Clinical Trial Results:
Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor (TEZ/IVA) in an Orkambi-experienced Population Who Are Homozygous for the F508del-CFTR Mutation
Summary
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EudraCT number |
2017-000540-18 |
Trial protocol |
FR DE |
Global end of trial date |
09 Aug 2018
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Results information
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Results version number |
v2(current) |
This version publication date |
03 Jan 2020
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First version publication date |
24 Feb 2019
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
VX16-661-114
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03150719 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Vertex Pharmaceuticals Incorporated
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Sponsor organisation address |
50 Northern Avenue, Boston, United States,
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Public contact |
Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
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Scientific contact |
Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Aug 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Aug 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Aug 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the respiratory safety of Tezacaftor/Ivacaftor (TEZ/IVA) in subjects with Cystic Fibrosis homozygous for F508del mutation of the CFTR gene that previously discontinued Lumacaftor/Ivacaftor (LUM/IVA) due to treatment-related respiratory signs or symptoms
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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).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 May 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
France: 12
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Country: Number of subjects enrolled |
Germany: 37
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Country: Number of subjects enrolled |
United States: 49
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Worldwide total number of subjects |
98
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EEA total number of subjects |
49
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
97
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 98 subjects were randomized: 47 in placebo group and 51 in TEZ/IVA group. One subject in TEZ/IVA group did not receive any study drug. | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Placebo (matched to TEZ/IVA)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received placebo matched to TEZ/IVA FDC once daily in the morning for 56 days.
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Investigational medicinal product name |
Placebo (matched to IVA)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received placebo matched to IVA once daily in the evening for 56 days.
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Arm title
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TEZ/IVA | |||||||||||||||||||||
Arm description |
Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
TEZ/IVA
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Investigational medicinal product code |
VX-661/VX-770
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Other name |
Tezacaftor/Ivacaftor
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received 100 milligram (mg) TEZ/ 150 mg IVA FDC once daily in the morning for 56 days.
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Investigational medicinal product name |
IVA
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Investigational medicinal product code |
VX-770
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Other name |
Ivacaftor
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received 150 mg IVA once daily in the evening for 56 days.
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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: A total of 98 subjects were randomized: 47 in placebo group and 51 in TEZ/IVA group. One subject in TEZ/IVA group did not receive any study drug. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEZ/IVA
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Reporting group description |
Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days. | ||
Reporting group title |
TEZ/IVA
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Reporting group description |
Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days. |
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End point title |
Incidence of Respiratory Adverse Events of Special Interest (RAESIs) [1] | |||||||||
End point description |
RAESIs included chest discomfort, dyspnea (shortness of breath), respiration abnormal (chest tightness), asthma, bronchial hyperreactivity, bronchospasm, and wheezing.
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End point type |
Primary
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End point timeframe |
Day 1 up to Day 84
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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 statistics were planned. No statistical comparisons were planned for primary safety endpoint. |
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No statistical analyses for this end point |
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End point title |
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements | ||||||||||||
End point description |
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 28 and Day 56
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
TEZ/IVA v Placebo
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Number of subjects included in analysis |
97
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean Difference | ||||||||||||
Point estimate |
2.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1 | ||||||||||||
upper limit |
4.4 |
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End point title |
Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements | ||||||||||||
End point description |
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 28 and Day 56
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
Placebo v TEZ/IVA
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Number of subjects included in analysis |
97
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean Difference | ||||||||||||
Point estimate |
6.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.5 | ||||||||||||
upper limit |
10.9 |
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End point title |
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements | ||||||||||||
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.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 28 and Day 56
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Statistical analysis title |
Statistical Analysis | ||||||||||||
Comparison groups |
Placebo v TEZ/IVA
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Number of subjects included in analysis |
97
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean Difference | ||||||||||||
Point estimate |
1.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.9 | ||||||||||||
upper limit |
7 |
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End point title |
Tolerability as Assessed by Number of Subjects Who Discontinued Treatment | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 1 through Day 56
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 1 up to Day 84
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 up to Day 84
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEZ/IVA
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Reporting group description |
Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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19 Apr 2017 |
Revised sample size, and the time from Orkambi initiation to discontinuation; Additional safety measures added; Subjects who completed Day 56 Visit were given the opportunity to enroll in a long-term, open-label safety study of TEZ/IVA |
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09 Jun 2017 |
Added post-dose spirometry on Day 1 for additional safety; Clarified the visits for pulse oximetry and vital sign assessments; Removed restrictions on the concomitant use of corticosteroids |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |