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A Study to Evaluate Safety, Efficacy, and Tolerability of TEZ/IVA in Orkambi® (Lumacaftor/Ivacaftor) -Experienced Subjects With Cystic Fibrosis (CF)

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ClinicalTrials.gov Identifier: NCT03150719
Recruitment Status : Completed
First Posted : May 12, 2017
Results First Posted : September 12, 2019
Last Update Posted : September 12, 2019
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Cystic Fibrosis
Interventions Drug: Tezacaftor/Ivacaftor
Drug: Ivacaftor
Drug: Placebo
Enrollment 98
Recruitment Details  
Pre-assignment Details A total of 98 participants were randomized: 47 in placebo group and 51 in tezacaftor (TEZ)/ivacaftor (IVA) group. One participant in TEZ/IVA group did not receive any study drug.
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days. Participants received TEZ 100 milligram (mg)/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
Period Title: Overall Study
Started 47 50
Completed 46 48
Not Completed 1 2
Reason Not Completed
Adverse Event             0             1
Death             0             1
Other             1             0
Arm/Group Title Placebo TEZ/IVA Total
Hide Arm/Group Description Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days. Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days. Total of all reporting groups
Overall Number of Baseline Participants 47 50 97
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 47 participants 50 participants 97 participants
33.3  (10.0) 34.3  (8.7) 33.8  (9.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 47 participants 50 participants 97 participants
Female
30
  63.8%
31
  62.0%
61
  62.9%
Male
17
  36.2%
19
  38.0%
36
  37.1%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 47 participants 50 participants 97 participants
Hispanic or Latino
3
   6.4%
1
   2.0%
4
   4.1%
Not Hispanic or Latino
40
  85.1%
41
  82.0%
81
  83.5%
Unknown or Not Reported
4
   8.5%
8
  16.0%
12
  12.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 47 participants 50 participants 97 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   2.1%
0
   0.0%
1
   1.0%
White
42
  89.4%
42
  84.0%
84
  86.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
4
   8.5%
8
  16.0%
12
  12.4%
1.Primary Outcome
Title Incidence of Respiratory Adverse Events of Special Interest (RAESIs)
Hide Description RAESIs included chest discomfort, dyspnea (shortness of breath), respiration abnormal (chest tightness), asthma, bronchial hyperreactivity, bronchospasm, and wheezing.
Time Frame Day 1 up to Day 84
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set included all participants who received at least 1 dose of study drug.
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description:
Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days.
Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
Overall Number of Participants Analyzed 47 50
Measure Type: Count of Participants
Unit of Measure: Participants
10
  21.3%
7
  14.0%
2.Secondary Outcome
Title Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements
Hide Description FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame Baseline, Day 28 and Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included all randomized participants who carried the intended cystic fibrosis transmembrane conductance regulator gene (CFTR) allele mutation and had received at least 1 dose of study drug.
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description:
Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days.
Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
Overall Number of Participants Analyzed 47 50
Mean (Standard Deviation)
Unit of Measure: percent predicted of FEV1
-0.6  (3.4) 2.2  (4.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, TEZ/IVA
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference
Estimated Value 2.7
Confidence Interval (2-Sided) 95%
1.0 to 4.4
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements
Hide Description FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame Baseline, Day 28 and Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description:
Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days.
Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
Overall Number of Participants Analyzed 47 50
Mean (Standard Deviation)
Unit of Measure: percent change
-1.5  (8.1) 5.2  (12.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, TEZ/IVA
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference
Estimated Value 6.7
Confidence Interval (2-Sided) 95%
2.5 to 10.9
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements
Hide 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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time Frame Baseline, Day 28 and Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
FAS.
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description:
Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days.
Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
Overall Number of Participants Analyzed 47 50
Mean (Standard Deviation)
Unit of Measure: units on a scale
4.7  (15.4) 5.7  (14.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, TEZ/IVA
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference
Estimated Value 1.1
Confidence Interval (2-Sided) 95%
-4.9 to 7.0
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Tolerability as Assessed by Number of Participants Who Discontinued Treatment
Hide Description [Not Specified]
Time Frame Day 1 through Day 56
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set.
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description:
Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days.
Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
Overall Number of Participants Analyzed 47 50
Measure Type: Count of Participants
Unit of Measure: Participants
2
   4.3%
2
   4.0%
6.Secondary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description [Not Specified]
Time Frame Day 1 up to Day 84
Hide Outcome Measure Data
Hide Analysis Population Description
Safety set.
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description:
Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days.
Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
Overall Number of Participants Analyzed 47 50
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with AEs
39
  83.0%
37
  74.0%
Participants with SAEs
9
  19.1%
5
  10.0%
Time Frame Day 1 up to Day 84
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo TEZ/IVA
Hide Arm/Group Description Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days. Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days.
All-Cause Mortality
Placebo TEZ/IVA
Affected / at Risk (%) Affected / at Risk (%)
Total   0/47 (0.00%)   1/50 (2.00%) 
Hide Serious Adverse Events
Placebo TEZ/IVA
Affected / at Risk (%) Affected / at Risk (%)
Total   9/47 (19.15%)   5/50 (10.00%) 
Cardiac disorders     
Pericardial effusion  1  1/47 (2.13%)  0/50 (0.00%) 
Gastrointestinal disorders     
Constipation  1  0/47 (0.00%)  1/50 (2.00%) 
General disorders     
Multiple organ dysfunction syndrome  1  0/47 (0.00%)  1/50 (2.00%) 
Infections and infestations     
Infective pulmonary exacerbation of cystic fibrosis  1  7/47 (14.89%)  3/50 (6.00%) 
Sepsis  1  0/47 (0.00%)  1/50 (2.00%) 
Lower respiratory tract infection  1  1/47 (2.13%)  0/50 (0.00%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal chest pain  1  1/47 (2.13%)  0/50 (0.00%) 
Psychiatric disorders     
Suicidal ideation  1  0/47 (0.00%)  1/50 (2.00%) 
Respiratory, thoracic and mediastinal disorders     
Pleuritic pain  1  1/47 (2.13%)  0/50 (0.00%) 
1
Term from vocabulary, MedDRA version 21.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo TEZ/IVA
Affected / at Risk (%) Affected / at Risk (%)
Total   28/47 (59.57%)   30/50 (60.00%) 
Gastrointestinal disorders     
Abdominal pain upper  1  5/47 (10.64%)  4/50 (8.00%) 
Constipation  1  0/47 (0.00%)  4/50 (8.00%) 
Nausea  1  2/47 (4.26%)  4/50 (8.00%) 
Diarrhoea  1  3/47 (6.38%)  1/50 (2.00%) 
General disorders     
Fatigue  1  4/47 (8.51%)  2/50 (4.00%) 
Infections and infestations     
Nasopharyngitis  1  0/47 (0.00%)  6/50 (12.00%) 
Infective pulmonary exacerbation of cystic fibrosis  1  9/47 (19.15%)  4/50 (8.00%) 
Investigations     
Bacterial test positive  1  0/47 (0.00%)  3/50 (6.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  3/47 (6.38%)  1/50 (2.00%) 
Nervous system disorders     
Headache  1  7/47 (14.89%)  6/50 (12.00%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  8/47 (17.02%)  9/50 (18.00%) 
Dyspnoea  1  5/47 (10.64%)  5/50 (10.00%) 
Haemoptysis  1  2/47 (4.26%)  3/50 (6.00%) 
Respiration abnormal  1  1/47 (2.13%)  3/50 (6.00%) 
Oropharyngeal pain  1  3/47 (6.38%)  2/50 (4.00%) 
Sputum increased  1  5/47 (10.64%)  2/50 (4.00%) 
1
Term from vocabulary, MedDRA version 21.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Monitor
Organization: Vertex Pharmaceuticals Incorporated
Phone: 617-341-6777
EMail: medicalinfo@vrtx.com
Layout table for additonal information
Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT03150719    
Other Study ID Numbers: VX16-661-114
2017-000540-18 ( EudraCT Number )
First Submitted: May 3, 2017
First Posted: May 12, 2017
Results First Submitted: August 8, 2019
Results First Posted: September 12, 2019
Last Update Posted: September 12, 2019