)  0 0/11 (0.00%)  0 2/27 (7.41%)  2 0/21 (0.00%)  0 1/20 (5.00%)  1 0/38 (0.00%)  0 1/11 (9.09%)  1 2/27 (7.41%)  2 7/63 (11.11%)  10 5/62 (8.06%)  5
ABDOMINAL DISCOMFORT † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 2/21 (9.52%)  2 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/63 (0.00%)  0 0/62 (0.00%)  0
ABDOMINAL PAIN † 1  1/41 (2.44%)  2 0/20 (0.00%)  0 0/20 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/23 (0.00%)  0 2/21 (9.52%)  3 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/21 (4.76%)  1 1/20 (5.00%)  1 2/38 (5.26%)  2 0/11 (0.00%)  0 1/27 (3.70%)  1 3/63 (4.76%)  5 1/62 (1.61%)  1
NAUSEA † 1  2/41 (4.88%)  2 0/20 (0.00%)  0 1/20 (5.00%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 1/21 (4.76%)  3 8/42 (19.05%)  8 1/11 (9.09%)  1 3/27 (11.11%)  3 0/21 (0.00%)  0 1/20 (5.00%)  2 3/38 (7.89%)  3 0/11 (0.00%)  0 2/27 (7.41%)  2 7/63 (11.11%)  9 7/62 (11.29%)  7
VOMITING † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 1/20 (5.00%)  1 0/21 (0.00%)  0 1/21 (4.76%)  1 0/23 (0.00%)  0 1/21 (4.76%)  2 2/42 (4.76%)  2 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 2/20 (10.00%)  2 2/38 (5.26%)  2 0/11 (0.00%)  0 1/27 (3.70%)  1 2/63 (3.17%)  2 4/62 (6.45%)  4
ABDOMINAL DISTENSION † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
ABDOMINAL PAIN LOWER † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
FLATULENCE † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 3/21 (14.29%)  3 3/42 (7.14%)  3 0/11 (0.00%)  0 0/27 (0.00%)  0 1/21 (4.76%)  1 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
GASTROOESOPHAGEAL REFLUX DISEASE † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 2/27 (7.41%)  2 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 5/62 (8.06%)  7
HYPOAESTHESIA ORAL † 1  0/41 (0.00%)  0 1/20 (5.00%)  1 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
CONSTIPATION † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 1/21 (4.76%)  1 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/21 (4.76%)  1 0/20 (0.00%)  0 2/38 (5.26%)  2 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
DISTAL ILEAL OBSTRUCTION SYNDROME † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 1/20 (5.00%)  1 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
DRY MOUTH † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/23 (4.35%)  1 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
DYSPEPSIA † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 3/62 (4.84%)  3
RECTAL HAEMORRHAGE † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 1/20 (5.00%)  1 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
TOOTHACHE † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 1/21 (4.76%)  1 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
FREQUENT BOWEL MOVEMENTS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 2/62 (3.23%)  3
FAECAL VOLUME INCREASED † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 1/62 (1.61%)  1
DYSPHAGIA † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
LIP SWELLING † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
POST-TUSSIVE VOMITING † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
STEATORRHOEA † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
General disorders                                   
FATIGUE † 1  1/41 (2.44%)  1 1/20 (5.00%)  1 0/20 (0.00%)  0 1/21 (4.76%)  1 3/21 (14.29%)  3 0/23 (0.00%)  0 1/21 (4.76%)  1 3/42 (7.14%)  4 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 1/20 (5.00%)  1 1/38 (2.63%)  1 0/11 (0.00%)  0 1/27 (3.70%)  1 6/63 (9.52%)  6 4/62 (6.45%)  6
PYREXIA † 1  3/41 (7.32%)  3 0/20 (0.00%)  0 0/20 (0.00%)  0 1/21 (4.76%)  1 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 6/42 (14.29%)  7 0/11 (0.00%)  0 3/27 (11.11%)  4 0/21 (0.00%)  0 1/20 (5.00%)  1 1/38 (2.63%)  1 0/11 (0.00%)  0 1/27 (3.70%)  1 9/63 (14.29%)  10 7/62 (11.29%)  7
PAIN † 1  3/41 (7.32%)  3 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 3/63 (4.76%)  3 0/62 (0.00%)  0
APPLICATION SITE PRURITUS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 1/20 (5.00%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
CATHETER SITE HAEMORRHAGE † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
CATHETER SITE PAIN † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 1/20 (5.00%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/63 (0.00%)  0 0/62 (0.00%)  0
CHEST DISCOMFORT † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
CHILLS † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/23 (4.35%)  1 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 2/63 (3.17%)  3 0/62 (0.00%)  0
FEELING HOT † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 2/63 (3.17%)  4 0/62 (0.00%)  0
INJECTION SITE HAEMORRHAGE † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Chest pain † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Exercise tolerance decreased † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Malaise † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Vessel puncture site bruise † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
NON-CARDIAC CHEST PAIN † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  2 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
APPLICATION SITE IRRITATION † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
FEELING OF BODY TEMPERATURE CHANGE † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  2 0/63 (0.00%)  0 0/62 (0.00%)  0
INFLUENZA LIKE ILLNESS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
Hepatobiliary disorders                                   
Hepatomegaly † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/63 (0.00%)  0 0/62 (0.00%)  0
Immune system disorders                                   
Seasonal allergy † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 1/27 (3.70%)  1 1/63 (1.59%)  1 0/62 (0.00%)  0
Infections and infestations                                   
VIRAL INFECTION † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 1/21 (4.76%)  1 1/21 (4.76%)  1 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
RHINITIS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 1/20 (5.00%)  1 0/21 (0.00%)  0 1/21 (4.76%)  1 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
UPPER RESPIRATORY TRACT INFECTION † 1  0/41 (0.00%)  0 2/20 (10.00%)  2 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 5/23 (21.74%)  5 1/21 (4.76%)  1 2/42 (4.76%)  2 0/11 (0.00%)  0 0/27 (0.00%)  0 3/21 (14.29%)  3 2/20 (10.00%)  2 3/38 (7.89%)  3 1/11 (9.09%)  1 4/27 (14.81%)  4 3/63 (4.76%)  4 3/62 (4.84%)  3
BACTERIAL DISEASE CARRIER † 1  0/41 (0.00%)  0 1/20 (5.00%)  2 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
CANDIDIASIS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 1/20 (5.00%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 0/62 (0.00%)  0
GASTROENTERITIS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 1/20 (5.00%)  1 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
ORAL HERPES † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 1/21 (4.76%)  1 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 1/27 (3.70%)  1 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
VIRAL UPPER RESPIRATORY TRACT INFECTION † 1  1/41 (2.44%)  1 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 2/42 (4.76%)  2 1/11 (9.09%)  1 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 4/63 (6.35%)  4 2/62 (3.23%)  2
Infective pulmonary exacerbation of cystic fibrosis † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 10/63 (15.87%)  11 7/62 (11.29%)  8
NASOPHARYNGITIS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 1/21 (4.76%)  1 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 1/21 (4.76%)  1 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 6/63 (9.52%)  6 2/62 (3.23%)  2
ORAL CANDIDIASIS † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 1/27 (3.70%)  1 0/63 (0.00%)  0 2/62 (3.23%)  2
PHARYNGITIS STREPTOCOCCAL † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 2/63 (3.17%)  2 0/62 (0.00%)  0
Rash pustular † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 2/62 (3.23%)  2
Acute sinusitis † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Bronchitis † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Bronchopulmonary aspergillosis allergic † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
INFLUENZA † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 1/23 (4.35%)  1 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 1/20 (5.00%)  1 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Conjunctivitis † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 1/42 (2.38%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 1/38 (2.63%)  1 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Gastroenteritis viral † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
Kidney infection † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 1/63 (1.59%)  1 0/62 (0.00%)  0
Lower respiratory tract infection bacterial † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/63 (0.00%)  0 1/62 (1.61%)  1
Lung infection † 1  0/41 (0.00%)  0 0/20 (0.00%)  0 0/20 (0.00%)  0 0/21 (0.00%)  0 0/21 (0.00%)  0 0/23 (0.00%)  0 0/21 (0.00%)  0 0/42 (0.00%)  0 0/11 (0.00%)  0 0/27 (0.00%)  0 0/21 (0.00%)  0 0/20 (0.00%)  0 0/38 (0.00%)  0 0/11 (0.00%)  0