A Phase 3 Rollover Study of Lumacaftor in Combination With Ivacaftor in Subjects 12 Years and Older With Cystic Fibrosis

Sponsor

Vertex Pharmaceuticals Incorporated (Industry)

Overall Status

Completed

CT.gov ID

NCT01931839

Collaborator

(none)

1,164

Enrollment

167

Locations

Arms

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of long-term treatment with lumacaftor in combination with ivacaftor in people 12 years and older with Cystic Fibrosis.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation	Drug: Lumacaftor Plus Ivacaftor Combination Drug: Ivacaftor	Phase 3

Detailed Description

This is a Phase 3, parallel group, multicenter, rollover study in participants with CF who are homozygous or heterozygous for the F508del CFTR mutation and who previously participated in Study 103 (Study VX12-809-103, NCT01807923), Study 104 (Study VX12-809-104, NCT01807949), or Cohort 4 of Study 102 (Study VX09-809-102, NCT01225211).

Study Design

Study Type:

Interventional

Actual Enrollment :

1164 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase 3, Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

Study Start Date :

Oct 1, 2013

Actual Primary Completion Date :

Apr 1, 2016

Actual Study Completion Date :

Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h Participants who received lumacaftor (LUM, VX-809) 600 milligram (mg) plus ivacaftor (IVA, VX-770) 250 mg fixed-dose combination (FDC) tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 or VX12-809-104, and will receive the same treatment in this study VX12-809-105 up to Week 96.	Drug: Lumacaftor Plus Ivacaftor Combination Fixed dose combination tablet, oral use Drug: Ivacaftor Film-coated tablet, oral use
Experimental: Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, and will receive LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 up to Week 96.	Drug: Lumacaftor Plus Ivacaftor Combination Fixed dose combination tablet, oral use Drug: Ivacaftor Film-coated tablet, oral use
Experimental: Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 or VX12-809-104, and will receive the same treatment in this study VX12-809-105 up to Week 96.	Drug: Lumacaftor Plus Ivacaftor Combination Fixed dose combination tablet, oral use
Experimental: Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, and will receive LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.	Drug: Lumacaftor Plus Ivacaftor Combination Fixed dose combination tablet, oral use
No Intervention: Arm 5 Part A: Observational Cohort Participants who received either LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening OR LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening OR placebo matched to LUM and IVA in the morning and evening, in the previous study VX12-809-103 or VX12-809-104, and will be observed (will not receive study drug) in this study VX12-809-105 for up to 2 years.
Experimental: Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102, and will receive the same treatment in this study VX12-809-105 up to Week 96.	Drug: Lumacaftor Plus Ivacaftor Combination Fixed dose combination tablet, oral use
Experimental: Arm 7 Part B: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102, and will receive LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.	Drug: Lumacaftor Plus Ivacaftor Combination Fixed dose combination tablet, oral use

Outcome Measures

Primary Outcome Measures

Part A Treatment Cohort: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Day 1 up to Week 105 (Study 105)]
AE: as 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 informed consent form is signed. AE includes serious as well as non-serious 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 newly developed at or after initial dosing of study drug was considered treatment-emergent.
Part B Treatment Cohort: Number of Participants With Treatment-Emergent AEs and SAEs [Day 1 up to Week 105 (Study 105)]
AE: as 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 informed consent form is signed. AE includes serious as well as non-serious 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 newly developed at or after initial dosing of study drug was considered treatment-emergent.

Secondary Outcome Measures

Part A Treatment Cohort: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) At Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)]
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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Part B Treatment Cohort: Absolute Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)]
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. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Part A Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)]
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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Part B Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)]
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. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Part A Treatment Cohort: Absolute Change From Baseline in Body Mass Index (BMI) at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)]
BMI = (Weight in kilogram [kg]) divided by (Stature in meters [m]) ^2. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Part B Treatment Cohort: Absolute Change From Baseline in BMI at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)]
BMI = (Weight [in kg]) divided by (Stature [in meters]) ^2. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Part A Treatment Cohort: Number of Pulmonary Exacerbations Events Per Patient-Year [Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)]
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events per patient year were reported, where patient years = total number of days on study/336. Analysis includes all events in the Cumulative Study Period for Arm 1 and 3, and all events in the Current Study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Part A Treatment Cohort: Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72 [Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 48, 72 (Study 105)]
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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Part B Treatment Cohort: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72 [Baseline (Study 102 Study), Day 15, Week 8, 16, 24, 48, 72 (Study 105)]
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. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Part A Treatment Cohort: Absolute Change From Baseline in BMI Z-score at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)]
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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Part A Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)]
Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Part B Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 [Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)]
Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Part A Treatment Cohort: Time-to-First Pulmonary Exacerbation [Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)]
Time-to-first pulmonary exacerbation was analyzed using the Kaplan-Meier estimates. Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Analysis was performed for the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Part A Treatment Cohort: Percentage of Participants With at Least 1 Pulmonary Exacerbation [Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)]
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Analysis was performed for the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Part A Treatment Cohort: Percentage of Participants With Response Based on Relative Change in Percent Predicted FEV1 From Baseline [Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60, 72, 84, 96 (Study 105)]
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). Percentage of participants with at least 5% and 10% relative change in percent predicted FEV1 from baseline were reported. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Part B Treatment Cohort: Percentage of Participants With Response Based on Relative Change in Percent Predicted FEV1 From Baseline [Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)]
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). Percentage of participants with at least 5% relative change in percent predicted FEV1 from Baseline were reported. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. As per planned analysis, endpoint evaluation included subjects from the parent study VX09-809-102 as well.
Part A Observation Cohort: Number of Participants With Serious Adverse Events (SAEs) [up to 2 years]
AE: as 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 non-serious 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent form (ICF), and where appropriate, signed assent form.
Participants entering the Part A Treatment Cohort: Completed 24 weeks of study drug treatment in Study 103 or Study 104 and elect to enroll in Part A treatment cohort.
Participants entering the Part B Treatment Cohort: Completed 56 days of study drug treatment in Cohort 4 of Study 102 and elect to enroll in Part B treatment cohort.
Participants entering the Part A Observational Cohort: Completed 24 weeks of study drug treatment in Study 103 or Study 104, but do not elect to enroll in the Part A Treatment Cohort or do not qualify to enroll in Part A treatment cohort.
Willing to remain on a stable CF medication regimen through the end of study (Part A and Part B Treatment Cohorts only).

Exclusion Criteria:

Any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant (e.g., cirrhosis with portal hypertension).
Pregnant and nursing females. Females of childbearing potential must have a negative pregnancy test at the Day 1 Visit.
History of drug intolerance in the prior study that would pose an additional risk to the participant in the opinion of investigator or Vertex.
History of poor compliance with study drug and/or procedures in the previous study as deemed by the investigator.
Participation in an investigational drug trial (including studies investigating lumacaftor and/or ivacaftor, or studies requiring blood collections with or without administration of study drug)

Contacts and Locations

Locations

	City	State	Country
1	Birmingham	Alabama	United States
2	Anchorage	Alaska	United States
3	Tucson	Arizona	United States
4	Little Rock	Arkansas	United States
5	La Jolla	California	United States
6	Loma Linda	California	United States
7	Longbeach	California	United States
8	Los Angeles	California	United States
9	Madera	California	United States
10	Oakland	California	United States
11	Palo Alto	California	United States
12	Sacramento	California	United States
13	Aurora	Colorado	United States
14	Denver	Colorado	United States
15	Hartford	Connecticut	United States
16	New Haven	Connecticut	United States
17	Altamonte Springs	Florida	United States
18	Hollywood	Florida	United States
19	Jacksonville	Florida	United States
20	Miami	Florida	United States
21	Orlando	Florida	United States
22	Tampa	Florida	United States
23	Atlanta	Georgia	United States
24	Boise	Idaho	United States
25	Chicago	Illinois	United States
26	Park Ridge	Illinois	United States
27	Peoria	Illinois	United States
28	Indianapolis	Indiana	United States
29	Iowa City	Iowa	United States
30	Kansas City	Kansas	United States
31	Lexington	Kentucky	United States
32	New Orleans	Louisiana	United States
33	South Portland	Maine	United States
34	Baltimore	Maryland	United States
35	Boston	Massachusetts	United States
36	Worcester	Massachusetts	United States
37	Ann Arbor	Michigan	United States
38	Detroit	Michigan	United States
39	Grand Rapids	Michigan	United States
40	Minneapolis	Minnesota	United States
41	Jackson	Mississippi	United States
42	Kansas City	Missouri	United States
43	St Louis	Missouri	United States
44	St. Louis	Missouri	United States
45	Omaha	Nebraska	United States
46	Bedford	New Hampshire	United States
47	Lebanon	New Hampshire	United States
48	Long Branch	New Jersey	United States
49	Morristown	New Jersey	United States
50	New Brunswick	New Jersey	United States
51	Albuquerque	New Mexico	United States
52	Albany	New York	United States
53	Buffalo	New York	United States
54	Lake Success	New York	United States
55	New York	New York	United States
56	Rochester	New York	United States
57	Syracuse	New York	United States
58	Valhalla	New York	United States
59	Chapel Hill	North Carolina	United States
60	Durham	North Carolina	United States
61	Akron	Ohio	United States
62	Cincinnati	Ohio	United States
63	Cleveland	Ohio	United States
64	Columbus	Ohio	United States
65	Dayton	Ohio	United States
66	Toledo	Ohio	United States
67	Oklahoma City	Oklahoma	United States
68	Portland	Oregon	United States
69	Hershey	Pennsylvania	United States
70	Philadelphia	Pennsylvania	United States
71	Pittsburgh	Pennsylvania	United States
72	Charelston	South Carolina	United States
73	Sioux Falls	South Dakota	United States
74	Knoxville	Tennessee	United States
75	Memphis	Tennessee	United States
76	Nashville	Tennessee	United States
77	Austin	Texas	United States
78	Dallas	Texas	United States
79	Fort Worth	Texas	United States
80	Houston	Texas	United States
81	San Antonio	Texas	United States
82	Tyler	Texas	United States
83	Salt Lake City	Utah	United States
84	Colchester	Vermont	United States
85	Charlottesville	Virginia	United States
86	Norfolk	Virginia	United States
87	Richmond	Virginia	United States
88	Seattle	Washington	United States
89	Spokane	Washington	United States
90	Morgantown	West Virginia	United States
91	Madison	Wisconsin	United States
92	Milwaukee	Wisconsin	United States
93	New Lambton Heights	New South Wales	Australia
94	Westmead	New South Wales	Australia
95	Adelaide	Queensland	Australia
96	Chermside	Queensland	Australia
97	Herston	Queensland	Australia
98	South Brisbane	Queensland	Australia
99	Nedlands		Australia
100	Subiaco		Australia
101	Innsbruck		Austria
102	Wels		Austria
103	Bruxelles		Belgium
104	Gent		Belgium
105	Leuven		Belgium
106	Liège		Belgium
107	Calgary	Alberta	Canada
108	Edmonton	Alberta	Canada
109	Vancouver	British Columbia	Canada
110	Halifax	Nova Scotia	Canada
111	Ottowa	Ontario	Canada
112	Toronto	Ontario	Canada
113	Montreal	Quebec	Canada
114	Brno		Czech Republic
115	Plzeň - Bory		Czech Republic
116	Praha 5		Czech Republic
117	Copenhagen		Denmark
118	Strasbourg	Bas Rhin	France
119	Marseille	Bouches-du-Rhone	France
120	Toulouse	Haute Garonne	France
121	Montpellier	Herault	France
122	Lille	Nord	France
123	Bron Cedex	Rhone	France
124	Bordeaux		France
125	Paris		France
126	Pierre Benite		France
127	Rhone		France
128	Roscoff		France
129	Muenchen	Bayem	Germany
130	Muenchen	Bayern	Germany
131	Berlin		Germany
132	Bochum		Germany
133	Erlangen		Germany
134	Essen		Germany
135	Frankfurt		Germany
136	Giessen		Germany
137	Hannover		Germany
138	Jena		Germany
139	Koeln		Germany
140	Leipzig		Germany
141	Muenchen		Germany
142	Tuebingen		Germany
143	Wuerzburg		Germany
144	Dublin		Ireland
145	Ancona		Italy
146	Firenze		Italy
147	Genova		Italy
148	Milano		Italy
149	Roma		Italy
150	Verona		Italy
151	Amsterdam		Netherlands
152	Den Haag		Netherlands
153	Nijmegen		Netherlands
154	Rotterdam		Netherlands
155	Barcelona		Spain
156	Valencia		Spain
157	Goteborg		Sweden
158	Stockholm		Sweden
159	Exeter	Devon	United Kingdom
160	Belfast		United Kingdom
161	Birmingham		United Kingdom
162	Bristol		United Kingdom
163	Leeds		United Kingdom
164	London		United Kingdom
165	Newcastle		United Kingdom
166	Nottingham		United Kingdom
167	Southampton		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:

NCT01931839

Other Study ID Numbers:

VX12-809-105

First Posted:

Aug 29, 2013

Last Update Posted:

May 12, 2017

Last Verified:

Apr 1, 2017

Additional relevant MeSH terms:

Cystic Fibrosis

Fibrosis

Ivacaftor

Study Results

Participant Flow

Recruitment Details	Study conducted in 2 parts: A & B. Part A consisted of Treatment Cohorts & Observational Cohort, which enrolled participants from Study VX12-809-103 (Study 103, NCT01807923) & Study VX12-809-104 (Study 104, NCT01807949). Part B consisted of Treatment Cohorts which enrolled participants from Cohort 4 of Study VX09-809-102 (Study 102, NCT01225211).
Pre-assignment Detail	Of 1164 participants enrolled, 1163 were dosed and included in this study.

Arm/Group Title	Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h	Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h	Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 5 Part A: Observational Cohort	Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7 Part B: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received lumacaftor (LUM, VX-809) 600 milligram (mg) plus ivacaftor (IVA, VX-770) 250 mg fixed-dose combination (FDC) tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 or VX12-809-104, received the same treatment in this study VX12-809-105 up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 or VX12-809-104, received the same treatment in this study VX12-809-105 up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.	Participants who received either LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening OR LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening OR placebo matched to LUM and IVA in the morning and evening, in the previous study VX12-809-103 or VX12-809-104, were observed (did not receive study drug) in this study VX12-809-105 for up to 2 years.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102, received the same treatment in this study VX12-809-105 up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102, received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.
Period Title: Overall Study
STARTED	335	178	340	176	19	55	60
Full Analysis Set (As Randomized)	334	179	340	176	19	55	60
Safety Analysis Set (As Dosed)	335	178	340	176	19	55	60
COMPLETED	294	152	301	162	18	50	56
NOT COMPLETED	41	26	39	14	1	5	4

Baseline Characteristics

Arm/Group Title	Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h	q12h Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h	Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 5 Part A: Observational Cohort	Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7 Part B: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h	Total
Arm/Group Description	Participants who received lumacaftor (LUM, VX-809) 600 milligram (mg) plus ivacaftor (IVA, VX-770) 250 mg fixed-dose combination (FDC) tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 or VX12-809-104, received the same treatment in this study VX12-809-105 up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 or VX12-809-104, received the same treatment in this study VX12-809-105 up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.	Participants who received either LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening OR LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening OR placebo matched to LUM and IVA in the morning and evening, in the previous study VX12-809-103 or VX12-809-104, were observed (did not receive study drug) in this study VX12-809-105 for up to 2 years.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102, received the same treatment in this study VX12-809-105 up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102, received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.	Total of all reporting groups
Overall Participants	335	178	340	176	19	55	60	1163
Age, Customized (Count of Participants)
12 years to less than 18 years	93 27.8%	47 26.4%	94 27.6%	47 26.7%	2 10.5%	0 0%	0 0%	283 24.3%
Greater than or equal to 18 years	242 72.2%	131 73.6%	246 72.4%	129 73.3%	17 89.5%	55 100%	60 100%	880 75.7%
Sex: Female, Male (Count of Participants)
Female	166 49.6%	89 50%	164 48.2%	86 48.9%	12 63.2%	25 45.5%	31 51.7%	573 49.3%
Male	169 50.4%	89 50%	176 51.8%	90 51.1%	7 36.8%	30 54.5%	29 48.3%	590 50.7%

Outcome Measures

1. Primary Outcome

Title	Part A Treatment Cohort: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	AE: as 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 informed consent form is signed. AE includes serious as well as non-serious 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 newly developed at or after initial dosing of study drug was considered treatment-emergent.
Time Frame	Day 1 up to Week 105 (Study 105)

Outcome Measure Data

Analysis Population Description
Safety Set (study 105) included all participants in Treatment Cohort Part A who were exposed to any amount of study drug.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	335	178	340	176
Participants with any AEs	331 98.8%	177 99.4%	333 97.9%	176 100%
Participants with SAEs	156 46.6%	77 43.3%	143 42.1%	89 50.6%

2. Primary Outcome

Title	Part B Treatment Cohort: Number of Participants With Treatment-Emergent AEs and SAEs
Description	AE: as 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 informed consent form is signed. AE includes serious as well as non-serious 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 newly developed at or after initial dosing of study drug was considered treatment-emergent.
Time Frame	Day 1 up to Week 105 (Study 105)

Outcome Measure Data

Analysis Population Description
Safety Set (study 105) included all participants in the Treatment Cohort Part B who were exposed to any amount of study drug.

Arm/Group Title	Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7: Part B Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received the same treatment in this VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	55	60
Participants with AEs	52 15.5%	57 32%
Participants with SAEs	18 5.4%	21 11.8%

3. Secondary Outcome

Title	Part A Treatment Cohort: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) At Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Time Frame	Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Outcome Measure Data

Analysis Population Description
Full Analysis Set (FAS) study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	319	173	317	165
Absolute Change at Day 15	3 (0.5)	2.8 (0.6)	2.8 (0.5)	3 (0.6)
Absolute Change at Week 8	3.1 (0.5)	2.8 (0.6)	3.4 (0.5)	4.2 (0.6)
Absolute Change at Week 16	2.6 (0.5)	2.7 (0.6)	2.5 (0.5)	3.6 (0.7)
Absolute Change at Week 24	2.9 (0.5)	2.4 (0.6)	2.7 (0.5)	3.4 (0.7)
Absolute Change at Week 36	2.7 (0.5)	2.2 (0.7)	1.9 (0.5)	3.1 (0.7)
Absolute Change at Week 48	1.5 (0.5)	1.8 (0.7)	1.4 (0.5)	2.1 (0.7)
Absolute Change at Week 60	1.7 (0.5)	2.1 (0.7)	1.6 (0.5)	1.4 (0.7)
Absolute Change at Week 72	1.2 (0.5)	1.9 (0.7)	0.5 (0.5)	1.5 (0.7)

4. Secondary Outcome

Title	Part B Treatment Cohort: Absolute Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	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. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Time Frame	Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7: Part B Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received the same treatment in this VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	52	57
Absolute Change at Day 15	-2 (8)	-3.4 (6.6)
Absolute Change at Week 8	-3.9 (7.4)	-1.8 (6.4)
Absolute Change at Week 16	-3.1 (9)	-2.8 (6.8)
Absolute Change at Week 24	-2.9 (7.7)	-2.5 (7.3)
Absolute Change at Week 36	-3.2 (7.9)	-2.3 (7.9)
Absolute Change at Week 48	-5.4 (11.2)	-2 (6)
Absolute Change at Week 60	-1.8 (10.1)	-1.9 (8.2)
Absolute Change at Week 72	-2.8 (9.2)	-7.8 (8.3)

5. Secondary Outcome

Title	Part A Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Time Frame	Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	319	173	317	165
Relative Change at Day 15	5.3 (0.9)	5.1 (1.2)	5.3 (0.9)	4.8 (1.2)
Relative Change at Week 8	5.6 (0.9)	5.6 (1.2)	6.2 (0.9)	7.1 (1.2)
Relative Change at Week 16	4.9 (0.9)	5.4 (1.2)	4.8 (0.9)	6.5 (1.2)
Relative Change at Week 24	5.1 (0.9)	4.9 (1.2)	5 (0.9)	6.1 (1.2)
Relative Change at Week 36	4.7 (0.9)	4 (1.2)	3.6 (0.9)	5.5 (1.2)
Relative Change at Week 48	2.7 (0.9)	3.6 (1.2)	2.9 (0.9)	3.6 (1.2)
Relative Change at Week 60	2.9 (0.9)	4.1 (1.2)	2.7 (0.9)	3.1 (1.2)
Relative Change at Week 72	2.4 (0.9)	3.8 (1.2)	1.4 (0.9)	2.6 (1.2)

6. Secondary Outcome

Title	Part B Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	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. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Time Frame	Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7: Part B Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received the same treatment in this VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	52	57
Relative Change at Day 15	-2.2 (13.6)	-5.8 (11.4)
Relative Change at Week 8	-5.2 (12.8)	-3.1 (11.4)
Relative Change at Week 16	-4.2 (15.8)	-4.9 (11.8)
Relative Change at Week 24	-3.4 (13.2)	-4.2 (12.6)
Relative Change at Week 36	-4.1 (12.5)	-3.5 (14.2)
Relative Change at Week 48	-6.9 (15.9)	-2.8 (10.6)
Relative Change at Week 60	-0.7 (16.6)	-2.6 (13.9)
Relative Change at Week 72	-3.3 (13.3)	-11.8 (10.7)

7. Secondary Outcome

Title	Part A Treatment Cohort: Absolute Change From Baseline in Body Mass Index (BMI) at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	BMI = (Weight in kilogram [kg]) divided by (Stature in meters [m]) ^2. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Time Frame	Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	329	178	338	175
Absolute Change at Day 15	0.56 (0.06)	0.06 (0.08)	0.5 (0.06)	0.1 (0.08)
Absolute Change at Week 8	0.58 (0.06)	0.14 (0.08)	0.55 (0.06)	0.27 (0.08)
Absolute Change at Week 16	0.58 (0.06)	0.19 (0.08)	0.53 (0.06)	0.35 (0.08)
Absolute Change at Week 24	0.61 (0.06)	0.22 (0.08)	0.62 (0.06)	0.41 (0.08)
Absolute Change at Week 36	0.66 (0.06)	0.33 (0.08)	0.72 (0.06)	0.59 (0.08)
Absolute Change at Week 48	0.63 (0.06)	0.42 (0.08)	0.71 (0.06)	0.62 (0.09)
Absolute Change at Week 60	0.71 (0.06)	0.54 (0.08)	0.8 (0.06)	0.62 (0.09)
Absolute Change at Week 72	0.72 (0.06)	0.52 (0.08)	0.69 (0.06)	0.62 (0.09)

8. Secondary Outcome

Title	Part B Treatment Cohort: Absolute Change From Baseline in BMI at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	BMI = (Weight [in kg]) divided by (Stature [in meters]) ^2. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Time Frame	Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7: Part B Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received the same treatment in this VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	55	60
Absolute Change at Day 15	-0.05 (0.52)	-0.03 (0.69)
Absolute Change at Week 8	-0.01 (0.82)	0.14 (0.84)
Absolute Change at Week 16	0.08 (1.02)	0.2 (1.09)
Absolute Change at Week 24	0.04 (0.92)	0.14 (1.08)
Absolute Change at Week 36	0.07 (0.54)	0.85 (1.23)
Absolute Change at Week 48	0.05 (0.64)	0.81 (1.55)
Absolute Change at Week 60	0.08 (0.7)	0.58 (1.23)
Absolute Change at Week 72	0.08 (0.71)	0.41 (1.28)

9. Secondary Outcome

Title	Part A Treatment Cohort: Number of Pulmonary Exacerbations Events Per Patient-Year
Description	Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events per patient year were reported, where patient years = total number of days on study/336. Analysis includes all events in the Cumulative Study Period for Arm 1 and 3, and all events in the Current Study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Time Frame	Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)

Outcome Measure Data

Analysis Population Description
FAS (Study 103/104) was used for Arm 1 & 3, & included all participants randomized in previous studies & dosed. FAS (Study 105) was used for Arm 2 & 4, & included all participants randomized in Part A Treatment Cohort & dosed in current study 105. 'Number Analyzed'=those participants who were evaluable at specified time points for each arm.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who were randomized to LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who were randomized to LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	368	179	369	176
Number (95% Confidence Interval) [events per patient year]	0.38	0.42	0.32	0.37

10. Secondary Outcome

Title	Part A Treatment Cohort: Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72
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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Time Frame	Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 48, 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	324	174	325	170
Absolute Change at Day 15	5.9 (0.9)	2.3 (1.2)	6.2 (0.9)	3.5 (1.2)
Absolute Change at Week 8	5 (0.9)	4.1 (1.2)	5.1 (0.9)	6.8 (1.2)
Absolute Change at Week 16	4.1 (0.9)	2.8 (1.2)	6.4 (0.9)	7 (1.2)
Absolute Change at Week 24	6 (0.9)	3.8 (1.2)	6.1 (0.9)	4.7 (1.3)
Absolute Change at Week 48	2 (0.9)	3.1 (1.3)	3.7 (0.9)	1.5 (1.3)
Absolute Change at Week 72	3.2 (0.9)	3.3 (1.3)	5.7 (0.9)	3.3 (1.3)

11. Secondary Outcome

Title	Part B Treatment Cohort: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72
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. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Time Frame	Baseline (Study 102 Study), Day 15, Week 8, 16, 24, 48, 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7: Part B Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received the same treatment in this VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	55	59
Absolute Change at Day 15	3.9 (18)	-4.1 (18.1)
Absolute Change at Week 8	4.8 (18.6)	1 (18.2)
Absolute Change at Week 16	6.2 (17.2)	-0.2 (17)
Absolute Change at Week 24	6.8 (19.1)	-1.2 (17.9)
Absolute Change at Week 48	2 (14)	4.9 (15.6)
Absolute Change at Week 72	8.5 (21.8)	2.2 (18.8)

12. Secondary Outcome

Title	Part A Treatment Cohort: Absolute Change From Baseline in BMI Z-score at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
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. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Time Frame	Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	117	56	109	60
Absolute Change at Day 15	0.16 (0.04)	-0.01 (0.06)	0.14 (0.04)	-0.02 (0.05)
Absolute Change at Week 8	0.15 (0.04)	0.04 (0.06)	0.16 (0.04)	0.08 (0.05)
Absolute Change at Week 16	0.12 (0.04)	0.08 (0.06)	0.15 (0.04)	0.07 (0.05)
Absolute Change at Week 24	0.14 (0.04)	0.08 (0.06)	0.17 (0.04)	0.1 (0.05)
Absolute Change at Week 36	0.14 (0.04)	0.13 (0.06)	0.16 (0.04)	0.14 (0.05)
Absolute Change at Week 48	0.09 (0.04)	0.13 (0.06)	0.11 (0.04)	0.12 (0.06)
Absolute Change at Week 60	0.11 (0.04)	0.16 (0.06)	0.14 (0.04)	0.13 (0.06)
Absolute Change at Week 72	0.06 (0.04)	0.12 (0.06)	0.04 (0.04)	0.08 (0.06)

13. Secondary Outcome

Title	Part A Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4.
Time Frame	Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received the same treatment in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	329	178	338	175
Absolute Change at Day 15	1.7 (2.6)	-0.1 (1.8)	1.3 (2.9)	0.1 (1.2)
Absolute Change at Week 8	1.8 (2.9)	0.2 (2.1)	1.5 (3.1)	0.6 (1.9)
Absolute Change at Week 16	1.9 (3.2)	0.4 (2.6)	1.6 (3.3)	1 (2.5)
Absolute Change at Week 24	2.2 (3.5)	0.6 (2.6)	2 (3.6)	1.2 (2.8)
Absolute Change at Week 36	2.3 (3.8)	1 (3.4)	2.4 (3.8)	1.9 (3.4)
Absolute Change at Week 48	2.4 (4.2)	1.3 (3.7)	2.5 (4.3)	2.1 (3.7)
Absolute Change at Week 60	2.7 (4.6)	1.7 (4.2)	2.9 (4.6)	2.2 (4.4)
Absolute Change at Week 72	2.9 (4.9)	1.7 (4.8)	2.7 (4.9)	2.3 (4.7)

14. Secondary Outcome

Title	Part B Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72
Description	Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.
Time Frame	Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Arm/Group Title	Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7: Part B Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received the same treatment in this VX12-809-105 (NCT01931839) up to Week 96.	Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (NCT01225211), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	55	60
Absolute Change at Day 15	-0.1 (1.5)	-0.1 (1.8)
Absolute Change at Week 8	0 (2.3)	0.4 (2.3)
Absolute Change at Week 16	0.3 (2.8)	0.6 (2.9)
Absolute Change at Week 24	0.2 (2.6)	0.4 (3)
Absolute Change at Week 36	0.3 (1.7)	2.3 (3.3)
Absolute Change at Week 48	0.2 (2)	2.2 (4.3)
Absolute Change at Week 60	0.3 (2.3)	1.5 (3.3)
Absolute Change at Week 72	0.2 (2.3)	1.1 (3.4)

15. Secondary Outcome

Title	Part A Treatment Cohort: Time-to-First Pulmonary Exacerbation
Description	Time-to-first pulmonary exacerbation was analyzed using the Kaplan-Meier estimates. Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Analysis was performed for the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Time Frame	Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)

Outcome Measure Data

Analysis Population Description
FAS (Study 103/104) was used for Arm 1 and 3, and included all participants randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all participants randomized in the Part A Treatment Cohort and dosed in current study 105.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who were randomized to LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who were randomized to LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	368	179	369	176
Median (Inter-Quartile Range) [days]	364	505	481	466

16. Secondary Outcome

Title	Part A Treatment Cohort: Percentage of Participants With at Least 1 Pulmonary Exacerbation
Description	Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Analysis was performed for the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Time Frame	Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period)

Outcome Measure Data

Analysis Population Description
FAS (Study 103/104) was used for Arm 1 and 3, and included all participants randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all participants randomized in the Part A Treatment Cohort and dosed in current study 105.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who were randomized to LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who were randomized to LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	368	179	369	176
Number (95% Confidence Interval) [percentage of participants]	64.7 19.3%	53.6 30.1%	59.9 17.6%	55.7 31.6%

17. Secondary Outcome

Title	Part A Treatment Cohort: Percentage of Participants With Response Based on Relative Change in Percent Predicted FEV1 From Baseline
Description	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). Percentage of participants with at least 5% and 10% relative change in percent predicted FEV1 from baseline were reported. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period.
Time Frame	Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60, 72, 84, 96 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS (Study 103/104) was used for Arm 1 and 3, and included all participants randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all participants randomized in the Part A Treatment Cohort and dosed in current study 105.

Arm/Group Title	Arm 1: Part A - LUM 600 mg qd/ IVA 250 mg q12h	Arm 2: Part A - Placebo- LUM 600 mg qd/ IVA 250 mg q12h	Arm 3: Part A - LUM 400 mg q12h/ IVA 250 mg q12h	Arm 4: Part A - Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who were randomized to LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 (NCT01931839) up to Week 96.	Participants who were randomized to LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949).	Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 (NCT01931839) up to Week 96.
Measure Participants	368	179	369	176
Day 15: >=5% Change	39.4 11.8%	42.5 23.9%	40.9 12%	42.6 24.2%
Day 15: >=10% Change	25 7.5%	26.8 15.1%	24.7 7.3%	26.7 15.2%
Week 8: >=5% Change	39.7 11.9%	38 21.3%	39.3 11.6%	48.9 27.8%
Week 8: >=10% Change	26.9 8%	23.5 13.2%	26.6 7.8%	35.8 20.3%
Week 16: >=5% Change	37.2 11.1%	36.9 20.7%	36.9 10.9%	46.6 26.5%
Week 16: >=10% Change	25.5 7.6%	25.1 14.1%	26.3 7.7%	28.4 16.1%
Week 24: >=5% Change	35.6 10.6%	38 21.3%	33.6 9.9%	42.6 24.2%
Week 24: >=10% Change	24.5 7.3%	21.8 12.2%	22.5 6.6%	32.4 18.4%
Week 36: >=5% Change	35.3 10.5%	32.4 18.2%	31.7 9.3%	38.6 21.9%
Week 36: >=10% Change	23.4 7%	22.9 12.9%	22.2 6.5%	27.3 15.5%
Week 48: >=5% Change	30.2 9%	32.4 18.2%	30.9 9.1%	36.4 20.7%
Week 48: >=10% Change	21.7 6.5%	21.8 12.2%	21.4 6.3%	19.9 11.3%
Week 60: >=5% Change	30.4 9.1%	32.4 18.2%	29.3 8.6%	38.6 21.9%
Week 60: >=10% Change	20.4 6.1%	25.1 14.1%	19.2 5.6%	24.4 13.9%
Week 72: >=5% Change	29.3 8.7%	34.6 19.4%	25.5 7.5%	33 18.8%
Week 72: >=10% Change	18.2 5.4%	22.3 12.5%	18.2 5.4%	23.3 13.2%
Week 84: >=5% Change	23.1 6.9%	28.5 16%	23.3 6.9%	26.1 14.8%
Week 84: >=10% Change	14.9 4.4%	21.2 11.9%	15.7 4.6%	19.9 11.3%
Week 96: >=5% Change	15.5 4.6%	14.5 8.1%	13.8 4.1%	15.3 8.7%
Week 96: >=10% Change	8.7 2.6%	10.1 5.7%	10.3 3%	9.1 5.2%

18. Secondary Outcome

Title	Part B Treatment Cohort: Percentage of Participants With Response Based on Relative Change in Percent Predicted FEV1 From Baseline
Description	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). Percentage of participants with at least 5% relative change in percent predicted FEV1 from Baseline were reported. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. As per planned analysis, endpoint evaluation included subjects from the parent study VX09-809-102 as well.
Time Frame	Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Outcome Measure Data

Analysis Population Description
FAS (Study 102) was used for Arm 6 and 7, and included all participants randomized in the cohort 4 of study 102 and dosed.

Arm/Group Title	Arm 6: Part B LUM 400 mg q12h/ IVA 250 mg q12h	Arm 7: Part B Placebo- LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who were randomized to LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102 (NCT01225211).	Participants who were randomized to placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102 (NCT01225211).
Measure Participants	62	63
Day 15: >=5% Change	21 6.3%	12.7 7.1%
Week 8: >=5% Change	11.3 3.4%	19 10.7%
Week 16: >=5% Change	19.4 5.8%	15.9 8.9%
Week 24: >=5% Change	12.9 3.9%	12.7 7.1%
Week 36: >=5% Change	6.5 1.9%	6.3 3.5%
Week 48: >=5% Change	6.5 1.9%	4.8 2.7%
Week 60: >=5% Change	6.5 1.9%	6.3 3.5%
Week 72: >=5% Change	3.2 1%	0 0%
Week 84: >=5% Change	1.6 0.5%	1.6 0.9%
Week 96: >=5% Change	0 0%	0 0%

19. Secondary Outcome

Title	Part A Observation Cohort: Number of Participants With Serious Adverse Events (SAEs)
Description	AE: as 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 non-serious 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.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description
Safety Set (study 105) included all participants who were enrolled in Part A Observation Cohort.

Arm/Group Title	Arm 5: Part A Observational Cohort
Arm/Group Description	Participants who received either LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening or LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening or placebo matched to LUM and IVA in the morning and evening, in the previous study VX12-809-103 (NCT01807923) or VX12-809-104 (NCT01807949), were observed (did not receive study drug) in this study VX12-809-105 (NCT01931839) for up to 2 years.
Measure Participants	19
Number [participants]	7 2.1%

Adverse Events

	Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h		Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h		Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h		Arm 5 Part A: Observational Cohort		Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 7 Part B: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h
Time Frame
Adverse Event Reporting Description	Non-SAEs were not collected for Arm 5: Part A Observational Cohort. Only SAEs were collected.

Arm/Group Title	Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h		Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h		Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h		Arm 5 Part A: Observational Cohort		Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 7 Part B: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Participants who received lumacaftor (LUM, VX-809) 600 milligram (mg) plus ivacaftor (IVA, VX-770) 250 mg fixed-dose combination (FDC) tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 or VX12-809-104, received the same treatment in this study VX12-809-105 up to Week 96.		Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, received LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 up to Week 96.		Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 or VX12-809-104, received the same treatment in this study VX12-809-105 up to Week 96.		Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.		Participants who received either LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening OR LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening OR placebo matched to LUM and IVA in the morning and evening, in the previous study VX12-809-103 or VX12-809-104, were observed (did not receive study drug) in this study VX12-809-105 for up to 2 years.		Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102, received the same treatment in this study VX12-809-105 up to Week 96.		Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102, received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96.
All Cause Mortality
	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	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h		Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h		Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h		Arm 5 Part A: Observational Cohort		Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 7 Part B: Placebo - 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
Total	156/335 (46.6%)		77/178 (43.3%)		143/340 (42.1%)		89/176 (50.6%)		7/19 (36.8%)		18/55 (32.7%)		21/60 (35%)
Blood and lymphatic system disorders
Haemolytic anaemia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Leukocytosis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Cardiac disorders
Bradycardia	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Cardiac arrest	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Myocardial ischaemia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Ventricular tachycardia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Cardiomyopathy	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		1/19 (5.3%)		0/55 (0%)		0/60 (0%)
Congenital, familial and genetic disorders
Cystic fibrosis related diabetes	2/335 (0.6%)		0/178 (0%)		3/340 (0.9%)		3/176 (1.7%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Cystic fibrosis pancreatic	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Ear and labyrinth disorders
Deafness	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Eye disorders
Cataract subcapsular	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Gastrointestinal disorders
Distal intestinal obstruction syndrome	2/335 (0.6%)		1/178 (0.6%)		6/340 (1.8%)		10/176 (5.7%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Small intestinal obstruction	5/335 (1.5%)		1/178 (0.6%)		1/340 (0.3%)		2/176 (1.1%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Abdominal pain	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Abdominal pain upper	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		3/176 (1.7%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Constipation	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Diarrhoea	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Intestinal obstruction	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Gastritis	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Gastrooesophageal reflux disease	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Abdominal wall haematoma	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Faecaloma	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Food poisoning	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Gastrointestinal angiodysplasia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Hiatus hernia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Inguinal hernia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Mechanical ileus	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pancreatitis	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
General disorders
Chest discomfort	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Chest pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Fatigue	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pyrexia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Medical device site thrombosis	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Hepatobiliary disorders
Cholelithiasis	2/335 (0.6%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Biliary colic	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Cholangitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Immune system disorders
Drug hypersensitivity	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Anaphylactic reaction	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Serum sickness	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Type IV hypersensitivity reaction	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	113/335 (33.7%)		61/178 (34.3%)		111/340 (32.6%)		59/176 (33.5%)		5/19 (26.3%)		15/55 (27.3%)		15/60 (25%)
Pneumonia	6/335 (1.8%)		4/178 (2.2%)		5/340 (1.5%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Influenza	0/335 (0%)		2/178 (1.1%)		6/340 (1.8%)		3/176 (1.7%)		1/19 (5.3%)		0/55 (0%)		0/60 (0%)
Appendicitis	3/335 (0.9%)		2/178 (1.1%)		1/340 (0.3%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Bronchopulmonary aspergillosis allergic	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Acute sinusitis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Bronchitis	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Device related infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Device related sepsis	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Gastroenteritis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Respiratory tract infection bacterial	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Sepsis	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Tracheobronchitis	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Anal abscess	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Bacteraemia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Cellulitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Chronic sinusitis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Gastroenteritis viral	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Hepatitis E	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Infective exacerbation of bronchiectasis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Lower respiratory tract infection bacterial	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		1/19 (5.3%)		0/55 (0%)		0/60 (0%)
Lung infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Lung infection pseudomonal	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Mediastinitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Mycobacterium abscessus infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Nasopharyngitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Parotitis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Periorbital abscess	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Peritonitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Peritonsillar abscess	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pneumonia bacterial	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pneumonia pseudomonal	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Post procedural infection	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pyelonephritis acute	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Respiratory syncytial virus infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Rhinovirus infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Sinusitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Staphylococcal sepsis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Tooth abscess	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Viral upper respiratory tract infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Kidney infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Injury, poisoning and procedural complications
Foot fracture	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Ligament rupture	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Lower limb fracture	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pelvic fracture	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Upper limb fracture	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Facial bones fracture	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		1/55 (1.8%)		0/60 (0%)
Investigations
Pulmonary function test decreased	3/335 (0.9%)		1/178 (0.6%)		3/340 (0.9%)		0/176 (0%)		0/19 (0%)		1/55 (1.8%)		0/60 (0%)
Alanine aminotransferase increased	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Aspartate aminotransferase increased	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Bacterial test positive	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Forced expiratory volume decreased	0/335 (0%)		0/178 (0%)		0/340 (0%)		3/176 (1.7%)		0/19 (0%)		1/55 (1.8%)		0/60 (0%)
Gammaglutamyltransferase increased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Influenza B virus test positive	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Weight decreased	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Influenza A virus test positive	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Dehydration	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Hyperglycaemia	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Hypoglycaemia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pathological fracture	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Polyarthritis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Rhabdomyolysis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Nervous system disorders
Cauda equina syndrome	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Cerebrovascular accident	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Dizziness	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Juvenile myoclonic epilepsy	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Lumbar radiculopathy	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Neurological symptom	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Vocal cord paralysis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Psychiatric disorders
Depression	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		1/60 (1.7%)
Anxiety	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Adjustment disorder	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Adjustment disorder with depressed mood	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Major depression	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Suicidal ideation	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		1/19 (5.3%)		0/55 (0%)		0/60 (0%)
Suicide attempt	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Renal and urinary disorders
Acute kidney injury	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Nephrolithiasis	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Renal colic	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Nephrotic syndrome	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	17/335 (5.1%)		7/178 (3.9%)		10/340 (2.9%)		6/176 (3.4%)		1/19 (5.3%)		0/55 (0%)		2/60 (3.3%)
Pneumothorax spontaneous	5/335 (1.5%)		1/178 (0.6%)		3/340 (0.9%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Respiration abnormal	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		3/176 (1.7%)		0/19 (0%)		1/55 (1.8%)		1/60 (1.7%)
Atelectasis	1/335 (0.3%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Nasal polyps	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Acute respiratory failure	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Asthma	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Bronchiectasis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Dyspnoea	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Hypoxia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Lower respiratory tract congestion	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pleural effusion	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pleuritic pain	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pulmonary bulla	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Pulmonary embolism	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Respiratory distress	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Respiratory failure	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Skin and subcutaneous tissue disorders
Drug eruption	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Rash maculo-papular	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Vascular disorders
Deep vein thrombosis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Hypertensive crisis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/19 (0%)		0/55 (0%)		0/60 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h		Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h		Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h		Arm 5 Part A: Observational Cohort		Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h		Arm 7 Part B: Placebo - 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
Total	328/335 (97.9%)		177/178 (99.4%)		332/340 (97.6%)		173/176 (98.3%)		0/0 (NaN)		52/55 (94.5%)		57/60 (95%)
Blood and lymphatic system disorders
Lymphadenopathy	7/335 (2.1%)		1/178 (0.6%)		5/340 (1.5%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Eosinophilia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Anaemia	3/335 (0.9%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Splenomegaly	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Thrombocytopenia	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bone marrow oedema	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haemoconcentration	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Increased tendency to bruise	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Iron deficiency anaemia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Leukocytosis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Macrocytosis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Neutropenia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Cardiac disorders
Cyanosis	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Palpitations	5/335 (1.5%)		0/178 (0%)		4/340 (1.2%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tachycardia	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		3/176 (1.7%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sinus tachycardia	1/335 (0.3%)		2/178 (1.1%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ventricular extrasystoles	2/335 (0.6%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sinus arrhythmia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Extrasystoles	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Atrioventricular block first degree	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Left ventricular hypertrophy	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ventricular tachycardia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Congenital, familial and genetic disorders
Thyroglossal cyst	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Cystic fibrosis related diabetes	10/335 (3%)		10/178 (5.6%)		8/340 (2.4%)		5/176 (2.8%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Cystic fibrosis hepatic disease	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Cystic fibrosis lung	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dermoid cyst	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Naevus flammeus	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ear and labyrinth disorders
Ear pain	6/335 (1.8%)		6/178 (3.4%)		5/340 (1.5%)		4/176 (2.3%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Tinnitus	5/335 (1.5%)		6/178 (3.4%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vertigo	1/335 (0.3%)		2/178 (1.1%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Cerumen impaction	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Deafness neurosensory	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypoacusis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Deafness unilateral	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ear congestion	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ear pruritus	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Middle ear effusion	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Motion sickness	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ototoxicity	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tympanic membrane perforation	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Vestibular disorder	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ear discomfort	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Endocrine disorders
Hypothyroidism	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Goitre	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Growth hormone deficiency	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Androgen deficiency	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Cushing's syndrome	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eye disorders
Blepharospasm	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Conjunctivitis allergic	2/335 (0.6%)		2/178 (1.1%)		4/340 (1.2%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vision blurred	0/335 (0%)		0/178 (0%)		0/340 (0%)		5/176 (2.8%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eye swelling	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ocular hyperaemia	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Diabetic retinopathy	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Visual acuity reduced	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eye haemorrhage	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eye pain	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glaucoma	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Myopia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ulcerative keratitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gastrointestinal disorders
Diarrhoea	46/335 (13.7%)		24/178 (13.5%)		41/340 (12.1%)		28/176 (15.9%)		0/0 (NaN)		5/55 (9.1%)		9/60 (15%)
Nausea	45/335 (13.4%)		24/178 (13.5%)		34/340 (10%)		27/176 (15.3%)		0/0 (NaN)		5/55 (9.1%)		4/60 (6.7%)
Abdominal pain	42/335 (12.5%)		20/178 (11.2%)		33/340 (9.7%)		15/176 (8.5%)		0/0 (NaN)		3/55 (5.5%)		2/60 (3.3%)
Constipation	28/335 (8.4%)		13/178 (7.3%)		24/340 (7.1%)		10/176 (5.7%)		0/0 (NaN)		3/55 (5.5%)		3/60 (5%)
Vomiting	26/335 (7.8%)		6/178 (3.4%)		27/340 (7.9%)		13/176 (7.4%)		0/0 (NaN)		1/55 (1.8%)		2/60 (3.3%)
Abdominal pain upper	18/335 (5.4%)		9/178 (5.1%)		20/340 (5.9%)		11/176 (6.3%)		0/0 (NaN)		6/55 (10.9%)		0/60 (0%)
Gastrooesophageal reflux disease	16/335 (4.8%)		8/178 (4.5%)		14/340 (4.1%)		4/176 (2.3%)		0/0 (NaN)		5/55 (9.1%)		2/60 (3.3%)
Flatulence	13/335 (3.9%)		5/178 (2.8%)		7/340 (2.1%)		7/176 (4%)		0/0 (NaN)		0/55 (0%)		3/60 (5%)
Dyspepsia	8/335 (2.4%)		5/178 (2.8%)		10/340 (2.9%)		6/176 (3.4%)		0/0 (NaN)		1/55 (1.8%)		2/60 (3.3%)
Abdominal distension	11/335 (3.3%)		2/178 (1.1%)		10/340 (2.9%)		4/176 (2.3%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Toothache	3/335 (0.9%)		4/178 (2.2%)		7/340 (2.1%)		3/176 (1.7%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Abdominal discomfort	4/335 (1.2%)		1/178 (0.6%)		5/340 (1.5%)		4/176 (2.3%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Distal intestinal obstruction syndrome	3/335 (0.9%)		5/178 (2.8%)		5/340 (1.5%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dental discomfort	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Lip swelling	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Pancreatitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Pancreatitis acute	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Post-tussive vomiting	1/335 (0.3%)		3/178 (1.7%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Gastritis	3/335 (0.9%)		3/178 (1.7%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Abdominal pain lower	0/335 (0%)		1/178 (0.6%)		3/340 (0.9%)		3/176 (1.7%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haemorrhoids	2/335 (0.6%)		1/178 (0.6%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Steatorrhoea	2/335 (0.6%)		0/178 (0%)		2/340 (0.6%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Frequent bowel movements	2/335 (0.6%)		1/178 (0.6%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dysphagia	2/335 (0.6%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Faecaloma	1/335 (0.3%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dry mouth	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Enteritis	0/335 (0%)		0/178 (0%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Food poisoning	0/335 (0%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haematochezia	2/335 (0.6%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Inguinal hernia	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tooth impacted	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Aphthous ulcer	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bowel movement irregularity	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Breath odour	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hiatus hernia	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ileus	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Intestinal obstruction	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Mouth ulceration	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Paraesthesia oral	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rectal haemorrhage	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Varices oesophageal	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Abdominal hernia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Abdominal tenderness	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Anal fistula	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Barrett's oesophagus	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Cheilitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Chronic gastritis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dental caries	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Diarrhoea haemorrhagic	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Diverticulum intestinal	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Duodenal ulcer	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Enterocolitis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Epigastric discomfort	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eructation	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Faecal volume decreased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Faecal volume increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Faeces discoloured	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Faeces soft	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gastric mucosal hypertrophy	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gastrointestinal motility disorder	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gastrointestinal pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gingival bleeding	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gingival erythema	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gingival pain	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gingival recession	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gingivitis ulcerative	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glossitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glossodynia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haemorrhoids thrombosed	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Impaired gastric emptying	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Intussusception	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Irritable bowel syndrome	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Malabsorption	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Malpositioned teeth	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Melaena	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Mucous stools	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oesophageal irritation	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oesophageal mucosal hyperplasia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oesophageal pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oesophagitis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oral disorder	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oral mucosal blistering	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oral pain	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oral papule	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pancreatic insufficiency	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pneumoperitoneum	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Reflux gastritis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Retching	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Salivary hypersecretion	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stomatitis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tooth delamination	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Umbilical hernia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Micturition urgency	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
General disorders
Pyrexia	60/335 (17.9%)		27/178 (15.2%)		47/340 (13.8%)		31/176 (17.6%)		0/0 (NaN)		6/55 (10.9%)		8/60 (13.3%)
Fatigue	45/335 (13.4%)		26/178 (14.6%)		36/340 (10.6%)		22/176 (12.5%)		0/0 (NaN)		7/55 (12.7%)		6/60 (10%)
Pain	12/335 (3.6%)		5/178 (2.8%)		6/340 (1.8%)		3/176 (1.7%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Malaise	3/335 (0.9%)		4/178 (2.2%)		9/340 (2.6%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Chest discomfort	7/335 (2.1%)		6/178 (3.4%)		3/340 (0.9%)		7/176 (4%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Chest pain	7/335 (2.1%)		6/178 (3.4%)		2/340 (0.6%)		4/176 (2.3%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Asthenia	6/335 (1.8%)		2/178 (1.1%)		5/340 (1.5%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Chills	4/335 (1.2%)		3/178 (1.7%)		6/340 (1.8%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Influenza like illness	2/335 (0.6%)		2/178 (1.1%)		5/340 (1.5%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Non-cardiac chest pain	3/335 (0.9%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oedema peripheral	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Feeling cold	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Application site vesicles	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Catheter site haematoma	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Catheter site pain	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Exercise tolerance decreased	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Peripheral swelling	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Sensation of foreign body	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vessel puncture site bruise	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Application site irritation	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Catheter site rash	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Drug intolerance	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Drug withdrawal syndrome	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Face oedema	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Facial pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hernia	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hunger	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Infusion site bruising	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Infusion site pruritus	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Injection site reaction	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Mass	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Medical device pain	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Medical device site ulcer	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Temperature intolerance	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vaccination site pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vessel puncture site pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vessel puncture site phlebitis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Infusion site inflammation	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Local swelling	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Medical device site extravasation	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Stress	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Adjustment disorder	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Adjustment disorder with anxiety	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hepatobiliary disorders
Cholecystitis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Jaundice	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Cholelithiasis	1/335 (0.3%)		2/178 (1.1%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Biliary colic	0/335 (0%)		0/178 (0%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hepatomegaly	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Cholecystitis chronic	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hepatic pain	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hepatic steatosis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Immune system disorders
Seasonal allergy	13/335 (3.9%)		5/178 (2.8%)		19/340 (5.6%)		5/176 (2.8%)		0/0 (NaN)		3/55 (5.5%)		3/60 (5%)
Drug hypersensitivity	4/335 (1.2%)		3/178 (1.7%)		4/340 (1.2%)		4/176 (2.3%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Hypersensitivity	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Allergy to arthropod bite	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Allergy to animal	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Allergy to arthropod sting	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
House dust allergy	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Immunisation reaction	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Mycotic allergy	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Reaction to food additive	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Serum sickness	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Smoke sensitivity	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	185/335 (55.2%)		92/178 (51.7%)		173/340 (50.9%)		91/176 (51.7%)		0/0 (NaN)		18/55 (32.7%)		20/60 (33.3%)
Nasopharyngitis	51/335 (15.2%)		31/178 (17.4%)		66/340 (19.4%)		27/176 (15.3%)		0/0 (NaN)		6/55 (10.9%)		6/60 (10%)
Upper respiratory tract infection	42/335 (12.5%)		26/178 (14.6%)		49/340 (14.4%)		29/176 (16.5%)		0/0 (NaN)		7/55 (12.7%)		6/60 (10%)
Sinusitis	41/335 (12.2%)		19/178 (10.7%)		47/340 (13.8%)		13/176 (7.4%)		0/0 (NaN)		7/55 (12.7%)		2/60 (3.3%)
Viral upper respiratory tract infection	34/335 (10.1%)		12/178 (6.7%)		24/340 (7.1%)		10/176 (5.7%)		0/0 (NaN)		3/55 (5.5%)		4/60 (6.7%)
Influenza	20/335 (6%)		11/178 (6.2%)		21/340 (6.2%)		15/176 (8.5%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Rhinitis	24/335 (7.2%)		7/178 (3.9%)		21/340 (6.2%)		12/176 (6.8%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Upper respiratory tract infection bacterial	16/335 (4.8%)		14/178 (7.9%)		18/340 (5.3%)		7/176 (4%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Bronchitis	15/335 (4.5%)		8/178 (4.5%)		12/340 (3.5%)		8/176 (4.5%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Oral candidiasis	21/335 (6.3%)		4/178 (2.2%)		7/340 (2.1%)		9/176 (5.1%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Vulvovaginal mycotic infection	13/335 (3.9%)		4/178 (2.2%)		14/340 (4.1%)		7/176 (4%)		0/0 (NaN)		2/55 (3.6%)		2/60 (3.3%)
Respiratory tract infection viral	11/335 (3.3%)		4/178 (2.2%)		11/340 (3.2%)		3/176 (1.7%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Pharyngitis	10/335 (3%)		3/178 (1.7%)		5/340 (1.5%)		8/176 (4.5%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urinary tract infection	8/335 (2.4%)		6/178 (3.4%)		7/340 (2.1%)		5/176 (2.8%)		0/0 (NaN)		2/55 (3.6%)		0/60 (0%)
Respiratory tract infection	6/335 (1.8%)		6/178 (3.4%)		7/340 (2.1%)		6/176 (3.4%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Gastroenteritis	8/335 (2.4%)		2/178 (1.1%)		7/340 (2.1%)		5/176 (2.8%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Bronchopulmonary aspergillosis allergic	9/335 (2.7%)		6/178 (3.4%)		4/340 (1.2%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Vulvovaginal candidiasis	4/335 (1.2%)		4/178 (2.2%)		6/340 (1.8%)		6/176 (3.4%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Otitis media	9/335 (2.7%)		1/178 (0.6%)		8/340 (2.4%)		1/176 (0.6%)		0/0 (NaN)		2/55 (3.6%)		0/60 (0%)
Gastroenteritis viral	12/335 (3.6%)		2/178 (1.1%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Lung infection pseudomonal	5/335 (1.5%)		3/178 (1.7%)		6/340 (1.8%)		3/176 (1.7%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Acute sinusitis	5/335 (1.5%)		1/178 (0.6%)		5/340 (1.5%)		4/176 (2.3%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Chronic sinusitis	4/335 (1.2%)		4/178 (2.2%)		5/340 (1.5%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Respiratory tract infection bacterial	9/335 (2.7%)		2/178 (1.1%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tonsillitis	5/335 (1.5%)		1/178 (0.6%)		5/340 (1.5%)		3/176 (1.7%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Conjunctivitis	6/335 (1.8%)		1/178 (0.6%)		2/340 (0.6%)		4/176 (2.3%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Viral infection	5/335 (1.5%)		2/178 (1.1%)		5/340 (1.5%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Pharyngitis streptococcal	7/335 (2.1%)		1/178 (0.6%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lower respiratory tract infection	3/335 (0.9%)		1/178 (0.6%)		5/340 (1.5%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		3/60 (5%)
Bacterial disease carrier	3/335 (0.9%)		0/178 (0%)		5/340 (1.5%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Laryngitis	4/335 (1.2%)		2/178 (1.1%)		2/340 (0.6%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Pneumonia	2/335 (0.6%)		4/178 (2.2%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lower respiratory tract infection bacterial	4/335 (1.2%)		1/178 (0.6%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Cellulitis	1/335 (0.3%)		2/178 (1.1%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Cystitis	0/335 (0%)		1/178 (0.6%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ear infection	2/335 (0.6%)		1/178 (0.6%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lower respiratory tract infection viral	3/335 (0.9%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oral herpes	2/335 (0.6%)		0/178 (0%)		2/340 (0.6%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		3/60 (5%)
Folliculitis	2/335 (0.6%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lung infection	1/335 (0.3%)		0/178 (0%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchitis viral	1/335 (0.3%)		2/178 (1.1%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Kidney infection	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Onychomycosis	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tooth abscess	3/335 (0.9%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchopulmonary aspergillosis	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Clostridium difficile colitis	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eye infection	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Fungal skin infection	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Genital candidiasis	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Herpes dermatitis	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hordeolum	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oral fungal infection	0/335 (0%)		0/178 (0%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Otitis externa	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rash pustular	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sinusitis bacterial	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stoma site infection	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tinea infection	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchitis bacterial	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Conjunctivitis bacterial	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hand-foot-and-mouth disease	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Herpes zoster	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Infectious mononucleosis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Mycobacterial disease carrier	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Superinfection bacterial	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gastrointestinal viral infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Infective exacerbation of bronchiectasis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Mycobacterium abscessus infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Oropharyngitis fungal	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Otitis externa fungal	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Parotitis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Vaginal infection	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Tracheitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Varicella	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Viral pharyngitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Wound infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Acarodermatitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Acne pustular	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Adenoiditis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Anal abscess	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Angular cheilitis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Arthritis infective	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Atypical mycobacterial lower respiratory tract infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Atypical mycobacterial pneumonia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bacterial vaginosis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchitis fungal	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Clostridium difficile infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Conjunctivitis viral	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Epididymitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Erythema infectiosum	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Febrile infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Fungal infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Furuncle	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gastroenteritis norovirus	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Genital herpes	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Genital herpes simplex	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Genital infection fungal	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gingivitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Groin abscess	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haemophilus infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Helicobacter infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hepatitis C	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Impetigo	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Implant site infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Labyrinthitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Localised infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oral bacterial infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Otitis media acute	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Overgrowth bacterial	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Overgrowth fungal	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Papilloma viral infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pneumonia staphylococcal	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Post procedural infection	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pseudomonas bronchitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pseudomonas infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pulpitis dental	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Salpingo-oophoritis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Respiratory syncytial virus bronchitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Respiratory tract infection fungal	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sepsis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin bacterial infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Small intestinal bacterial overgrowth	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sputum purulent	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Subcutaneous abscess	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tooth infection	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tracheobronchitis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Trichomoniasis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Upper respiratory fungal infection	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urinary tract infection enterococcal	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vaginitis bacterial	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vulvovaginitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Injury, poisoning and procedural complications
Contusion	7/335 (2.1%)		3/178 (1.7%)		8/340 (2.4%)		3/176 (1.7%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Procedural pain	10/335 (3%)		3/178 (1.7%)		8/340 (2.4%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Ligament sprain	5/335 (1.5%)		2/178 (1.1%)		5/340 (1.5%)		6/176 (3.4%)		0/0 (NaN)		2/55 (3.6%)		0/60 (0%)
Muscle strain	5/335 (1.5%)		4/178 (2.2%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Arthropod bite	4/335 (1.2%)		3/178 (1.7%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		2/55 (3.6%)		0/60 (0%)
Laceration	2/335 (0.6%)		3/178 (1.7%)		5/340 (1.5%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Fall	1/335 (0.3%)		0/178 (0%)		5/340 (1.5%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Joint dislocation	2/335 (0.6%)		1/178 (0.6%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Joint injury	3/335 (0.9%)		0/178 (0%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rib fracture	4/335 (1.2%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Concussion	2/335 (0.6%)		2/178 (1.1%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sunburn	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Ligament rupture	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Limb injury	4/335 (1.2%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Periorbital haemorrhage	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Post procedural swelling	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Skin abrasion	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Tooth fracture	1/335 (0.3%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Foot fracture	2/335 (0.6%)		1/178 (0.6%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Road traffic accident	5/335 (1.5%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Chest injury	3/335 (0.9%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Post-traumatic pain	2/335 (0.6%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Facial bones fracture	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Back injury	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hand fracture	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ligament injury	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Meniscus injury	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sports injury	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Superficial injury of eye	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Animal bite	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Arthropod sting	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Incisional hernia	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Post procedural discomfort	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Procedural nausea	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stoma site discomfort	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stoma site irritation	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Thermal burn	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Traumatic haematoma	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Wrist fracture	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Accidental exposure to product	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Animal scratch	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ankle fracture	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Avulsion fracture	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Burns second degree	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Confusion postoperative	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Corneal abrasion	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ear injury	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Epicondylitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Excoriation	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Exposure to toxic agent	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eye injury	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Face injury	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Forearm fracture	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Head injury	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Heat stroke	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Incision site haematoma	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Infusion related reaction	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Limb crushing injury	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lip injury	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Muscle injury	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Muscle rupture	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Neck injury	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nerve injury	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Peripheral nerve injury	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Post procedural complication	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Procedural anxiety	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Procedural headache	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Procedural vomiting	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Radius fracture	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sinus barotrauma	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Soft tissue injury	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Splinter	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stoma site erythema	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stoma site haemorrhage	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stoma site pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stoma site ulcer	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Stress fracture	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Upper limb fracture	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Wound	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Investigations
Pulmonary function test decreased	35/335 (10.4%)		23/178 (12.9%)		29/340 (8.5%)		15/176 (8.5%)		0/0 (NaN)		2/55 (3.6%)		3/60 (5%)
Blood creatine phosphokinase increased	26/335 (7.8%)		23/178 (12.9%)		23/340 (6.8%)		15/176 (8.5%)		0/0 (NaN)		5/55 (9.1%)		10/60 (16.7%)
Forced expiratory volume decreased	26/335 (7.8%)		12/178 (6.7%)		28/340 (8.2%)		15/176 (8.5%)		0/0 (NaN)		2/55 (3.6%)		7/60 (11.7%)
Bacterial test positive	29/335 (8.7%)		7/178 (3.9%)		30/340 (8.8%)		11/176 (6.3%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Alanine aminotransferase increased	10/335 (3%)		14/178 (7.9%)		14/340 (4.1%)		15/176 (8.5%)		0/0 (NaN)		2/55 (3.6%)		4/60 (6.7%)
Aspartate aminotransferase increased	12/335 (3.6%)		13/178 (7.3%)		15/340 (4.4%)		13/176 (7.4%)		0/0 (NaN)		1/55 (1.8%)		7/60 (11.7%)
Blood glucose decreased	4/335 (1.2%)		1/178 (0.6%)		4/340 (1.2%)		2/176 (1.1%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Blood alkaline phosphatase increased	2/335 (0.6%)		1/178 (0.6%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Weight decreased	16/335 (4.8%)		7/178 (3.9%)		18/340 (5.3%)		3/176 (1.7%)		0/0 (NaN)		2/55 (3.6%)		0/60 (0%)
Blood creatinine increased	5/335 (1.5%)		6/178 (3.4%)		3/340 (0.9%)		7/176 (4%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Blood glucose increased	5/335 (1.5%)		7/178 (3.9%)		2/340 (0.6%)		6/176 (3.4%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Fungal test positive	5/335 (1.5%)		4/178 (2.2%)		6/340 (1.8%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Vitamin D decreased	6/335 (1.8%)		3/178 (1.7%)		3/340 (0.9%)		5/176 (2.8%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Liver function test increased	1/335 (0.3%)		6/178 (3.4%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
White blood cell count increased	4/335 (1.2%)		5/178 (2.8%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Atypical mycobacterium test positive	3/335 (0.9%)		5/178 (2.8%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Influenza A virus test positive	3/335 (0.9%)		3/178 (1.7%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Neutrophil count increased	2/335 (0.6%)		3/178 (1.7%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Gamma-glutamyltransferase increased	3/335 (0.9%)		1/178 (0.6%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Blood magnesium decreased	2/335 (0.6%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Clostridium test positive	2/335 (0.6%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Oxygen saturation decreased	2/335 (0.6%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Transaminases increased	2/335 (0.6%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
White blood cells urine positive	2/335 (0.6%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Activated partial thromboplastin time prolonged	1/335 (0.3%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Blood bicarbonate decreased	2/335 (0.6%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood immunoglobulin E increased	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Body temperature increased	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Crystal urine present	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haemoglobin decreased	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Protein urine present	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Staphylococcus test positive	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood calcium increased	1/335 (0.3%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood potassium increased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood pressure systolic increased	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood thyroid stimulating hormone increased	2/335 (0.6%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood urea increased	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Breath sounds abnormal	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eosinophil count increased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Forced vital capacity decreased	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glucose urine present	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glycosylated haemoglobin increased	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hepatic enzyme increased	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Monocyte count increased	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pseudomonas test positive	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood lactate dehydrogenase increased	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood pressure increased	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Candida test positive	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Electrocardiogram QT prolonged	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glucose tolerance test abnormal	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Heart rate increased	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Human rhinovirus test positive	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Influenza B virus test positive	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
International normalised ratio increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood albumin decreased	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Blood immunoglobulin G increased	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Blood iron decreased	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Blood potassium decreased	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Helicobacter test positive	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Influenza virus test positive	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Lymphocyte count increased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Reticulocyte percentage increased	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Sputum abnormal	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Platelet count increased	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Prothrombin time prolonged	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Respiratory syncytial virus test positive	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Weight increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Aspergillus test positive	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood androstenedione increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood cholesterol increased	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood cortisol decreased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood creatine increased	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood glucose fluctuation	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood magnesium increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood phosphorus decreased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood phosphorus increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood sodium decreased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood sodium increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood testosterone decreased	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood testosterone increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blood urine present	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Burkholderia test positive	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Citrobacter test positive	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Computerised tomogram thorax abnormal	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Coronavirus test positive	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dehydroepiandrosterone increased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Electrocardiogram PR shortened	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Electrocardiogram ST segment elevation	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Electrocardiogram abnormal	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Epstein-Barr virus antibody positive	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Escherichia test positive	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Grip strength decreased	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haemoglobin increased	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Human metapneumovirus test positive	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Human papilloma virus test positive	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Mean cell volume increased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Myoglobin blood increased	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Precancerous cells present	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Red blood cells urine positive	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Reticulocyte count increased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rubulavirus test positive	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ultrasound liver abnormal	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urine analysis abnormal	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urine bilirubin increased	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urine ketone body present	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Viral test positive	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vitamin A decreased	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vitamin B12 decreased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vitamin E decreased	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
White blood cell count decreased	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Metabolism and nutrition disorders
Vitamin D deficiency	11/335 (3.3%)		5/178 (2.8%)		16/340 (4.7%)		6/176 (3.4%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Decreased appetite	12/335 (3.6%)		8/178 (4.5%)		6/340 (1.8%)		9/176 (5.1%)		0/0 (NaN)		2/55 (3.6%)		3/60 (5%)
Hypoglycaemia	5/335 (1.5%)		7/178 (3.9%)		3/340 (0.9%)		3/176 (1.7%)		0/0 (NaN)		1/55 (1.8%)		2/60 (3.3%)
Hyperglycaemia	7/335 (2.1%)		4/178 (2.2%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		3/60 (5%)
Iron deficiency	6/335 (1.8%)		1/178 (0.6%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glucose tolerance impaired	3/335 (0.9%)		1/178 (0.6%)		2/340 (0.6%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Dehydration	1/335 (0.3%)		1/178 (0.6%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hyponatraemia	2/335 (0.6%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Alcohol intolerance	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Gout	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Hypokalaemia	0/335 (0%)		3/178 (1.7%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Hyperkalaemia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Hypomagnesaemia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Hypovitaminosis	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Selenium deficiency	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Vitamin A deficiency	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Vitamin E deficiency	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Malnutrition	2/335 (0.6%)		1/178 (0.6%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vitamin K deficiency	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Diabetes mellitus	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Metabolic acidosis	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypocalcaemia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hyponatraemic syndrome	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Underweight	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vitamin B12 deficiency	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Weight gain poor	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	20/335 (6%)		11/178 (6.2%)		25/340 (7.4%)		13/176 (7.4%)		0/0 (NaN)		3/55 (5.5%)		8/60 (13.3%)
Back pain	20/335 (6%)		12/178 (6.7%)		14/340 (4.1%)		10/176 (5.7%)		0/0 (NaN)		1/55 (1.8%)		5/60 (8.3%)
Myalgia	19/335 (5.7%)		7/178 (3.9%)		13/340 (3.8%)		5/176 (2.8%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Musculoskeletal chest pain	13/335 (3.9%)		9/178 (5.1%)		12/340 (3.5%)		3/176 (1.7%)		0/0 (NaN)		2/55 (3.6%)		3/60 (5%)
Musculoskeletal pain	8/335 (2.4%)		6/178 (3.4%)		5/340 (1.5%)		6/176 (3.4%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Pain in extremity	6/335 (1.8%)		5/178 (2.8%)		7/340 (2.1%)		2/176 (1.1%)		0/0 (NaN)		2/55 (3.6%)		2/60 (3.3%)
Muscle spasms	3/335 (0.9%)		2/178 (1.1%)		7/340 (2.1%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Arthritis	4/335 (1.2%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Neck pain	5/335 (1.5%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Musculoskeletal stiffness	2/335 (0.6%)		2/178 (1.1%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Osteopenia	4/335 (1.2%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tendonitis	2/335 (0.6%)		0/178 (0%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Joint swelling	0/335 (0%)		0/178 (0%)		5/340 (1.5%)		0/176 (0%)		0/0 (NaN)		2/55 (3.6%)		0/60 (0%)
Arthropathy	1/335 (0.3%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Osteoporosis	2/335 (0.6%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Bursitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Costochondritis	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Flank pain	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Groin pain	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Intervertebral disc degeneration	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Joint stiffness	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Pathological fracture	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Tenosynovitis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Medial tibial stress syndrome	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Muscular weakness	2/335 (0.6%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Osteochondrosis	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Polyarthritis	1/335 (0.3%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Spinal pain	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Temporomandibular joint syndrome	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Exostosis	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Joint range of motion decreased	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Juvenile idiopathic arthritis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Muscle contracture	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Muscle tightness	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Musculoskeletal discomfort	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Myalgia intercostal	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Plantar fasciitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rheumatoid arthritis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Synovial cyst	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tendon pain	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Torticollis	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bone pain	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Chondropathy	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Coccydynia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Intervertebral disc annular tear	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Intervertebral disc protrusion	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Mastication disorder	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Muscle fatigue	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Muscle oedema	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pain in jaw	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rhabdomyolysis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rotator cuff syndrome	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Scoliosis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tendon disorder	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign breast neoplasm	0/335 (0%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Melanocytic naevus	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Basal cell carcinoma	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lipoma	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Malignant melanoma	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Metastases to bone	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Neurofibroma	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Seborrhoeic keratosis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin papilloma	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Uterine leiomyoma	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nervous system disorders
Headache	58/335 (17.3%)		25/178 (14%)		56/340 (16.5%)		22/176 (12.5%)		0/0 (NaN)		7/55 (12.7%)		7/60 (11.7%)
Sinus headache	13/335 (3.9%)		9/178 (5.1%)		11/340 (3.2%)		3/176 (1.7%)		0/0 (NaN)		2/55 (3.6%)		2/60 (3.3%)
Dizziness	9/335 (2.7%)		7/178 (3.9%)		6/340 (1.8%)		6/176 (3.4%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Migraine	6/335 (1.8%)		2/178 (1.1%)		5/340 (1.5%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Lethargy	2/335 (0.6%)		1/178 (0.6%)		2/340 (0.6%)		4/176 (2.3%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Syncope	2/335 (0.6%)		1/178 (0.6%)		2/340 (0.6%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Paraesthesia	3/335 (0.9%)		0/178 (0%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypoaesthesia	4/335 (1.2%)		0/178 (0%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Anosmia	3/335 (0.9%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Somnolence	2/335 (0.6%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Circadian rhythm sleep disorder	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Carpal tunnel syndrome	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Migraine with aura	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Neuralgia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Presyncope	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Restless legs syndrome	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sciatica	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Seizure	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tension headache	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tremor	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ageusia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Aphonia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Coordination abnormal	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dysgeusia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypersomnia	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hyposmia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Intercostal neuralgia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nerve compression	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Neuropathy peripheral	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nystagmus	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Olfactory nerve disorder	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Disturbance in attention	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Dry eye	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eye pruritus	1/335 (0.3%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lacrimation increased	1/335 (0.3%)		0/178 (0%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Product Issues
Device dislocation	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Device occlusion	4/335 (1.2%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Device leakage	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Psychiatric disorders
Anxiety	14/335 (4.2%)		5/178 (2.8%)		9/340 (2.6%)		3/176 (1.7%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Insomnia	7/335 (2.1%)		9/178 (5.1%)		9/340 (2.6%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Depressed mood	1/335 (0.3%)		0/178 (0%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Panic attack	4/335 (1.2%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Attention deficit/hyperactivity disorder	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Adjustment disorder with depressed mood	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Agitation	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Confusional state	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Decreased interest	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Disturbance in social behaviour	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Encopresis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Food aversion	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hallucination, visual	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Intentional self-injury	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Listless	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nervousness	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Obsessive-compulsive disorder	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sleep disorder	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Somnambulism	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Suicidal ideation	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Depression	7/335 (2.1%)		4/178 (2.2%)		8/340 (2.4%)		10/176 (5.7%)		0/0 (NaN)		1/55 (1.8%)		2/60 (3.3%)
Renal and urinary disorders
Stress urinary incontinence	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Nephrolithiasis	3/335 (0.9%)		3/178 (1.7%)		2/340 (0.6%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Acute kidney injury	1/335 (0.3%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dysuria	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Chromaturia	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Chronic kidney disease	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nocturia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pollakiuria	0/335 (0%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Calculus urinary	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Glycosuria	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Haematuria	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hydronephrosis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypernatriuria	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypocitraturia	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pyelocaliectasis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Renal colic	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Renal failure	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Renal hypertrophy	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Renal pain	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Renal tubular disorder	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tubulointerstitial nephritis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urinary retention	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urine abnormality	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	6/335 (1.8%)		3/178 (1.7%)		8/340 (2.4%)		4/176 (2.3%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Metrorrhagia	6/335 (1.8%)		2/178 (1.1%)		2/340 (0.6%)		3/176 (1.7%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Abnormal withdrawal bleeding	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Cervical polyp	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Ovarian cyst	1/335 (0.3%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Vaginal haemorrhage	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Menstruation irregular	3/335 (0.9%)		1/178 (0.6%)		3/340 (0.9%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Menorrhagia	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vaginal discharge	1/335 (0.3%)		0/178 (0%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Polycystic ovaries	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Breast tenderness	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Endometriosis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Uterine haemorrhage	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vulvovaginal pruritus	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Acquired hydrocele	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Adnexa uteri mass	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Amenorrhoea	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Balanoposthitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bartholin's cyst	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Erectile dysfunction	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Gynaecomastia	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ovarian cyst ruptured	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ovarian hyperfunction	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pelvic pain	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Polymenorrhoea	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pruritus genital	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rectocele	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Testicular cyst	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Testicular pain	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Uterine prolapse	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vaginal inflammation	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vulvovaginal discomfort	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vulvovaginal pain	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	167/335 (49.9%)		92/178 (51.7%)		145/340 (42.6%)		82/176 (46.6%)		0/0 (NaN)		18/55 (32.7%)		18/60 (30%)
Sputum increased	75/335 (22.4%)		36/178 (20.2%)		79/340 (23.2%)		37/176 (21%)		0/0 (NaN)		11/55 (20%)		18/60 (30%)
Haemoptysis	61/335 (18.2%)		37/178 (20.8%)		68/340 (20%)		29/176 (16.5%)		0/0 (NaN)		8/55 (14.5%)		10/60 (16.7%)
Dyspnoea	52/335 (15.5%)		33/178 (18.5%)		53/340 (15.6%)		36/176 (20.5%)		0/0 (NaN)		9/55 (16.4%)		13/60 (21.7%)
Oropharyngeal pain	45/335 (13.4%)		21/178 (11.8%)		44/340 (12.9%)		22/176 (12.5%)		0/0 (NaN)		8/55 (14.5%)		7/60 (11.7%)
Respiration abnormal	39/335 (11.6%)		30/178 (16.9%)		34/340 (10%)		25/176 (14.2%)		0/0 (NaN)		7/55 (12.7%)		21/60 (35%)
Nasal congestion	40/335 (11.9%)		20/178 (11.2%)		37/340 (10.9%)		23/176 (13.1%)		0/0 (NaN)		8/55 (14.5%)		4/60 (6.7%)
Productive cough	20/335 (6%)		10/178 (5.6%)		21/340 (6.2%)		13/176 (7.4%)		0/0 (NaN)		2/55 (3.6%)		2/60 (3.3%)
Sinus congestion	22/335 (6.6%)		9/178 (5.1%)		18/340 (5.3%)		12/176 (6.8%)		0/0 (NaN)		7/55 (12.7%)		3/60 (5%)
Rhinorrhoea	26/335 (7.8%)		8/178 (4.5%)		12/340 (3.5%)		7/176 (4%)		0/0 (NaN)		2/55 (3.6%)		4/60 (6.7%)
Wheezing	16/335 (4.8%)		7/178 (3.9%)		13/340 (3.8%)		12/176 (6.8%)		0/0 (NaN)		3/55 (5.5%)		3/60 (5%)
Paranasal sinus hypersecretion	14/335 (4.2%)		4/178 (2.2%)		18/340 (5.3%)		7/176 (4%)		0/0 (NaN)		3/55 (5.5%)		1/60 (1.7%)
Respiratory tract congestion	19/335 (5.7%)		5/178 (2.8%)		14/340 (4.1%)		3/176 (1.7%)		0/0 (NaN)		5/55 (9.1%)		1/60 (1.7%)
Asthma	13/335 (3.9%)		6/178 (3.4%)		16/340 (4.7%)		5/176 (2.8%)		0/0 (NaN)		2/55 (3.6%)		1/60 (1.7%)
Lower respiratory tract congestion	20/335 (6%)		3/178 (1.7%)		12/340 (3.5%)		5/176 (2.8%)		0/0 (NaN)		0/55 (0%)		4/60 (6.7%)
Rales	10/335 (3%)		9/178 (5.1%)		10/340 (2.9%)		11/176 (6.3%)		0/0 (NaN)		1/55 (1.8%)		2/60 (3.3%)
Sputum discoloured	13/335 (3.9%)		4/178 (2.2%)		12/340 (3.5%)		6/176 (3.4%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Rhinitis allergic	9/335 (2.7%)		2/178 (1.1%)		12/340 (3.5%)		7/176 (4%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Dysphonia	10/335 (3%)		2/178 (1.1%)		10/340 (2.9%)		6/176 (3.4%)		0/0 (NaN)		0/55 (0%)		3/60 (5%)
Bronchospasm	7/335 (2.1%)		4/178 (2.2%)		8/340 (2.4%)		8/176 (4.5%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Upper-airway cough syndrome	9/335 (2.7%)		10/178 (5.6%)		7/340 (2.1%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Epistaxis	10/335 (3%)		2/178 (1.1%)		10/340 (2.9%)		4/176 (2.3%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Nasal polyps	5/335 (1.5%)		3/178 (1.7%)		8/340 (2.4%)		9/176 (5.1%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Pleuritic pain	10/335 (3%)		5/178 (2.8%)		4/340 (1.2%)		6/176 (3.4%)		0/0 (NaN)		1/55 (1.8%)		4/60 (6.7%)
Dyspnoea exertional	8/335 (2.4%)		4/178 (2.2%)		6/340 (1.8%)		4/176 (2.3%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Increased viscosity of bronchial secretion	7/335 (2.1%)		6/178 (3.4%)		4/340 (1.2%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Upper respiratory tract congestion	1/335 (0.3%)		2/178 (1.1%)		5/340 (1.5%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Increased bronchial secretion	4/335 (1.2%)		1/178 (0.6%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Painful respiration	2/335 (0.6%)		1/178 (0.6%)		5/340 (1.5%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Throat irritation	4/335 (1.2%)		0/178 (0%)		5/340 (1.5%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal discharge discolouration	2/335 (0.6%)		1/178 (0.6%)		4/340 (1.2%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchiectasis	3/335 (0.9%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Hypoxia	4/335 (1.2%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Paranasal sinus discomfort	2/335 (0.6%)		2/178 (1.1%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Bronchial hyperreactivity	2/335 (0.6%)		1/178 (0.6%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Lung infiltration	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Nocturnal dyspnoea	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Obstructive airways disorder	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Oropharyngeal discomfort	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Rhinalgia	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Bronchial obstruction	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		5/176 (2.8%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchial secretion retention	2/335 (0.6%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Increased upper airway secretion	1/335 (0.3%)		1/178 (0.6%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sneezing	2/335 (0.6%)		0/178 (0%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal oedema	1/335 (0.3%)		1/178 (0.6%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal mucosal disorder	0/335 (0%)		2/178 (1.1%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pleurisy	2/335 (0.6%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pulmonary pain	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sinus disorder	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sputum retention	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Upper respiratory tract inflammation	1/335 (0.3%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal dryness	3/335 (0.9%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal inflammation	1/335 (0.3%)		2/178 (1.1%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal obstruction	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pharyngeal erythema	1/335 (0.3%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pneumothorax spontaneous	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Allergic sinusitis	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lung disorder	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal septum deviation	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pleural effusion	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rhonchi	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sinus polyp	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Sleep apnoea syndrome	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Acquired diaphragmatic eventration	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Allergic cough	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Allergic respiratory disease	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchial irritation	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Bronchostenosis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hyperventilation	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypopnoea	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Increased viscosity of upper respiratory secretion	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lung consolidation	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Lung hyperinflation	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal discomfort	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Nasal turbinate hypertrophy	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Orthopnoea	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Paranasal cyst	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pharyngeal oedema	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pleural fibrosis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pneumomediastinum	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pneumonitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pulmonary arterial hypertension	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pulmonary bulla	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pulmonary embolism	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pulmonary hypertension	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Reflux laryngitis	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Respiratory tract haemorrhage	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Respiratory tract inflammation	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Respiratory tract irritation	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tachypnoea	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Throat tightness	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tonsillolith	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tracheal disorder	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Tracheal inflammation	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin and subcutaneous tissue disorders
Rash	10/335 (3%)		9/178 (5.1%)		22/340 (6.5%)		7/176 (4%)		0/0 (NaN)		0/55 (0%)		2/60 (3.3%)
Acne	3/335 (0.9%)		3/178 (1.7%)		8/340 (2.4%)		7/176 (4%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pruritus	6/335 (1.8%)		3/178 (1.7%)		6/340 (1.8%)		6/176 (3.4%)		0/0 (NaN)		0/55 (0%)		4/60 (6.7%)
Night sweats	5/335 (1.5%)		7/178 (3.9%)		4/340 (1.2%)		2/176 (1.1%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Urticaria	6/335 (1.8%)		5/178 (2.8%)		5/340 (1.5%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Alopecia	4/335 (1.2%)		3/178 (1.7%)		3/340 (0.9%)		4/176 (2.3%)		0/0 (NaN)		2/55 (3.6%)		2/60 (3.3%)
Dermatitis contact	1/335 (0.3%)		0/178 (0%)		4/340 (1.2%)		6/176 (3.4%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Dermatitis allergic	5/335 (1.5%)		1/178 (0.6%)		4/340 (1.2%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Drug eruption	5/335 (1.5%)		3/178 (1.7%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Eczema	1/335 (0.3%)		2/178 (1.1%)		3/340 (0.9%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Red man syndrome	1/335 (0.3%)		3/178 (1.7%)		3/340 (0.9%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Erythema	3/335 (0.9%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pruritus allergic	4/335 (1.2%)		0/178 (0%)		1/340 (0.3%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rash erythematous	1/335 (0.3%)		4/178 (2.2%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rash papular	1/335 (0.3%)		0/178 (0%)		5/340 (1.5%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dry skin	2/335 (0.6%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Rash maculo-papular	2/335 (0.6%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dermatitis	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hyperhidrosis	2/335 (0.6%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		1/60 (1.7%)
Dermal cyst	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Ecchymosis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Pain of skin	0/335 (0%)		1/178 (0.6%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Swelling face	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Photosensitivity reaction	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Psoriasis	1/335 (0.3%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rash macular	0/335 (0%)		2/178 (1.1%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin exfoliation	0/335 (0%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dermatitis acneiform	0/335 (0%)		0/178 (0%)		0/340 (0%)		2/176 (1.1%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hand dermatitis	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hyperkeratosis	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Ingrowing nail	0/335 (0%)		0/178 (0%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Petechiae	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin disorder	1/335 (0.3%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin mass	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin warm	1/335 (0.3%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Solar dermatitis	2/335 (0.6%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Acne cystic	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Blister	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Dermatitis atopic	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eczema asteatotic	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Eczema nummular	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Fixed drug eruption	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Henoch-Schonlein purpura	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypersensitivity vasculitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Keratosis pilaris	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Madarosis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Onycholysis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Pruritus generalised	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Purpura senile	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rash generalised	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rash morbilliform	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rash pruritic	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Rosacea	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Scar pain	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin irritation	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin lesion	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Skin wrinkling	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Urticarial vasculitis	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Social circumstances
Menopause	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Surgical and medical procedures
Ethmoid sinus surgery	0/335 (0%)		0/178 (0%)		0/340 (0%)		1/176 (0.6%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Wisdom teeth removal	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Vascular disorders
Hypertension	3/335 (0.9%)		2/178 (1.1%)		4/340 (1.2%)		3/176 (1.7%)		0/0 (NaN)		1/55 (1.8%)		0/60 (0%)
Deep vein thrombosis	3/335 (0.9%)		1/178 (0.6%)		2/340 (0.6%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Hot flush	1/335 (0.3%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Flushing	0/335 (0%)		2/178 (1.1%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Haematoma	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Hypotension	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Peripheral coldness	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Phlebitis	0/335 (0%)		1/178 (0.6%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Vasodilatation	0/335 (0%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		1/60 (1.7%)
Thrombophlebitis superficial	1/335 (0.3%)		0/178 (0%)		0/340 (0%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)
Thrombosis	0/335 (0%)		0/178 (0%)		1/340 (0.3%)		0/176 (0%)		0/0 (NaN)		0/55 (0%)		0/60 (0%)

Limitations/Caveats

Analysis using baseline values of the current study 105 (NCT01931839) was not performed for Part B Treatment Cohort.

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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:

NCT01931839

Other Study ID Numbers:

VX12-809-105

First Posted:

Aug 29, 2013

Last Update Posted:

May 12, 2017

Last Verified:

Apr 1, 2017

A Phase 3 Rollover Study of Lumacaftor in Combination With Ivacaftor in Subjects 12 Years and Older With Cystic Fibrosis

Study Details

Study Description

Brief Summary

Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact