Study of the Effect of Ivacaftor on Lung Clearance Index in Subjects With Cystic Fibrosis and the G551D Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01262352
• Collaborator: Cystic Fibrosis Foundation (Other)
• Enrollment: 21
• Locations: 8
• Arms: 2
• Duration (Months): 10
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of ivacaftor (VX-770) on lung clearance index (LCI) in subjects aged 6 years and older with cystic fibrosis (CF) who have the G551D-CFTR mutation on at least 1 allele.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Ivacaftor; Drug: Placebo	Phase 2

Detailed Description

Currently, limited objective measures are available to quantify lung function in CF patients with mild lung disease. Lung clearance index (LCI) derived from inert gas multiple-breath washout (MBW) testing hold considerable promise to evaluate early lung disease as studies have detected abnormalities in a high percentage of CF patients with normal spirometry in both infants and children.

This study explored the effect of ivacaftor on LCI and the efficacy of ivacaftor on other clinical and biomarker endpoints of CF lung disease in subjects aged 6 years and older with CF who have the G551D-CFTR mutation on at least 1 allele.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of VX-770 on Lung Clearance Index in Subjects With Cystic Fibrosis, the G551D Mutation, and FEV1 >90% Predicted
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Sequence 1 Ivacaftor administered in Treatment Period 1 and placebo administered in Treatment Period 2.	Drug: Ivacaftor; 150 mg tablet, oral use, twice daily every 12 hours (q12h); Drug: Placebo; Tablet, oral use, twice daily every 12 hours (q12h)
Experimental: Treatment Sequence 2 Placebo administered in Treatment Period 1 and ivacaftor administered in Treatment Sequence 2.	Drug: Ivacaftor; 150 mg tablet, oral use, twice daily every 12 hours (q12h); Drug: Placebo; Tablet, oral use, twice daily every 12 hours (q12h)

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Lung Clearance Index (LCI) [Baseline through Day 29]

   Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal SF6 concentration to 1/40th of the starting value.

Secondary Outcome Measures

1. Absolute Change From Baseline in Percent Predicted FEV1 [Baseline through Day 29]

   Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

2. Change From Baseline in Sweat Chloride [Baseline through Day 29]

   The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

3. Change From Baseline in CF Questionnaire-Revised (CFQ-R) Score (Respiratory Domain Score, Pooled) [Baseline through Day 29]

   The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID). The primary analytical focus was the respiratory health domain, which was analyzed by combining all self-response questionnaire versions from different age groups (e.g., Adult/Adolescent and Child versions).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female subjects with confirmed diagnosis of CF

• Must have the G551D-CFTR mutation in at least 1 allele

• FEV1 >90% of predicted normal for age, gender, and height

Exclusion Criteria:

• Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening

• Use of inhaled hypertonic saline treatment within 2 weeks of the Period 1, Day 1 visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Stanford	California	United States
2		Iowa City	Iowa	United States
3		Durham	North Carolina	United States
4		Pittsburgh	Pennsylvania	United States
5		Toronto	Ontario	Canada
6		Belfast		United Kingdom
7		Edinburgh		United Kingdom
8		London		United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated
• Cystic Fibrosis Foundation

Investigators

• Principal Investigator: Jane Davies, Royal Brompton Hospital and Imperial College
• Principal Investigator: Felix Ratjen, The Hospital for Sick Children

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT01262352
• Other Study ID Numbers: VX10-770-106
• First Posted: Dec 17, 2010
• Last Update Posted: Feb 11, 2013
• Last Verified: Feb 1, 2013

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

Study Results

Participant Flow

Recruitment Details	The study started on 14 February 2011 (signing of first informed consent). After obtaining informed consent and assent (where applicable), screening evaluations were completed at any time during the period 10 to 18 days (Days -18 to -10) before first dose of study drug (Day 1).
Pre-assignment Detail	A total of 21 subjects were randomized; 20 subjects received at least 1 dose of the study drug.

Arm/Group Title	Ivacaftor Then Placebo	Placebo Then Ivacaftor
Arm/Group Description	Ivacaftor administered in Treatment Period 1 and placebo administered in Treatment Period 2.	Placebo administered in Treatment Period 1 and ivacaftor administered in Treatment Period 2.
Period Title: Period 1
STARTED	11	10
Dosed	10	10
COMPLETED	10	10
NOT COMPLETED	1	0
Period Title: Period 1
STARTED	10	10
COMPLETED	9	8
NOT COMPLETED	1	2
Period Title: Period 1
STARTED	9	8
Dosed	9	8
COMPLETED	9	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ivacaftor Then Placebo	Placebo Then Ivacaftor	Total
Arm/Group Description	Ivacaftor administered in Treatment Period 1 and placebo administered in Treatment Period 2.	Placebo administered in Treatment Period 1 and ivacaftor administered in Treatment Period 2.	Total of all reporting groups
Overall Participants	10	10	20
Age (Count of Participants)
<=18 years	9 90%	7 70%	16 80%
Between 18 and 65 years	1 10%	3 30%	4 20%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.4 (7.12)	19.8 (13.35)	16.6 (10.92)
Sex: Female, Male (Count of Participants)
Female	6 60%	4 40%	10 50%
Male	4 40%	6 60%	10 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	10 100%	10 100%	20 100%
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	10 100%	10 100%	20 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
North America	6 60%	5 50%	11 55%
Europe	4 40%	5 50%	9 45%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	148.9 (19.54)	156.0 (17.92)	152.5 (18.61)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	45.06 (20.018)	58.78 (30.576)	51.92 (26.119)
Body Mass Index (kilograms per square meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms per square meter]	19.36 (3.707)	22.66 (6.964)	21.01 (5.687)
Lung Clearance Index (LCI) (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	9.17 (1.657)	8.88 (1.462)	9.03 (1.528)
Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	101.83 (11.587)	92.58 (7.427)	97.20 (10.595)
Sweat Chloride (millimoles per liter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimoles per liter]	97.10 (7.400)	86.17 (19.219)	91.92 (14.933)

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Lung Clearance Index (LCI)
Description	Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal SF6 concentration to 1/40th of the starting value.
Time Frame	Baseline through Day 29

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.

Arm/Group Title	Placebo	Ivacaftor
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 28 days.	Oral tablet of 150 mg of ivacaftor q12h for up to 28 days.
Measure Participants	18	17
Least Squares Mean (Standard Error) [ratio]	0.77 (0.291)	-1.30 (0.303)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments	The primary analysis for the primary efficacy variable was based on a mixed effect model. The model included the absolute change from the baseline in each period as the dependent variable, sequence, treatment, and period as fixed effects, study baseline LCI as the covariate, and subject nested within sequence as the random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.069
	Confidence Interval	(2-Sided) 95%; -2.98 to -1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Absolute Change From Baseline in Percent Predicted FEV1
Description	Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.
Time Frame	Baseline through Day 29

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.

Arm/Group Title	Placebo	Ivacaftor
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 28 days.	Oral tablet of 150 mg of ivacaftor q12h for up to 28 days.
Measure Participants	19	18
Least Squares Mean (Standard Error) [percent]	0.00 (1.916)	7.00 (1.978)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments	Analysis for this efficacy variable was performed in a similar way as the analysis for the primary efficacy variable.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0117
	Comments	P-value was not adjusted for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.007
	Confidence Interval	(2-Sided) 95%; 1.80 to 12.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Sweat Chloride
Description	The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.
Time Frame	Baseline through Day 29

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.

Arm/Group Title	Placebo	Ivacaftor
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 28 days.	Oral tablet of 150 mg of ivacaftor q12h for up to 28 days.
Measure Participants	18	16
Least Squares Mean (Standard Error) [millimoles per liter]	0.11 (2.351)	-45.74 (2.632)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments	Analysis for change from baseline in average sweat chloride was similar to the analysis of the primary efficacy variable.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value was not adjusted for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-45.848
	Confidence Interval	(2-Sided) 95%; -53.54 to -38.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in CF Questionnaire-Revised (CFQ-R) Score (Respiratory Domain Score, Pooled)
Description	The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID). The primary analytical focus was the respiratory health domain, which was analyzed by combining all self-response questionnaire versions from different age groups (e.g., Adult/Adolescent and Child versions).
Time Frame	Baseline through Day 29

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.

Arm/Group Title	Placebo	Ivacaftor
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 28 days.	Oral tablet of 150 mg of ivacaftor q12h for up to 28 days.
Measure Participants	19	18
Least Squares Mean (Standard Error) [score on a scale]	1.33 (3.067)	5.32 (3.166)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments	The raw scores in CFQ-R were summarized into different domains of health (12 domains for adolescents and adults 14 years of age and older, 8 domains for children ages 12 and 13 years, 8 domains for children ages 6 to 11 years, and 11 domains for parents/caregivers). Each domain was analyzed in a similar way as for the primary efficacy variable. The primary analytical focus was the respiratory health domain which was analyzed by combining all self-response questionnaire versions.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3796
	Comments	P-value was not adjusted for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.991
	Confidence Interval	(2-Sided) 95%; -5.40 to 13.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	For enrolled subjects, all adverse events were collected through the Follow-up Visit (4 weeks [+/-7 days] after the last dose of study drug).
Adverse Event Reporting Description	For subjects who were screened but were not subsequently enrolled in the study, all adverse events were collected until the subject was deemed ineligible for the study.
Arm/Group Title	Placebo		Ivacaftor
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 28 days.		Oral tablet of 150 mg of ivacaftor q12h for up to 28 days.
All Cause Mortality
	Placebo		Ivacaftor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Ivacaftor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		2/18 (11.1%)
Congenital, familial and genetic disorders
Cystic fibrosis lung	0/19 (0%)	0	1/18 (5.6%)	1
Gastrointestinal disorders
Distal ileal obstruction syndrome	0/19 (0%)	0	1/18 (5.6%)	1
Infections and infestations
Bronchopulmonary aspergillosis allergic	1/19 (5.3%)	1	0/18 (0%)	0
Pseudomonas infection	0/19 (0%)	0	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Ivacaftor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/19 (78.9%)		13/18 (72.2%)
Congenital, familial and genetic disorders
Cystic fibrosis lung	1/19 (5.3%)	1	0/18 (0%)	0
Ear and labyrinth disorders
Ear pain	1/19 (5.3%)	1	0/18 (0%)	0
Gastrointestinal disorders
Vomiting	4/19 (21.1%)	4	1/18 (5.6%)	1
Abdominal pain upper	2/19 (10.5%)	2	0/18 (0%)	0
Constipation	1/19 (5.3%)	1	1/18 (5.6%)	2
Abdominal pain	0/19 (0%)	0	1/18 (5.6%)	1
Abdominal tenderness	1/19 (5.3%)	1	0/18 (0%)	0
Flatulence	0/19 (0%)	0	1/18 (5.6%)	1
Hiatus hernia	1/19 (5.3%)	1	0/18 (0%)	0
Nausea	1/19 (5.3%)	1	0/18 (0%)	0
General disorders
Pyrexia	3/19 (15.8%)	3	1/18 (5.6%)	1
Fatigue	1/19 (5.3%)	1	1/18 (5.6%)	1
Application site papules	1/19 (5.3%)	1	0/18 (0%)	0
Immune system disorders
Seasonal allergy	0/19 (0%)	0	2/18 (11.1%)	2
Infections and infestations
Lower respiratory tract infection	2/19 (10.5%)	2	0/18 (0%)	0
Gastrointestinal viral infection	1/19 (5.3%)	1	0/18 (0%)	0
Mycobacterium abscessus infection	0/19 (0%)	0	1/18 (5.6%)	1
Oral candidiasis	1/19 (5.3%)	1	0/18 (0%)	0
Pneumococcal infection	1/19 (5.3%)	1	0/18 (0%)	0
Sinusitis	1/19 (5.3%)	1	0/18 (0%)	0
Staphylococcal infection	1/19 (5.3%)	1	0/18 (0%)	0
Vulvovaginal mycotic infection	1/19 (5.3%)	1	0/18 (0%)	0
Injury, poisoning and procedural complications
Bite	0/19 (0%)	0	1/18 (5.6%)	1
Fall	0/19 (0%)	0	1/18 (5.6%)	1
Joint sprain	1/19 (5.3%)	1	0/18 (0%)	0
Medical device complication	0/19 (0%)	0	1/18 (5.6%)	1
Investigations
Bacteria sputum identified	0/19 (0%)	0	1/18 (5.6%)	1
Bacterial culture positive	1/19 (5.3%)	1	0/18 (0%)	0
Lymph node palpable	1/19 (5.3%)	1	0/18 (0%)	0
Prothrombin time prolonged	0/19 (0%)	0	1/18 (5.6%)	1
Metabolism and nutrition disorders
Glucose tolerance impaired	1/19 (5.3%)	1	0/18 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/19 (0%)	0	1/18 (5.6%)	1
Back pain	0/19 (0%)	0	1/18 (5.6%)	1
Myalgia	0/19 (0%)	0	1/18 (5.6%)	1
Pain in extremity	0/19 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Headache	1/19 (5.3%)	1	4/18 (22.2%)	4
Dizziness	0/19 (0%)	0	2/18 (11.1%)	3
Hypoaesthesia	0/19 (0%)	0	1/18 (5.6%)	1
Renal and urinary disorders
Glycosuria	0/19 (0%)	0	1/18 (5.6%)	1
Haematuria	0/19 (0%)	0	1/18 (5.6%)	1
Reproductive system and breast disorders
Nipple disorder	0/19 (0%)	0	1/18 (5.6%)	1
Nipple pain	0/19 (0%)	0	1/18 (5.6%)	1
Respiratory, thoracic and mediastinal disorders
Cough	7/19 (36.8%)	10	5/18 (27.8%)	5
Nasal congestion	2/19 (10.5%)	2	1/18 (5.6%)	1
Oropharyngeal pain	2/19 (10.5%)	2	0/18 (0%)	0
Productive cough	1/19 (5.3%)	1	1/18 (5.6%)	1
Epistaxis	1/19 (5.3%)	1	1/18 (5.6%)	1
Nasal inflammation	1/19 (5.3%)	1	0/18 (0%)	0
Nasal oedema	1/19 (5.3%)	1	0/18 (0%)	0
Rales	0/19 (0%)	0	1/18 (5.6%)	1
Respiratory tract congestion	1/19 (5.3%)	1	0/18 (0%)	0
Rhinorrhoea	1/19 (5.3%)	1	0/18 (0%)	0
Sinus congestion	1/19 (5.3%)	2	0/18 (0%)	0
Sneezing	1/19 (5.3%)	1	0/18 (0%)	0
Skin and subcutaneous tissue disorders
Rash macular	1/19 (5.3%)	1	1/18 (5.6%)	1
Acne	0/19 (0%)	0	1/18 (5.6%)	1
Blister	1/19 (5.3%)	1	0/18 (0%)	0
Rash	0/19 (0%)	0	1/18 (5.6%)	1
Swelling face	0/19 (0%)	0	1/18 (5.6%)	1

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.