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Safety Study of Ivacaftor in Subjects With Cystic Fibrosis

Sponsor
Vertex Pharmaceuticals Incorporated (Industry)
Overall Status
Completed
CT.gov ID
NCT00457821
Collaborator
Cystic Fibrosis Foundation (Other)
39
Enrollment
15
Locations
4
Arms
15
Duration (Months)
2.6
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.

Condition or Disease Intervention/Treatment Phase
  • Drug: Ivacaftor 25 mg/75 mg
  • Drug: Ivacaftor 75 mg/150 mg
  • Drug: Ivacaftor 150 mg or 250 mg
  • Drug: Placebo
 Phase 2

Detailed Description

This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. Enrollment of 39 subjects occurred at 15 centers in the US, Canada, and Germany.

The study was conducted in 2 parts:

  • Part 1 consisted of Group A and Group B. Subjects in Group A (10 subjects) were randomized to receive 25 mg of ivacaftor every 12 hours [q12h] (4 subjects), 75 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. Subjects in Group B (10 subjects) were randomized to receive 75 mg of ivacaftor q12h (4 subjects), 150 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, the subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days.

  • Part 2 consisted of Group C; these subjects did not participate in Part 1. Subjects were randomized to receive 150 mg of ivacaftor q12h (7 subjects), 250 mg of ivacaftor q12h (7 subjects), or placebo (4 subjects) for a total of 28 days. Ivacaftor doses studied in Part 2 were selected following an interim pharmacokinetic/pharmacodynamic (PK/PD) and statistical analyses of data from Part 1. The 2 doses selected for Part 2 were anticipated to enable better definition of the optimal therapeutic dose.

Study Design

Study Type:
Interventional
Actual Enrollment :
39 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D
Study Start Date :
May 1, 2007
Actual Primary Completion Date :
Aug 1, 2008
Actual Study Completion Date :
Aug 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ivacaftor Group A

Subjects in Part 1 who first received 25 mg or 75 mg of ivacaftor every 12 hours (q12h) for 14 days, then crossed over to receive the alternate dose for another 14 days.

Drug: Ivacaftor 25 mg/75 mg
25 mg or 75 mg q12h for a total of 28 days (Part 1)
Other Names:
  • VX-770

    		•
    Experimental: Ivacaftor Group B

    Subjects in Part 1 who first received 75 mg or 150 mg of ivacaftor q12h for 14 days then crossed over to receive the alternate dose for another 14 days.

    Drug: Ivacaftor 75 mg/150 mg
    75 mg or 150 mg q12h for a total of 28 days (Part 1)
    Other Names:
  • VX-770

    		•
    Experimental: Ivacaftor Group C

    Subjects in Part 2 who received 150 mg or 250 mg of ivacaftor q12h for 28 days.

    Drug: Ivacaftor 150 mg or 250 mg
    150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2)
    Other Names:
  • VX-770

    		•
    Placebo Comparator: Placebo

    Subjects who received placebo in Part 1 and subjects who received placebo in Part 2.

    Drug: Placebo
    Given q12h for 28 days each in Part 1 and Part 2 of the study

    Outcome Measures

    Primary Outcome Measures

    1. Number of Subjects With Adverse Events (Combined Part 1 and Part 2) [Baseline to Follow-up]

      Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.

    2. Number of Adverse Events (Combined Part 1 and Part 2) [Baseline to Follow-up]

      Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.

    Secondary Outcome Measures

    1. Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) [14 days and 28 days]

      The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest.

    2. Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) [14 days and 28 days]

      Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Relative change reflects the percent change from the baseline values [100% * (X-Y)/Y], where X and Y are post-baseline and baseline values, respectively.

    3. Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) [14 days and 28 days]

      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).

    4. Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) [14 days and 28 days]

      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.

    Eligibility Criteria

    Criteria

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

    • Weighing at least 40 kg

    • Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele

    • Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height

    • Willing to remain on stable medication regimen for the duration of study participation

    • No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study

    • No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator

    Exclusion Criteria:

    • History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject

    • Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study

    • History of alcohol, medication or illicit drug abuse within one year prior to Day 1

    • Abnormal liver function ≥ 3x the upper limit of normal

    • History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation)

    • History of solid organ or hematological transplantation

    • Pregnant or breast-feeding (for women)

    • Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout

    • Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama Hospital Birmingham Alabama United States 35211
    2 Stanford University Medical Center Palo Alto California United States 34304
    3 The Children's Hospital Aurora Colorado United States 80045
    4 Roy J. and Lucille A. Carver College of Medicine, The University of Iowa Iowa City Iowa United States 52242-1083
    5 Johns Hopkins Hospital Baltimore Maryland United States 21287
    6 Pulmonary and Critical Care Medicine, Massachusetts General Hospital Boston Massachusetts United States 02114
    7 Children's Hospital of Boston Boston Massachusetts United States 02215
    8 Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota Minneapolis Minnesota United States 55455
    9 Cystic Fibrosis Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill Chapel Hill North Carolina United States 27599
    10 Rainbow Babies and Children's Hospital Cleveland Ohio United States 44106
    11 The Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104-4399
    12 University of Pittsburgh Pittsburgh Pennsylvania United States 15213
    13 Pulmonary Critical Care, University of Washington Seattle Washington United States 98195
    14 Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children Toronto Ontario Canada M5G 1X8
    15 CF Clinic, Pediatric Pulmonology and Neonatology, Medical School of Hannover Strasse Hannover Germany D-30625

    Sponsors and Collaborators

    • Vertex Pharmaceuticals Incorporated
    • Cystic Fibrosis Foundation

    Investigators

    • Study Director: Medical Monitor, Vertex Pharmaceuticals Incorporated

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Vertex Pharmaceuticals Incorporated
    ClinicalTrials.gov Identifier:
    NCT00457821
    Other Study ID Numbers:
    • VX06-770-101
    First Posted:
    Apr 9, 2007
    Last Update Posted:
    Oct 5, 2012
    Last Verified:
    Oct 1, 2012
    Keywords provided by Vertex Pharmaceuticals Incorporated
    G551D mutation
    Fibrosis
    Pancreatic Diseases
    Digestive System Diseases
    Lung Diseases
    Respiratory Tract Diseases
    Genetic Diseases, Inborn
    Infant, Newborn, Diseases
    Pathologic Processes
    Additional relevant MeSH terms:
    Cystic Fibrosis
    Fibrosis
    Ivacaftor

    Study Results

    Participant Flow

    Recruitment Details Part 1 started on 10 May 2007 (signing of first informed consent). After obtaining consent, Part 1 screening evaluations were completed during Day -28 to Day -2. Part 2 started on 28 May 2008 (signing of first informed consent). Part 2 screening evaluations were also completed during Day -28 to Day -2 before the first dose of study drug.
    Pre-assignment Detail In Part 1, 21 subjects were randomized but 1 subject was excluded prior to dosing because the subject needed a protocol-prohibited medication. In Part 2, 20 subjects were randomized but 1 subject withdrew consent to the study prior to dosing.
    Arm/Group Title Part 1: Placebo Part 1: 25 mg/75 mg Part 1: 75 mg/25 mg Part 1: 75 mg/150 mg Part 1: 150 mg/75 mg Part 2: 150 mg Part 2: 250 mg Part 2: Placebo
    Arm/Group Description Part 1: placebo every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (25 mg/75 mg) every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (75 mg/25 mg) every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (75 mg/150 mg) every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (150 mg/75 mg) every 12 hours (q12h); 14 days/14 days. Part 2: Ivacaftor (150 mg) q12h; 28 days Part 2: Ivacaftor (250 mg) q12h; 28 days Part 2: placebo q12h; 28 days
    Period Title: Part 1
    STARTED 4 4 5 4 4 0 0 0
    COMPLETED 4 4 4 4 4 0 0 0
    NOT COMPLETED 0 0 1 0 0 0 0 0
    Period Title: Part 1
    STARTED 0 0 0 0 0 8 7 5
    Completed Study Drug Treatment 0 0 0 0 0 8 7 4
    COMPLETED 0 0 0 0 0 8 7 4
    NOT COMPLETED 0 0 0 0 0 0 0 1

    Baseline Characteristics

    Arm/Group Title Part 1: Placebo Part 1: 25 mg/75 mg Part 1: 75 mg/25 mg Part 1: 75 mg/150 mg Part 1: 150 mg/75 mg Part 2: 150 mg Part 2: 250 mg Part 2: Placebo Total
    Arm/Group Description Part 1: placebo every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (25 mg/75 mg) every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (75 mg/25 mg) every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (75 mg/150 mg) every 12 hours (q12h); 14 days/14 days. Part 1: Ivacaftor (150 mg/75 mg) every 12 hours (q12h); 14 days/14 days. Part 2: Ivacaftor (150 mg) q12h; 28 days Part 2: Ivacaftor (250 mg) q12h; 28 days Part 2: placebo q12h; 28 days Total of all reporting groups
    Overall Participants 4 4 4 4 4 8 7 4 39
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    34.5
    (14.66)
    33.5
    (12.50)
    38.5
    (11.82)
    26.3
    (7.85)
    23.5
    (6.45)
    25.6
    (7.98)
    26.0
    (7.07)
    26.8
    (10.69)
    28.7
    (10.03)
    Sex: Female, Male (Count of Participants)
    Female
    2
    50%
    3
    75%
    0
    0%
    3
    75%
    3
    75%
    5
    62.5%
    3
    42.9%
    1
    25%
    20
    51.3%
    Male
    2
    50%
    1
    25%
    4
    100%
    1
    25%
    1
    25%
    3
    37.5%
    4
    57.1%
    3
    75%
    19
    48.7%
    Race/Ethnicity, Customized (participants) [Number]
    Caucasian
    4
    100%
    4
    100%
    4
    100%
    4
    100%
    4
    100%
    8
    100%
    7
    100%
    4
    100%
    39
    100%
    Weight (kilograms) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kilograms]
    70.05
    (16.507)
    66.05
    (12.628)
    73.43
    (14.366)
    57.48
    (8.663)
    59.35
    (18.401)
    61.19
    (9.857)
    64.46
    (13.027)
    63.50
    (7.391)
    64.1
    (12.42)
    Body Mass Index (kilograms per square meter) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kilograms per square meter]
    24.195
    (3.2002)
    22.455
    (2.3133)
    23.653
    (3.6216)
    20.960
    (2.2522)
    20.788
    (4.1527)
    21.896
    (0.9770)
    22.703
    (1.3980)
    22.035
    (0.6999)
    22.3
    (2.37)
    Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) (percentage of volume in liters) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage of volume in liters]
    64.902
    (22.6821)
    71.073
    (27.2307)
    54.885
    (9.6772)
    68.284
    (24.7014)
    49.270
    (7.5615)
    70.443
    (25.4442)
    72.674
    (21.5223)
    79.351
    (28.7018)
    67.3
    (22.17)
    Genotype (participants) [Number]
    G551D/1078 DEL T
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.6%
    G551D/DELTA F508
    3
    75%
    4
    100%
    4
    100%
    2
    50%
    3
    75%
    7
    87.5%
    5
    71.4%
    4
    100%
    32
    82.1%
    G551D/G551D
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    1
    2.6%
    G551D/N1303K
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.6%
    G551D/R553X
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.6%
    G551D/3849 AND 10KBC
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    1
    2.6%
    G551D/6214 + 1G > 7T
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    0
    0%
    1
    2.6%
    G551D/G542X
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    1
    2.6%

    Outcome Measures

    1. Primary Outcome
    Title Number of Subjects With Adverse Events (Combined Part 1 and Part 2)
    Description Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
    Time Frame Baseline to Follow-up

    Outcome Measure Data

    Analysis Population Description
    All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
    Arm/Group Title Placebo Ivacaftor
    Arm/Group Description All subjects given placebo in Part 1 (n=4) and Part 2 (n=4) All subjects given Ivacaftor in Part 1 (n=16) and Part 2 (n=15)
    Measure Participants 8 31
    Subjects with AEs
    7
    175%
    26
    650%
    Subjects with Related or Possibly Related AEs
    3
    75%
    13
    325%
    Subjects with SAEs
    0
    0%
    1
    25%
    Subjects with Related or Possibly Related SAEs
    0
    0%
    0
    0%
    2. Secondary Outcome
    Title Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)
    Description The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest.
    Time Frame 14 days and 28 days

    Outcome Measure Data

    Analysis Population Description
    Due to the crossover design in Part 1, subjects were counted once for each period; therefore, the 4 unique subjects who received placebo were counted as 8 subjects in the analyses for Part 1.
    Arm/Group Title Placebo 25 mg Ivacaftor q12h 75 mg Ivacaftor q12h 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Arm/Group Description All subjects given placebo every 12 hours (q12h) in Part 1 (n=4) and Part 2 (n=4) All subjects given the 25 mg dose q12h in Group A in Part 1 (n=4 x 2). All subjects given the 75 mg dose q12h in Group A (n=4 x 2) and Group B (n=4 x 2) in Part 1. All subjects given the 150 mg dose q12h in Group B in Part 1 (n=4 x 2) and Group C in Part 2 (n=8). All subjects given the 250 mg dose q12h in Group C (n=7) in Part 2.
    Measure Participants 12 7 15 16 7
    Zero Chloride + Isoproterenol, Day 14
    -0.3
    -1.4
    -4.4
    -4.6
    -7.6
    Zero Chloride + Isoproterenol, Day ≥ 14
    -0.5
    -1.3
    -4.5
    -5.3
    -8.4
    Amiloride, Day 14
    0.3
    -0.1
    -4.2
    -9.9
    -5.5
    Amiloride, Day ≥ 14
    -0.7
    -0.3
    -3.7
    -8.8
    -4.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Ivacaftor, 75 mg Ivacaftor q12h, 150 mg Ivacaftor q12h, 250 mg Ivacaftor q12h
    Comments Within-dose group and between-dose group analyses were performed, using a linear mixed effect model with baseline, dose, and period as fixed effects and subject as a random effect.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.05
    Comments There was no adjustment for multiple comparisons.
    Method Mixed Models Analysis
    Comments
    3. Secondary Outcome
    Title Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)
    Description Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Relative change reflects the percent change from the baseline values [100% * (X-Y)/Y], where X and Y are post-baseline and baseline values, respectively.
    Time Frame 14 days and 28 days

    Outcome Measure Data

    Analysis Population Description
    Due to the crossover design in Part 1, subjects were counted once for each period; therefore, the 4 unique subjects who received placebo were counted as 8 subjects in the analyses for Part 1.
    Arm/Group Title Placebo 25 mg Ivacaftor q12h 75 mg Ivacaftor q12h 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Arm/Group Description All subjects given placebo every 12 hours (q12h) in Part 1 (n=4) and Part 2 (n=4) All subjects given the 25 mg dose q12h in Group A in Part 1 (n=4 x 2). All subjects given the 75 mg dose q12h in Group A (n=4 x 2) and Group B (n=4 x 2) in Part 1. All subjects given the 150 mg dose q12h in Group B in Part 1 (n=4 x 2) and Group C in Part 2 (n=8). All subjects given the 250 mg dose q12h in Group C (n=7) in Part 2.
    Measure Participants 10 7 15 16 7
    Absolute Change from Baseline, Day 14
    0.5
    2.7
    5.1
    6.9
    8.4
    Absolute Change from Baseline, Day ≥ 14
    2.1
    2.5
    5.3
    6.9
    6.7
    Relative Change from Baseline, Day 14
    2.0
    4.7
    9.5
    10.8
    12.0
    Relative Change from Baseline, Day ≥ 14
    3.3
    4.1
    9.3
    10.6
    9.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Ivacaftor, 75 mg Ivacaftor q12h, 150 mg Ivacaftor q12h, 250 mg Ivacaftor q12h
    Comments Within-dose group and between-dose group analyses were performed, using a linear mixed effect model with baseline, dose, and period as fixed effects and subject as a random effect.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.05
    Comments There was no adjustment for multiple comparisons.
    Method Mixed Models Analysis
    Comments
    4. Secondary Outcome
    Title Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)
    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).
    Time Frame 14 days and 28 days

    Outcome Measure Data

    Analysis Population Description
    Part 2 is a parallel study. Subjects were counted only once for each treatment group.
    Arm/Group Title Placebo 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Arm/Group Description Subjects given placebo every 12 hours (q12h) for 28 days. Subjects given 150 mg of ivacaftor q12h for 28 days. Subjects given 250 mg of ivacaftor q12h for 28 days.
    Measure Participants 4 8 7
    Baseline Respiratory Domain Score
    70.8
    (21.5)
    68.8
    (23.9)
    73.0
    (8.7)
    Change from Baseline in Respiratory Score, Day 14
    2.8
    (7.2)
    6.3
    (6.9)
    5.6
    (7.9)
    Change from Baseline in Respiratory Score, Day 28
    2.8
    (7.2)
    6.9
    (6.5)
    11.9
    (14.1)
    5. Secondary Outcome
    Title Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)
    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 14 days and 28 days

    Outcome Measure Data

    Analysis Population Description
    Due to the crossover design in Part 1, subjects were counted once for each period; therefore, the 4 unique subjects who received placebo were counted as 8 subjects in the analyses for Part 1.
    Arm/Group Title Placebo 25 mg Ivacaftor q12h 75 mg Ivacaftor q12h 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Arm/Group Description All subjects given placebo every 12 hours (q12h) in Part 1 (n=4) and Part 2 (n=4) All subjects given the 25 mg dose q12h in Group A in Part 1 (n=4 x 2). All subjects given the 75 mg dose q12h in Group A (n=4 x 2) and Group B (n=4 x 2) in Part 1. All subjects given the 150 mg dose q12h in Group B in Part 1 (n=4 x 2) and Group C in Part 2 (n=8). All subjects given the 250 mg dose q12h in Group C (n=7) in Part 2.
    Measure Participants 12 8 14 16 7
    Change from Baseline in Sweat Chloride, Day 14
    2.0
    -33.8
    -42.0
    -46.0
    -27.1
    Change from Baseline in Sweat Chloride, Day ≥14
    4.9
    -32.9
    -40.8
    -44.2
    -28.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Ivacaftor, 75 mg Ivacaftor q12h, 150 mg Ivacaftor q12h, 250 mg Ivacaftor q12h
    Comments Within-dose group and between-dose group analyses were performed, using a linear mixed effect model with baseline, dose, and period as fixed effects and subject as a random effect.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.05
    Comments There was no adjustment for multiple comparisons.
    Method Mixed Models Analysis
    Comments
    6. Primary Outcome
    Title Number of Adverse Events (Combined Part 1 and Part 2)
    Description Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
    Time Frame Baseline to Follow-up

    Outcome Measure Data

    Analysis Population Description
    All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
    Arm/Group Title Placebo Ivacaftor
    Arm/Group Description All subjects given placebo in Part 1 (n=4) and Part 2 (n=4) All subjects given Ivacaftor in Part 1 (n=16) and Part 2 (n=15)
    Measure Participants 8 31
    Number of Adverse Events (AEs)
    32
    179
    Number of Related or Possibly Related AEs
    11
    40
    Number of Serious Adverse Events (SAEs)
    0
    2
    Number of Related or Possibly Related SAEs
    0
    0

    Adverse Events

    Time Frame Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug).
    Adverse Event Reporting Description
    Arm/Group Title Placebo 25 mg Ivacaftor q12h 75 mg Ivacaftor q12h 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Arm/Group Description All subjects given placebo every 12 hours (q12h) in Part 1 (n=4) and Part 2 (n=4) All subjects given the 25 mg dose q12h in Group A in Part 1 (n=4 x 2). All subjects given the 75 mg dose q12h in Group A (n=4 x 2) and Group B (n=4 x 2) in Part 1. All subjects given the 150 mg dose q12h in Group B in Part 1 (n=4 x 2) and Group C in Part 2 (n=8). All subjects given the 250 mg dose q12h in Group C (n=7) in Part 2.
    All Cause Mortality
    Placebo 25 mg Ivacaftor q12h 75 mg Ivacaftor q12h 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Placebo 25 mg Ivacaftor q12h 75 mg Ivacaftor q12h 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/8 (0%) 0/8 (0%) 0/16 (0%) 1/16 (6.3%) 0/7 (0%)
    Congenital, familial and genetic disorders
    Cystic fibrosis lung 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Skin and subcutaneous tissue disorders
    Rash macular 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Other (Not Including Serious) Adverse Events
    Placebo 25 mg Ivacaftor q12h 75 mg Ivacaftor q12h 150 mg Ivacaftor q12h 250 mg Ivacaftor q12h
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 7/8 (87.5%) 4/8 (50%) 13/16 (81.3%) 13/16 (81.3%) 6/7 (85.7%)
    Blood and lymphatic system disorders
    Lymphadenopathy 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Congenital, familial and genetic disorders
    Cystic fibrosis lung 0/8 (0%) 0 2/8 (25%) 3 1/16 (6.3%) 1 1/16 (6.3%) 1 1/7 (14.3%) 1
    Ear and labyrinth disorders
    Tympanic membrane hyperaemia 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Gastrointestinal disorders
    Bowel sounds abnormal 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Constipation 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Diarrhoea 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 3/16 (18.8%) 3 0/7 (0%) 0
    Epigastric discomfort 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Nausea 0/8 (0%) 0 1/8 (12.5%) 1 3/16 (18.8%) 3 2/16 (12.5%) 2 0/7 (0%) 0
    Abdominal pain 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Abdominal pain upper 1/8 (12.5%) 1 1/8 (12.5%) 1 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Oral pain 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Painful defaecation 0/8 (0%) 0 1/8 (12.5%) 1 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Vomiting 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 1/7 (14.3%) 1
    Abdominal distension 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Flatulence 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    General disorders
    Pyrexia 0/8 (0%) 0 0/8 (0%) 0 4/16 (25%) 5 2/16 (12.5%) 4 0/7 (0%) 0
    Catheter related complication 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Chills 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Infusion site haemorrhage 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 2 0/7 (0%) 0
    Infusion site reaction 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 2 0/7 (0%) 0
    Pain 0/8 (0%) 0 0/8 (0%) 0 3/16 (18.8%) 3 1/16 (6.3%) 1 0/7 (0%) 0
    Chest discomfort 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Fatigue 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Injection site oedema 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Mucosal erosion 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Immune system disorders
    Allergy to arthropod bite 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 2
    Infections and infestations
    Pharyngitis 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Vulvovaginal mycotic infection 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 1/7 (14.3%) 1
    Upper respiratory tract infection 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 2/7 (28.6%) 2
    Chronic sinusitis 1/8 (12.5%) 2 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Oral candidiasis 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Sinusitis 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Injury, poisoning and procedural complications
    Thermal burn 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Contusion 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Medical device complication 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Excoriation 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Skin laceration 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Investigations
    Blood glucose increased 0/8 (0%) 0 0/8 (0%) 0 2/16 (12.5%) 3 1/16 (6.3%) 1 0/7 (0%) 0
    Blood pressure increased 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Glucose urine present 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Activated partial thromboplastin time prolonged 1/8 (12.5%) 2 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Breath sounds abnormal 1/8 (12.5%) 1 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Sputum abnormal 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 2 1/7 (14.3%) 1
    White blood cells urine positive 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 1/7 (14.3%) 1
    Blood creatinine increased 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Cardiac murmur 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Metabolism and nutrition disorders
    Decreased appetite 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Joint crepitation 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Nervous system disorders
    Sinus headache 0/8 (0%) 0 0/8 (0%) 0 2/16 (12.5%) 2 1/16 (6.3%) 2 1/7 (14.3%) 1
    Dysgeusia 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Headache 1/8 (12.5%) 2 0/8 (0%) 0 2/16 (12.5%) 2 0/16 (0%) 0 1/7 (14.3%) 2
    Somnolence 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 1/7 (14.3%) 1
    Tension headache 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Psychiatric disorders
    Abnormal dreams 0/8 (0%) 0 1/8 (12.5%) 1 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Renal and urinary disorders
    Glycosuria 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Proteinuria 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Nephrolithiasis 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Pyuria 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Reproductive system and breast disorders
    Genital pruritus female 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 2/16 (12.5%) 2 0/7 (0%) 0
    Nasal oedema 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 3/16 (18.8%) 3 0/7 (0%) 0
    Sinus congestion 0/8 (0%) 0 0/8 (0%) 0 2/16 (12.5%) 2 3/16 (18.8%) 3 1/7 (14.3%) 1
    Cough 4/8 (50%) 4 0/8 (0%) 0 2/16 (12.5%) 2 2/16 (12.5%) 3 3/7 (42.9%) 3
    Postnasal drip 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Productive cough 3/8 (37.5%) 3 0/8 (0%) 0 2/16 (12.5%) 2 2/16 (12.5%) 3 0/7 (0%) 0
    Rales 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Rhinorrhoea 0/8 (0%) 0 0/8 (0%) 0 3/16 (18.8%) 3 1/16 (6.3%) 1 0/7 (0%) 0
    Upper respiratory tract congestion 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Cough decreased 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Dysphonia 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Increased bronchial secretion 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Increased viscosity of bronchial secretion 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Nasal discomfort 0/8 (0%) 0 1/8 (12.5%) 1 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Nasal dryness 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Nasal turbinate abnormality 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Painful respiration 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Pharyngolaryngeal pain 1/8 (12.5%) 1 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 2/7 (28.6%) 2
    Sputum decreased 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 1/16 (6.3%) 1 0/7 (0%) 0
    Wheezing 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Increased upper airway secretion 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 1/7 (14.3%) 1
    Nasal congestion 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 1/7 (14.3%) 1
    Pharyngeal erythema 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 2/7 (28.6%) 2
    Epistaxis 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Nasal septum disorder 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Pharyngeal oedema 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Respiratory tract congestion 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Rhonchi 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Sputum discoloured 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Tonsillar hypertrophy 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Skin and subcutaneous tissue disorders
    Rash 0/8 (0%) 0 0/8 (0%) 0 1/16 (6.3%) 1 2/16 (12.5%) 2 1/7 (14.3%) 1
    Rash maculo-papular 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Ecchymosis 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Erythema 0/8 (0%) 0 2/8 (25%) 2 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Rash papular 1/8 (12.5%) 1 0/8 (0%) 0 1/16 (6.3%) 1 0/16 (0%) 0 0/7 (0%) 0
    Dermatitis contact 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0
    Photosensitivity reaction 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 1/7 (14.3%) 1
    Pruritus 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Vascular disorders
    Flushing 0/8 (0%) 0 0/8 (0%) 0 0/16 (0%) 0 1/16 (6.3%) 1 0/7 (0%) 0
    Haematoma 1/8 (12.5%) 1 0/8 (0%) 0 0/16 (0%) 0 0/16 (0%) 0 0/7 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Medical Monitor
    Organization Vertex
    Phone 617-444-6777
    Email medicalinfo@vrtx.com
    Responsible Party:
    Vertex Pharmaceuticals Incorporated
    ClinicalTrials.gov Identifier:
    NCT00457821
    Other Study ID Numbers:
    • VX06-770-101
    First Posted:
    Apr 9, 2007
    Last Update Posted:
    Oct 5, 2012
    Last Verified:
    Oct 1, 2012