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

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03150719
• Collaborator: (none)
• Enrollment: 98
• Locations: 53
• Arms: 2
• Actual Duration (Months): 14.5
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Study VX16-661-114 (Study 114) is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects aged 12 years and older with CF who are homozygous for the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment. This study is designed to evaluate the safety and efficacy of Tezacaftor/Ivacaftor (TEZ/IVA).

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Tezacaftor/Ivacaftor; Drug: Ivacaftor; Drug: Placebo; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 24, 2017
• Actual Primary Completion Date: Aug 9, 2018
• Actual Study Completion Date: Aug 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 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.	Drug: Placebo; Placebo matched to TEZ/IVA fixed-dose combination tablet.; Drug: Placebo; Placebo matched to IVA tablet.
Experimental: TEZ/IVA 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.	Drug: Tezacaftor/Ivacaftor; TEZ 100 mg/IVA 150 mg fixed-dose combination tablet.; Other Names: TEZ/IVA; VX-661/VX-770 ; Drug: Ivacaftor; IVA 150 mg tablet.; Other Names: VX-770; IVA

Outcome Measures

Primary Outcome Measures

1. Incidence of Respiratory Adverse Events of Special Interest (RAESIs) [Day 1 up to Day 84]

   RAESIs included chest discomfort, dyspnea (shortness of breath), respiration abnormal (chest tightness), asthma, bronchial hyperreactivity, bronchospasm, and wheezing.

Secondary Outcome Measures

1. Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements [Baseline, Day 28 and Day 56]

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

2. Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements [Baseline, Day 28 and Day 56]

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

3. Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements [Baseline, Day 28 and Day 56]

   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.

4. Tolerability as Assessed by Number of Participants Who Discontinued Treatment [Day 1 through Day 56]

5. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Day 1 up to Day 84]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.

• Prior discontinuation of Orkambi, with at least 1 respiratory sign or symptom considered related to therapy.

• Resolution or stabilization of qualifying event(s) >28 days prior to Screening.

• Discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from the first dose of Orkambi.

• Homozygous for F508del mutation in the CFTR gene as documented in the subject's medical record. If genotype documentation is not available in the medical record, genotyping will be performed during screening.

• FEV1 ≥25% and ≤90% of predicted normal for age, sex, and height.

• Stable CF disease as judged by the investigator.

• Other protocol defined inclusion criteria could apply.

Exclusion Criteria:

• History of any comorbidity 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 subject.

• Recent rapid or progressive deterioration in respiratory status.

• Receiving continuous oxygen at >2L/min or on face-mask ventilation.

• Any protocol-defined exclusionary laboratory values at Screening.

• Child-Pugh Class B or C hepatic impairment.

• An acute upper or lower respiratory infection, pulmonary exacerbation, or change in therapy for pulmonary disease within 28 days before Day 1.

• Documentation of colonization with organisms associated with a more rapid decline in pulmonary status.

• History of lung transplantation since most recent initiation of Orkambi.

• History of alcohol or drug abuse in the past year as deemed by the investigator.

• Participation in an investigational drug study or use of a CFTR modulator within 28 days or 5 terminal half-lives of the investigational drug or modulator (whichever is longer).

• Use of restricted medications or foods within the specified window before the first dose of study drug, or an anticipated need or use of restricted medication or foods after the first dose of study drug.

• Pregnant or nursing females: Females of child-bearing potential must have a negative pregnancy test at Screening and Day 1.

• Other protocol defined exclusion criteria could apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	UCSF - Fresno, Community Regional Medical Center	Fresno	California	United States	93701
4	Miller Children's Hospital / Long Beach Memorial	Long Beach	California	United States	90806
5	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
6	Rady Children's Hospital	San Diego	California	United States	92123
7	National Jewish Health	Denver	Colorado	United States	80206
8	Yale New Haven Hospital	New Haven	Connecticut	United States	06510
9	Central Florida Pulmonary Group	Orlando	Florida	United States	32803
10	Arnold Palmer Hospital	Orlando	Florida	United States	32806
11	Tampa General Hospital Cardiac and Lung Transplant Clinic	Tampa	Florida	United States	33606
12	Children's Speciality Services at North Druid Hills	Atlanta	Georgia	United States	30324
13	St. Luke's CF Center of Idaho	Boise	Idaho	United States	83702
14	Advocate Children's Hospital - Park Ridge / North Suburban Pulmonary and Critical Care Consultants	Niles	Illinois	United States	60714
15	Southern Illinois University	Springfield	Illinois	United States	62702
16	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana	United States	46202
17	The University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
18	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
19	Kentucky Clinic	Lexington	Kentucky	United States	40536
20	Tulane Medical Center	New Orleans	Louisiana	United States	70112
21	Massachusetts General Hospital Cystic Fibrosis Center	Boston	Massachusetts	United States	02114
22	Boston Children's Hospital	Boston	Massachusetts	United States	02115
23	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
24	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
25	Billings Clinic	Billings	Montana	United States	59101
26	Mount Sinai Beth Israel	New York	New York	United States	10003
27	New York Medical College	Valhalla	New York	United States	10595
28	Duke University Medical Center	Durham	North Carolina	United States	27710
29	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
30	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
31	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
32	Santiago Reyes, M.D.	Oklahoma City	Oklahoma	United States	73112
33	Drexel University College of Medicine/ Drexel Adult Cystic Fibrosis Center	Philadelphia	Pennsylvania	United States	19107
34	Medical University of South Carolina	Charleston	South Carolina	United States	29425
35	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
36	The University of Tennessee Medical Center	Nashville	Tennessee	United States	37920
37	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
38	The University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78207
39	University of Utah / Primary Children's Medical Center	Salt Lake City	Utah	United States	84132
40	Children's Hospital of the King's Daughters	Norfolk	Virginia	United States	23507
41	Children's Hospital of Richmond at VCU, Children's Pavilion	Richmond	Virginia	United States	23298
42	Centre Hospitalier Intercommunal de Créteil	Créteil		France
43	Centre Hospitalier Universitaire De Grenoble - Hopital Michallon	Grenoble		France
44	CHU de Montpellier - Hopital Arnaud de Villeneuve	Montpellier Cedex 5		France
45	Centre Hospitalier Universitaire De Nantes	Nantes		France
46	Centre hospitalier universitaire de Nice, Pulmonology	Nice		France
47	Hopital Cochin	Paris Cedex 14		France
48	Centre Hospitalier Universitaire - Hopitaux de Rouen	Rouen		France
49	Charite Paediatric Pulmonology Department	Berlin		Germany
50	Ruhrlandklinik Westdeutsches Lungenzentrum am Klinikum Essen	Essen		Germany
51	Klinikum Innenstadt, University of Munich	Muenchen		Germany
52	Pneumologische Praxis Pasing	Muenchen		Germany
53	Universitaetsklinikum Tuebingen Klinik fuer Kinder- und Jugendmedizin	Tuebingen		Germany

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 9, 2017
• Statistical Analysis Plan - May 21, 2018

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT03150719
• Other Study ID Numbers: VX16-661-114; 2017-000540-18
• First Posted: May 12, 2017
• Last Update Posted: Sep 12, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Pre-assignment Detail	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
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

Baseline Characteristics

Arm/Group Title	Placebo	TEZ/IVA	Total
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 Participants	47	50	97
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.3 (10.0)	34.3 (8.7)	33.8 (9.3)
Sex: Female, Male (Count of Participants)
Female	30 63.8%	31 62%	61 62.9%
Male	17 36.2%	19 38%	36 37.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 6.4%	1 2%	4 4.1%
Not Hispanic or Latino	40 85.1%	41 82%	81 83.5%
Unknown or Not Reported	4 8.5%	8 16%	12 12.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 2.1%	0 0%	1 1%
White	42 89.4%	42 84%	84 86.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 8.5%	8 16%	12 12.4%

Outcome Measures

1. Primary Outcome

Title	Incidence of Respiratory Adverse Events of Special Interest (RAESIs)
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

Outcome Measure Data

Analysis Population Description

Safety set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	TEZ/IVA
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.
Measure Participants	47	50
Count of Participants [Participants]	10 21.3%	7 14%

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
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

Outcome Measure Data

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
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.
Measure Participants	47	50
Mean (Standard Deviation) [percent predicted of FEV1]	-0.6 (3.4)	2.2 (4.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TEZ/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; 1.0 to 4.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements
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

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	TEZ/IVA
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.
Measure Participants	47	50
Mean (Standard Deviation) [percent change]	-1.5 (8.1)	5.2 (12.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TEZ/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; 2.5 to 10.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	TEZ/IVA
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.
Measure Participants	47	50
Mean (Standard Deviation) [units on a scale]	4.7 (15.4)	5.7 (14.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TEZ/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -4.9 to 7.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Tolerability as Assessed by Number of Participants Who Discontinued Treatment
Time Frame	Day 1 through Day 56

Outcome Measure Data

Analysis Population Description

Safety set.

Arm/Group Title	Placebo	TEZ/IVA
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.
Measure Participants	47	50
Count of Participants [Participants]	2 4.3%	2 4%

6. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	Day 1 up to Day 84

Outcome Measure Data

Analysis Population Description

Safety set.

Arm/Group Title	Placebo	TEZ/IVA
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.
Measure Participants	47	50
Participants with AEs	39 83%	37 74%
Participants with SAEs	9 19.1%	5 10%

Adverse Events

Time Frame	Day 1 up to Day 84
Arm/Group Title	Placebo		TEZ/IVA
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		1/50 (2%)
Serious Adverse Events
	Placebo		TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/47 (19.1%)		5/50 (10%)
Cardiac disorders
Pericardial effusion	1/47 (2.1%)		0/50 (0%)
Gastrointestinal disorders
Constipation	0/47 (0%)		1/50 (2%)
General disorders
Multiple organ dysfunction syndrome	0/47 (0%)		1/50 (2%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	7/47 (14.9%)		3/50 (6%)
Sepsis	0/47 (0%)		1/50 (2%)
Lower respiratory tract infection	1/47 (2.1%)		0/50 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/47 (2.1%)		0/50 (0%)
Psychiatric disorders
Suicidal ideation	0/47 (0%)		1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Pleuritic pain	1/47 (2.1%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/47 (59.6%)		30/50 (60%)
Gastrointestinal disorders
Abdominal pain upper	5/47 (10.6%)		4/50 (8%)
Constipation	0/47 (0%)		4/50 (8%)
Nausea	2/47 (4.3%)		4/50 (8%)
Diarrhoea	3/47 (6.4%)		1/50 (2%)
General disorders
Fatigue	4/47 (8.5%)		2/50 (4%)
Infections and infestations
Nasopharyngitis	0/47 (0%)		6/50 (12%)
Infective pulmonary exacerbation of cystic fibrosis	9/47 (19.1%)		4/50 (8%)
Investigations
Bacterial test positive	0/47 (0%)		3/50 (6%)
Metabolism and nutrition disorders
Decreased appetite	3/47 (6.4%)		1/50 (2%)
Nervous system disorders
Headache	7/47 (14.9%)		6/50 (12%)
Respiratory, thoracic and mediastinal disorders
Cough	8/47 (17%)		9/50 (18%)
Dyspnoea	5/47 (10.6%)		5/50 (10%)
Haemoptysis	2/47 (4.3%)		3/50 (6%)
Respiration abnormal	1/47 (2.1%)		3/50 (6%)
Oropharyngeal pain	3/47 (6.4%)		2/50 (4%)
Sputum increased	5/47 (10.6%)		2/50 (4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.