A Phase 2 Study to Evaluate Effects of VX-661/Ivacaftor on Lung and Extrapulmonary Systems in Subjects With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02508207
• Collaborator: (none)
• Enrollment: 34
• Locations: 7
• Arms: 2
• Duration (Months): 16
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To evaluate the clinical mechanisms of action in lung and extrapulmonary systems of VX-661 (tezacaftor; TEZ) in combination with ivacaftor (IVA) (TEZ/IVA) in participants with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Tezacaftor/Ivacaftor; Drug: Ivacaftor; Drug: Tezacaftor/Ivacaftor matching placebo; Drug: Ivacaftor matching placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Exploratory Study to Evaluate Effects of VX-661 in Combination With Ivacaftor on Lung and Extrapulmonary Systems in Subjects Aged 18 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation
• Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Jun 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo matched to tezacaftor (TEZ)/ivacaftor (IVA) fixed dose combination (FDC) tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Drug: Tezacaftor/Ivacaftor matching placebo; Drug: Ivacaftor matching placebo
Experimental: TEZ/IVA Participants received 100 milligram (mg) TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.	Drug: Tezacaftor/Ivacaftor; Tezacaftor/Ivacaftor FDC; Drug: Ivacaftor

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Mucociliary Clearance (MCC) at Day 28 [Baseline, Day 28]

   MCC was assessed using an imaging technique that enables the tracking of mucus within the airways. MCC was expressed as the percentage of whole-lung clearance through 60 minutes at Baseline and Day 28.

Secondary Outcome Measures

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

   Percent predicted FEV1 is the ratio of FEV1 to the predicted FEV1, expressed as a percentage. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

2. Absolute Change From Baseline in Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments at Day 29 [Baseline, Day 29]

   Absolute change from Baseline in small bowel AUC over 1-minute mean pH increments through 30 minutes at Day 29 was assessed.

3. Absolute Change From Baseline in Sweat Chloride at Day 29 [Baseline, Day 29]

4. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to Day 57]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female participants, homozygous for the F508del CFTR mutation

• Confirmed diagnosis of CF by sweat chloride testing

• Forced Expiratory Volume in 1 Second (FEV1) ≥40% and ≤90% of predicted normal for age, sex, and height at Screening Visit

• Stable CF disease as judged by the investigator.

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.

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

• History or evidence of clinically significant findings on ophthalmologic examination during the Screening Period.

• History of solid organ or hematological transplantation

• Pregnant or nursing females

• Participants who have had radiation exposure within 1 year before the first mucociliary clearance (MCC) procedure that would cause them to exceed federal regulations by participating in this study

• In the opinion of the investigator, unable to adequately perform inhalation maneuvers during the MCC procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Indianapolis	Indiana	United States
3		Baltimore	Maryland	United States
4		Chapel Hill	North Carolina	United States
5		Cincinnati	Ohio	United States
6		Toledo	Ohio	United States
7		Pittsburgh	Pennsylvania	United States

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 19, 2016
• Statistical Analysis Plan - Jul 27, 2017

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02508207
• Other Study ID Numbers: VX14-661-111
• First Posted: Jul 24, 2015
• Last Update Posted: Jul 19, 2021
• Last Verified: Jun 1, 2018

• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Arm/Group Title	Placebo	TEZ/IVA
Arm/Group Description	Participants received placebo matched to tezacaftor (TEZ)/ivacaftor (IVA) fixed dose combination (FDC) tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Participants received 100 milligram (mg) TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
Period Title: Overall Study
STARTED	7	27
COMPLETED	7	27
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	TEZ/IVA	Total
Arm/Group Description	Participants received placebo matched to TEZ/IVA FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.	Total of all reporting groups
Overall Participants	7	27	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38 (11.8)	32.1 (8.6)	33.4 (9.5)
Sex: Female, Male (Count of Participants)
Female	4 57.1%	15 55.6%	19 55.9%
Male	3 42.9%	12 44.4%	15 44.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	7 100%	27 100%	34 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
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	0 0%	0 0%	0 0%
White	7 100%	27 100%	34 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Mucociliary Clearance (MCC): Percentage of Whole-lung Clearance (percentage of whole-lung clearance) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of whole-lung clearance]	15.3 (15.1)	18.4 (11.3)	17.8 (12.0)
Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments (pH minutes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pH minutes]	5.8 (0.4)	5.7 (0.6)	5.8 (0.6)

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Mucociliary Clearance (MCC) at Day 28
Description	MCC was assessed using an imaging technique that enables the tracking of mucus within the airways. MCC was expressed as the percentage of whole-lung clearance through 60 minutes at Baseline and Day 28.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized participants who carry the relevant cystic fibrosis transmembrane conductance regulator (CFTR) allele and received at least 1 dose of study drug.

Arm/Group Title	Placebo	TEZ/IVA
Arm/Group Description	Participants received placebo matched to TEZ/IVA FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
Measure Participants	7	27
Mean (Standard Deviation) [percentage of whole-lung clearance]	-0.5 (11.2)	-0.9 (12.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TEZ/IVA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7151
	Comments	p-value for within TEZ/IVA group was analyzed using a 2-sided, paired, t-test at a 5% level of significance.
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28
Description	Percent predicted FEV1 is the ratio of FEV1 to the predicted FEV1, expressed as a percentage. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

The FAS was used.

Arm/Group Title	Placebo	TEZ/IVA
Arm/Group Description	Participants received placebo matched to TEZ/IVA FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
Measure Participants	7	27
Mean (Standard Deviation) [percentage of predicted FEV1]	-0.4 (5.9)	2.4 (3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TEZ/IVA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	p-value for within TEZ/IVA group was analyzed using a 2-sided, paired, t-test at a 5% level of significance.
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Absolute Change From Baseline in Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments at Day 29
Description	Absolute change from Baseline in small bowel AUC over 1-minute mean pH increments through 30 minutes at Day 29 was assessed.
Time Frame	Baseline, Day 29

Outcome Measure Data

Analysis Population Description

The FAS was used. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TEZ/IVA
Arm/Group Description	Participants received placebo matched to TEZ/IVA FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
Measure Participants	6	23
Mean (Standard Deviation) [pH minutes]	0.3 (0.5)	-0.2 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TEZ/IVA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3345
	Comments
	Method	t-test, 2 sided
	Comments	p-value for within TEZ/IVA group was analyzed using a 2-sided, paired, t-test at a 5% level of significance.

4. Secondary Outcome

Title	Absolute Change From Baseline in Sweat Chloride at Day 29
Time Frame	Baseline, Day 29

Outcome Measure Data

Analysis Population Description

The FAS was used. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	TEZ/IVA
Arm/Group Description	Participants received placebo matched to TEZ/IVA FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
Measure Participants	7	23
Mean (Standard Deviation) [millimoles per liter]	-0.2 (6.0)	-8.4 (9.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TEZ/IVA
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	p-value for within TEZ/IVA group was analyzed using a 2-sided, paired, t-test at a 5% level of significance.
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	Baseline up to Day 57

Outcome Measure Data

Analysis Population Description

The 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 FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.	Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
Measure Participants	7	27
Participants with SAEs	0 0%	0 0%
Participants with AEs	2 28.6%	24 88.9%

Adverse Events

Time Frame	Baseline up to Day 57: 29 days of dosing + 28 days of safety follow up
Adverse Event Reporting Description	Other adverse events table reports the participants with adverse events that exceed a frequency threshold of at least 5% within any arm of the study.
Arm/Group Title	Placebo		TEZ/IVA
Arm/Group Description	Participants received placebo matched to TEZ/IVA FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days.		Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days.
All Cause Mortality
	Placebo		TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/27 (0%)
Serious Adverse Events
	Placebo		TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)		18/27 (66.7%)
Gastrointestinal disorders
Nausea	0/7 (0%)		3/27 (11.1%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	0/7 (0%)		7/27 (25.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/7 (14.3%)		0/27 (0%)
Renal and urinary disorders
Renal impairment	1/7 (14.3%)		0/27 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/7 (0%)		8/27 (29.6%)
Haemoptysis	0/7 (0%)		3/27 (11.1%)
Sputum increased	0/7 (0%)		2/27 (7.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PI is free to publish results of the study after (1) the first multi-center publication, (2) if the sponsor elects not to publish the results, or (3) 18 months after close of the study, whichever occurs first. Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 45 days (which may be extended under certain circumstances related to protection of intellectual property); the sponsor cannot require changes to the proposed publications.