Clinical Trial Results:
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis

Clinical trials

Clinical Trial Results:
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis

Clinical trials

Clinical Trial Results: A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis

Clinical Trial Results:
A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis

Trial information

Subject disposition

Baseline characteristics

End points

Adverse events

More information

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Adverse events

Adverse events

More information

More information

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Adverse events

Adverse events

More information

More information

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Absolute Change in Sweat Chloride Concentrations

Secondary: Relative Change in ppFEV1

Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

Secondary: Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Absolute Change in Sweat Chloride Concentrations

Secondary: Absolute Change in Sweat Chloride Concentrations

Secondary: Relative Change in ppFEV1

Secondary: Relative Change in ppFEV1

Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

Secondary: Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA

Secondary: Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

Secondary: Absolute Change in Sweat Chloride Concentrations

Secondary: Absolute Change in Sweat Chloride Concentrations

Secondary: Relative Change in ppFEV1

Secondary: Relative Change in ppFEV1

Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score

Secondary: Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA

Secondary: Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Summary
EudraCT number	2016-000454-36
Trial protocol	GB AT DK DE BE ES NL IT
Global end of trial date	09 Aug 2017

Results information
Results version number	v2(current)
This version publication date	10 Dec 2020
First version publication date	14 Dec 2018
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Top of page

Sponsor protocol code

VX15-440-101

ISRCTN number

US NCT number

NCT02951182

WHO universal trial number (UTN)

Sponsor organisation name

Vertex Pharmaceuticals Incorporated

Sponsor organisation address

50 Northern Avenue, Massachusetts, Boston, United States, 02210-1862

Public contact

Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com

Scientific contact

Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

07 Sep 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Aug 2017

Global end of trial reached?

Yes

Global end of trial date

09 Aug 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the safety, tolerability and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ) and ivacaftor (IVA)

Protection of trial subjects

The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Nov 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

United States: 45

Country: Number of subjects enrolled

Australia: 6

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Canada: 4

Country: Number of subjects enrolled

Denmark: 2

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Italy: 2

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

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Recruitment details

Screening details

Four parts were planned for the study, but only Parts 1 and 2 were conducted. Part 3 was removed from the protocol in Version 2.0. Part 4 was not conducted at the Sponsor’s discretion.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Part 1: Placebo - Cohort 1A and 1B Combined

Arm description

Subjects received placebo matched to VX-440, placebo matched to tezacaftor (TEZ; VX-661) and placebo matched to ivacaftor (IVA, VX-770) triple combination administered orally for 4 weeks in part 1.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matched with VX-440, TEZ, and IVA triple combination in part 1.

Part 1 Cohort 1A: Triple Combination (TC)

Arm description

Subjects received VX-440 at a dose of 200 milligram (mg) along with TEZ 100 mg and IVA 150 mg triple combination administered orally up to Week 4.

Arm type

Experimental

Investigational medicinal product name

VX-440

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received VX-440 at a dose of 200 mg administered every 12 hours (q12h) up to 4 weeks.

Investigational medicinal product name

TEZ

Investigational medicinal product code

VX-661

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received TEZ at a dose of 100 mg administered once daily (qd) up to 4 weeks.

Investigational medicinal product name

IVA

Investigational medicinal product code

VX-770

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received IVA at a dose of 150 mg administered q12h up to 4 weeks.

Part 1 Cohort 1B: TC Low Dose

Arm description

Subjects received VX-440 at a dose of 200 mg along with TEZ 50 mg and IVA 150 mg triple combination administered orally up to Week 4.

Arm type

Experimental

Investigational medicinal product name

VX-440

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received VX-440 at a dose of 200 mg administered q12h up to 4 weeks.

Investigational medicinal product name

TEZ

Investigational medicinal product code

Other name

VX-661

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received TEZ at a dose of 50 mg administered every q12h up to 4 weeks.

Investigational medicinal product name

IVA

Investigational medicinal product code

Other name

VX-770

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received IVA at a dose of 150 mg administered q12h up to 4 weeks.

Part 1 Cohort 1B: TC High Dose

Arm description

Subjects received VX-440 at a dose of 600 mg along with TEZ 50 mg and IVA 300 mg triple combination administered orally up to Week 4.

Arm type

Experimental

Investigational medicinal product name

VX-440

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received VX-440 at a dose of 600 mg administered q12h up to 4 weeks.

Investigational medicinal product name

IVA

Investigational medicinal product code

VX-770

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received IVA at a dose of 300 mg administered q12h up to 4 weeks.

Investigational medicinal product name

TEZ

Investigational medicinal product code

VX-661

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received TEZ at a dose of 50 mg administered every q12h up to 4 weeks.

Part 2: TEZ/IVA

Arm description

Following a 4-week run-in period on TEZ/IVA, subjects received TEZ 100 mg and IVA 150 mg administered orally up to Week 8.

Arm type

Active comparator

Investigational medicinal product name

TEZ

Investigational medicinal product code

VX-661

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received TEZ at a dose of 100 mg administered once daily up to 12 weeks.

Investigational medicinal product name

IVA

Investigational medicinal product code

VX-770

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received IVA at a dose of 150 mg administered q12h up to 12 weeks.

Part 2: TC-2

Arm description

Following a 4-week run-in period on TEZ/IVA, subjects received VX-440 at a dose of 600 mg for 4 weeks along with TEZ 50 mg and IVA 300 mg administered orally up to Week 8.

Arm type

Experimental

Investigational medicinal product name

TEZ

Investigational medicinal product code

VX-661

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received TEZ at a dose of 50 mg administered q12h up to 12 weeks.

Investigational medicinal product name

IVA

Investigational medicinal product code

VX-770

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received IVA at a dose of 300 mg administered q12h up to 12 weeks.

Investigational medicinal product name

VX-440

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received VX-440 at a dose of 600 mg administered q12h up to 4 weeks.

Number of subjects in period 1 ^[1]	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1A: Triple Combination (TC)	Part 1 Cohort 1B: TC Low Dose	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2
Started	11	9	9	18	6	20
Completed	11	9	9	18	6	20

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Of the 74 subjects enrolled (47 subjects in Part 1 and 27 subjects in Part 2 Run-in Period), 1 subject from Run-in period discontinued before randomization at the start of the Treatment Period because continuation criteria were not met.

Top of page

Reporting group title

Part 1: Placebo - Cohort 1A and 1B Combined

Reporting group description

Subjects received placebo matched to VX-440, placebo matched to tezacaftor (TEZ; VX-661) and placebo matched to ivacaftor (IVA, VX-770) triple combination administered orally for 4 weeks in part 1.

Reporting group title

Part 1 Cohort 1A: Triple Combination (TC)

Reporting group description

Subjects received VX-440 at a dose of 200 milligram (mg) along with TEZ 100 mg and IVA 150 mg triple combination administered orally up to Week 4.

Reporting group title

Part 1 Cohort 1B: TC Low Dose

Reporting group description

Subjects received VX-440 at a dose of 200 mg along with TEZ 50 mg and IVA 150 mg triple combination administered orally up to Week 4.

Reporting group title

Part 1 Cohort 1B: TC High Dose

Reporting group description

Subjects received VX-440 at a dose of 600 mg along with TEZ 50 mg and IVA 300 mg triple combination administered orally up to Week 4.

Reporting group title

Part 2: TEZ/IVA

Reporting group description

Following a 4-week run-in period on TEZ/IVA, subjects received TEZ 100 mg and IVA 150 mg administered orally up to Week 8.

Reporting group title

Part 2: TC-2

Reporting group description

Following a 4-week run-in period on TEZ/IVA, subjects received VX-440 at a dose of 600 mg for 4 weeks along with TEZ 50 mg and IVA 300 mg administered orally up to Week 8.

Reporting group values	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1A: Triple Combination (TC)	Part 1 Cohort 1B: TC Low Dose	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2	Total
Number of subjects	11	9	9	18	6	20	73
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	38.2 ± 9.2	36.3 ± 13.2	30.6 ± 13.3	29.3 ± 6.7	33.2 ± 3.7	30.8 ± 5.9	-
Gender categorical
Units: Subjects
Female	2	1	3	1	0	4	11
Male	9	8	6	17	6	16	62
Ethnicity
Units: Subjects
Hispanic or Latino	1	0	1	0	0	1	3
Not Hispanic or Latino	10	9	8	17	6	18	68
Unknown or Not Reported	0	0	0	1	0	1	2
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0
White	10	9	9	18	6	20	72
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	1	0	0	0	0	0	1

Top of page

Reporting group title

Part 1: Placebo - Cohort 1A and 1B Combined

Reporting group description

Subjects received placebo matched to VX-440, placebo matched to tezacaftor (TEZ; VX-661) and placebo matched to ivacaftor (IVA, VX-770) triple combination administered orally for 4 weeks in part 1.

Reporting group title

Part 1 Cohort 1A: Triple Combination (TC)

Reporting group description

Subjects received VX-440 at a dose of 200 milligram (mg) along with TEZ 100 mg and IVA 150 mg triple combination administered orally up to Week 4.

Reporting group title

Part 1 Cohort 1B: TC Low Dose

Reporting group description

Subjects received VX-440 at a dose of 200 mg along with TEZ 50 mg and IVA 150 mg triple combination administered orally up to Week 4.

Reporting group title

Part 1 Cohort 1B: TC High Dose

Reporting group description

Subjects received VX-440 at a dose of 600 mg along with TEZ 50 mg and IVA 300 mg triple combination administered orally up to Week 4.

Reporting group title

Part 2: TEZ/IVA

Reporting group description

Following a 4-week run-in period on TEZ/IVA, subjects received TEZ 100 mg and IVA 150 mg administered orally up to Week 8.

Reporting group title

Part 2: TC-2

Reporting group description

Following a 4-week run-in period on TEZ/IVA, subjects received VX-440 at a dose of 600 mg for 4 weeks along with TEZ 50 mg and IVA 300 mg administered orally up to Week 8.

Subject analysis set title

Part 1: TC-1A/ TC-1B-low Pooled

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects pooled together for Part 1: TC-1A arm and Part 1: TC-1B low dose arm.

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[1]

End point description

Safety Set included all subjects who received at least 1 dose of study drug in the Treatment Period.

End point type

Primary

End point timeframe

From first dose of Study Drug in the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be analysed for this endpoint. No statistical comparisons were planned.

No statistical analyses for this end point

Top of page

End point title

Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) ^[2]

End point description

FEV1 is the volume of air that can forcibly be blown out in first second, after full inspiration. Full Analysis Set (FAS) included all randomized subjects who have received at least 1 dose of study drug in the Treatment Period.

End point type

Primary

End point timeframe

From Baseline through Day 29

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per pre-specified planned analysis, reporting group "Part 1 Cohort 1A: TC" and "Part 1 Cohort 1B: TC Low Dose" were pooled for the purpose of efficacy analysis.

End point values	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2	Part 1: TC-1A/ TC-1B-low Pooled
Number of subjects analysed	11	18	6	20	18
Units: percentage points
least squares mean (confidence interval 95%)	1.4 (-2.7 to 5.5)	12.0 (8.8 to 15.2)	-2.5 (-7.2 to 2.2)	9.5 (6.9 to 12.2)	10.0 (6.9 to 13.2)

Statistical Analysis 1

Comparison groups

Part 1: Placebo - Cohort 1A and 1B Combined v Part 1: TC-1A/ TC-1B-low Pooled

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016

Method

Mixed-effects Model for Repeated Measure

Parameter type

Least Squares (LS) Mean Difference

Point estimate

8.6

Confidence interval

level

95%

sides

2-sided

lower limit

3.5

upper limit

13.8

Statistical Analysis 2

Comparison groups

Part 1 Cohort 1B: TC High Dose v Part 1: Placebo - Cohort 1A and 1B Combined

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed-effects Model for Repeated Measure

Parameter type

LS Mean Difference

Point estimate

10.6

Confidence interval

level

95%

sides

2-sided

lower limit

5.5

upper limit

15.8

Statistical Analysis 3

Comparison groups

Part 2: TC-2 v Part 2: TEZ/IVA

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed-effects Model for Repeated Measure

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

6.7

upper limit

17.4

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End point title

Absolute Change in Sweat Chloride Concentrations ^[3]

End point description

Sweat samples were collected using an approved collection device. FAS.

End point type

Secondary

End point timeframe

From Baseline through Day 29

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per pre-specified planned analysis, reporting group "Part 1 Cohort 1A: TC" and "Part 1 Cohort 1B: TC Low Dose" were pooled for the purpose of efficacy analysis.

End point values	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2	Part 1: TC-1A/ TC-1B-low Pooled
Number of subjects analysed	11	18	6	20	18
Units: millimole per liter (mmol/L)
least squares mean (confidence interval 95%)	1.6 (-6.2 to 9.4)	-33.1 (-39.1 to -27.1)	2.1 (-10.9 to 15.1)	-31.3 (-38.6 to -24.1)	-20.7 (-26.6 to -14.7)

Statistical Analysis 1

Comparison groups

Part 1: Placebo - Cohort 1A and 1B Combined v Part 1: TC-1A/ TC-1B-low Pooled

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-22.3

Confidence interval

level

95%

sides

2-sided

lower limit

-32.1

upper limit

-12.4

Statistical Analysis 2

Comparison groups

Part 1 Cohort 1B: TC High Dose v Part 1: Placebo - Cohort 1A and 1B Combined

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-34.7

Confidence interval

level

95%

sides

2-sided

lower limit

-44.7

upper limit

-24.8

Statistical Analysis 3

Comparison groups

Part 2: TC-2 v Part 2: TEZ/IVA

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-33.4

Confidence interval

level

95%

sides

2-sided

lower limit

-48.5

upper limit

-18.3

Top of page

End point title

Relative Change in ppFEV1 ^[4]

End point description

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. FAS.

End point type

Secondary

End point timeframe

From Baseline through Day 29

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per pre-specified planned analysis, reporting group "Part 1 Cohort 1A: TC" and "Part 1 Cohort 1B: TC Low Dose" were pooled for the purpose of efficacy analysis.

End point values	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2	Part 1: TC-1A/ TC-1B-low Pooled
Number of subjects analysed	11	18	6	20	18
Units: percent change
least squares mean (confidence interval 95%)	2.6 (-4.9 to 10.0)	21.7 (15.9 to 27.5)	-3.4 (-11.4 to 4.6)	16.6 (12.1 to 21.1)	17.3 (11.5 to 23.2)

Statistical Analysis 1

Comparison groups

Part 1: Placebo - Cohort 1A and 1B Combined v Part 1: TC-1A/ TC-1B-low Pooled

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

14.8

Confidence interval

level

95%

sides

2-sided

lower limit

5.3

upper limit

24.2

Statistical Analysis 2

Comparison groups

Part 1 Cohort 1B: TC High Dose v Part 1: Placebo - Cohort 1A and 1B Combined

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

19.1

Confidence interval

level

95%

sides

2-sided

lower limit

9.7

upper limit

28.6

Statistical Analysis 3

Comparison groups

Part 2: TC-2 v Part 2: TEZ/IVA

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

10.8

upper limit

29.1

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End point title

Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score ^[5]

End point description

The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. FAS.

End point type

Secondary

End point timeframe

From Baseline at Day 29

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per pre-specified planned analysis, reporting group "Part 1 Cohort 1A: TC" and "Part 1 Cohort 1B: TC Low Dose" were pooled for the purpose of efficacy analysis.

End point values	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2	Part 1: TC-1A/ TC-1B-low Pooled
Number of subjects analysed	11	18	6	20	18
Units: units on a scale
least squares mean (confidence interval 95%)	2.2 (-6.2 to 10.6)	20.7 (14.2 to 27.1)	-7.8 (-14.8 to -0.8)	12.3 (8.7 to 16.0)	18.3 (11.7 to 24.9)

Statistical Analysis 1

Comparison groups

Part 1: Placebo - Cohort 1A and 1B Combined v Part 1: TC-1A/ TC-1B-low Pooled

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

16.1

Confidence interval

level

95%

sides

2-sided

lower limit

5.4

upper limit

26.8

Statistical Analysis 2

Comparison groups

Part 1 Cohort 1B: TC High Dose v Part 1: Placebo - Cohort 1A and 1B Combined

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

18.5

Confidence interval

level

95%

sides

2-sided

lower limit

7.9

upper limit

29.1

Statistical Analysis 3

Comparison groups

Part 2: TC-2 v Part 2: TEZ/IVA

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

20.2

Confidence interval

level

95%

sides

2-sided

lower limit

11.9

upper limit

28.4

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End point title

Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA ^[6]

End point description

Pharmacokinetic Set (PK) included all subjects who have received at least 1 dose of study drug in Treatment Period. Here "n" signifies those subjects who were evaluable at specified time points for each reporting group respectively. Day 8 assessment was planned for only TC-1A arm and VX-440 Ctrough category was not applicable for TEZ/IVA arm. Here 99999 represents "not applicable" categories for Ctrough assessment.

End point type

Secondary

End point timeframe

Predose at Day 8, Day 15 and Day 29

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 1: TC (Cohort 1A and 1B) and Part 2 (TEZ/IVA and TC) reporting groups were applicable for this endpoint. Part 1: Placebo- Cohort 1A and 1B Combined reporting group was not included in this endpoint.

End point values	Part 1 Cohort 1A: Triple Combination (TC)	Part 1 Cohort 1B: TC Low Dose	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2
Number of subjects analysed	9	9	18	6	19
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
VX-440: Day 8 (n=9, 0, 0, 0, 0)	1670 ± 1910	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
VX-440: Day 15 (n=9, 8, 16, 0, 18)	1840 ± 1460	1120 ± 707	8540 ± 6850	99999 ± 99999	12900 ± 9940
VX-440: Day 29 (n=9, 9, 17, 0, 17)	1090 ± 1010	1440 ± 1870	6650 ± 3500	99999 ± 99999	10300 ± 7340
TEZ: Day 8 (n=8, 0, 0, 0, 0)	810 ± 323	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
TEZ: Day 15 (n=9, 8, 16, 6, 18)	749 ± 271	1070 ± 422	928 ± 558	2240 ± 1010	1250 ± 837
TEZ: Day 29 (n=9, 9, 17, 6, 17)	761 ± 320	1040 ± 659	846 ± 514	1420 ± 565	893 ± 579
M1-TEZ: Day 8 (n=8, 0, 0, 0, 0)	3160 ± 645	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
M1-TEZ: Day 15 (n=9, 8, 16, 6, 18)	3490 ± 486	4610 ± 1170	3400 ± 1270	4640 ± 1730	3940 ± 1200
M1-TEZ: Day 29 (n=9, 9, 17, 6, 17)	3560 ± 378	4180 ± 1950	3050 ± 1260	4060 ± 1560	3280 ± 1230
IVA: Day 8 (n=8, 0, 0, 0, 0)	281 ± 167	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
IVA: Day 15 (n=9, 8, 16, 6, 18)	245 ± 92.7	192 ± 97.0	233 ± 149	1040 ± 352	380 ± 312
IVA: Day 29 (n=9, 9, 17, 6, 17)	209 ± 112	164 ± 108	219 ± 139	902 ± 344	290 ± 263
M1-IVA: Day 8 (n=8, 0, 0, 0, 0)	795 ± 327	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
M1-IVA: Day 15 (n=9, 8, 16, 6, 18)	854 ± 427	566 ± 245	850 ± 546	1640 ± 218	1220 ± 796
M1-IVA: Day 29 (n=9, 9, 17, 6, 17)	702 ± 372	520 ± 338	792 ± 466	1580 ± 764	1080 ± 732

No statistical analyses for this end point

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Timeframe for reporting adverse events

From first dose of Study Drug in the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Part 1: Placebo - Cohort 1A and 1B Combined

Reporting group description

Subjects received placebo matched to VX-440, placebo matched to tezacaftor (TEZ; VX-661) and placebo matched to ivacaftor (IVA, VX-770) triple combination administered orally for 4 weeks in part 1.

Reporting group title

Part 1 Cohort 1A: Triple Combination (TC)

Reporting group description

Subjects received VX-440 at a dose of 200 milligram (mg) along with TEZ 100 mg and IVA 150 mg triple combination administered orally up to Week 4.

Reporting group title

Part 1 Cohot 1B: TC Low Dose

Reporting group description

Subjects received VX-440 at a dose of 200 mg along with TEZ 50 mg and IVA 150 mg triple combination administered orally up to Week 4.

Reporting group title

Part 1 Cohort 1B: TC High Dose

Reporting group description

Subjects received VX-440 at a dose of 600 mg along with TEZ 50 mg and IVA 300 mg triple combination administered orally up to Week 4.

Reporting group title

Part 2: TEZ/IVA

Reporting group description

Following a 4-week run-in period on TEZ/IVA, subjects received TEZ 100 mg and IVA 150 mg administered orally up to Week 8.

Reporting group title

Part 2: TC-2

Reporting group description

Following a 4-week run-in period on TEZ/IVA, subjects received VX-440 at a dose of 600 mg for 4 weeks along with TEZ 50 mg and IVA 300 mg administered orally up to Week 8.

Serious adverse events	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1A: Triple Combination (TC)	Part 1 Cohot 1B: TC Low Dose	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 18 (11.11%)	2 / 6 (33.33%)	1 / 20 (5.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Distal intestinal obstruction syndrome
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Adjustment disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	1 / 6 (16.67%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part 1: Placebo - Cohort 1A and 1B Combined	Part 1 Cohort 1A: Triple Combination (TC)	Part 1 Cohot 1B: TC Low Dose	Part 1 Cohort 1B: TC High Dose	Part 2: TEZ/IVA	Part 2: TC-2
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 11 (81.82%)	9 / 9 (100.00%)	9 / 9 (100.00%)	15 / 18 (83.33%)	6 / 6 (100.00%)	15 / 20 (75.00%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 9 (22.22%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	2	0	0	0
Chills
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Pyrexia
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypersensitivity
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Reproductive system and breast disorders
Testicular cyst
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 11 (36.36%)	3 / 9 (33.33%)	1 / 9 (11.11%)	1 / 18 (5.56%)	0 / 6 (0.00%)	5 / 20 (25.00%)
occurrences all number	4	3	1	1	0	5
Sputum increased
subjects affected / exposed	3 / 11 (27.27%)	1 / 9 (11.11%)	1 / 9 (11.11%)	1 / 18 (5.56%)	1 / 6 (16.67%)	3 / 20 (15.00%)
occurrences all number	3	1	1	1	1	3
Haemoptysis
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 9 (11.11%)	1 / 18 (5.56%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	1	1	0	2
Dyspnoea
subjects affected / exposed	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	1	0	0	2
Oropharyngeal pain
subjects affected / exposed	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	1
Paranasal sinus hypersecretion
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	1
Respiration abnormal
subjects affected / exposed	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	1
Dysphonia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	2
Lower respiratory tract congestion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	0	2
Productive cough
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	0	0
Rhinorrhoea
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	1
Wheezing
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	1	0	0	0
Dyspnoea exertional
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Increased viscosity of bronchial secretion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Paranasal sinus discomfort
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Pulmonary pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Rales
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Sinus disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Sinus pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Throat irritation
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Insomnia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0
Mood swings
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 18 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)
occurrences all number	1	0	1	2	0	2
Aspartate aminotransferase increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 9 (11.11%)	2 / 18 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	1	2	0	1
Blood urine present
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	2	0	0
International normalised ratio increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	1
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Blood bicarbonate decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood bilirubin unconjugated increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood chloride increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood pressure increased
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Crystal urine present
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Lipase decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Monocyte count increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Prothrombin time prolonged
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Pulmonary function test decreased
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Injury, poisoning and procedural complications
Anaesthetic complication neurological
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Contusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Joint injury
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Ligament rupture
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Post procedural swelling
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Post-traumatic neck syndrome
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Procedural nausea
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Procedural pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Sunburn
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	1	1	0	0	1
Dizziness
subjects affected / exposed	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	1
Lethargy
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Presyncope
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Syncope
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Eye disorders
Eye pruritus
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 9 (11.11%)	2 / 18 (11.11%)	0 / 6 (0.00%)	4 / 20 (20.00%)
occurrences all number	1	1	1	5	0	4
Abdominal pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	2 / 18 (11.11%)	1 / 6 (16.67%)	0 / 20 (0.00%)
occurrences all number	0	0	0	2	1	0
Abdominal pain upper
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	1
Abnormal faeces
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0	0
Flatulence
subjects affected / exposed	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	1	0	0	0	0
Anorectal discomfort
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0
Dyspepsia
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Faeces pale
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Nausea
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Alopecia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Blister
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Night sweats
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Pruritus
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	0	0
Arthralgia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 9 (11.11%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0
Back pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Flank pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0
Muscle twitching
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Myalgia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Neck pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Tendon discomfort
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0
Tendonitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis
subjects affected / exposed	2 / 11 (18.18%)	6 / 9 (66.67%)	0 / 9 (0.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)
occurrences all number	2	7	0	2	0	3
Viral upper respiratory tract infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 9 (22.22%)	2 / 18 (11.11%)	2 / 6 (33.33%)	1 / 20 (5.00%)
occurrences all number	1	0	2	2	2	1
Upper respiratory tract infection
subjects affected / exposed	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 9 (0.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	2	0	2	0	2
Folliculitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Influenza
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Pharyngitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	2	0	0
Hyperglycaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 9 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Increased appetite
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 9 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

31 May 2016

- Sample size was reduced - Clarification in the study drug interruption and discontinuation - Modified contraception requirements

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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End point values

Part 1: Placebo - Cohort 1A and 1B Combined

Part 1 Cohort 1A: Triple Combination (TC)

Part 1 Cohort 1B: TC Low Dose

Part 1 Cohort 1B: TC High Dose

Part 2: TEZ/IVA

Part 2: TC-2

Number of subjects analysed

Units: Subjects

number (not applicable)