Clinical trial NCT02742519
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2016-05-01; Completion date: 2017-08-01
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To evaluate the efficacy of ivacaftor treatment, as measured by lung clearance index (LCI), in subjects with cystic fibrosis (CF) who have a specified CF transmembrane conductance regulator (CFTR) gating mutation

Detailed description:

Arms: arm 1: ivacaftor in Treatment Period 1 →washout→placebo in Treatment Period 2 arm 2: placebo in Treatment Period 1→washout→ivacaftor in Treatment Period 2 arm 3: open label period
Interventions: intervention 1: ivacaftor intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 




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3 
SCHEDULE OF ASSESSMENTS
Table 3-1 
Study VX15-770-123: Screening
Event/Assessment
Screening Period 
(Day -28 to Day -1)a
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Table 3-2 
Study VX15-770-123: Part 1 and Part 2 
Part 1 Placebo-controlled Crossover Perioda
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Table 3-2 
Study VX15-770-123: Part 1 and Part 2 
Part 1 Placebo-controlled Crossover Perioda
Part 2 Open-label Perioda
(Wk 24 to Wk 144)
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5 
INTRODUCTION
5.1
Overview of Cystic Fibrosis 
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5.2
Overview of Ivacaftor
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5.3
Rationale for Present Study
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6 
STUDY OBJECTIVES
6.1
Primary Objective  
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STUDY ENDPOINTS
7.1
Part 1
7.1.1
Primary Endpoint
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8 
STUDY DESIGN
8.1
Overview of Study Design
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8.1.1
Screening Period
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8.1.1.1
Repetition of Screening Period Assessments
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8.1.1.2
Rescreening
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Extension of Screening Period Window
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8.1.2
Part 1: Treatment Period 1 (8 Weeks)
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8.1.3
Part 1: Washout Period (8 Weeks)
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8.1.4
Part 1: Treatment Period 2 (8 Weeks)
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8.1.5
Part 2: Open-label Period
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8.1.6
Follow-up Telephone Contact
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8.1.7
Early Termination of Treatment
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8.1.8
Safety Follow-up Visit
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Independent Data Monitoring Committee
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8.2
Rationale for Study Design and Study Drug Regimens
8.2.1
Study Design
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9.2
Exclusion Criteria
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9.3
Prior and Concomitant Medications
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9.4
Removal of Subjects in the Study
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9.5
Replacement of Subjects
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10
STUDY DRUG ADMINISTRATION AND MANAGEMENT
10.1
Preparation and Dispensing
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10.2
Administration
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10.3
Method of Assigning Subjects to Treatment Groups
Part 1
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10.4
Dose Modification for Toxicity
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10.5
Packaging and Labeling
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10.6
Study Drug Supply, Storage, and Handling
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Table 10-1 
Identity of Study Drugs
Dosage
Packaging
Formulation/
Route of Administration
Storage Condition
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10.7
Drug Accountability
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10.8
Disposal, Return, or Retention of Unused Drug
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10.9
Compliance 
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10.10
Blinding and Unblinding
10.10.1
Blinding
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10.10.2
Unblinding
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11.5
Safety
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11.5.1
Adverse Events
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11.5.2
Clinical Laboratory Assessments
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Table 11-1 
Safety Laboratory Test Panels 
Serum Chemistry
Hematology
Urinalysisa
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Coagulation Studiesa
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6SHFLILFLQVWUXFWLRQVZLOOEHSURYLGHGLQWKH/DERUDWRU\0DQXDO
Mandatory Liver Function Testing: 
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Study Drug Interruption or Discontinuation Due to Elevated Liver Function Test 
Parameters:
6WXG\GUXJDGPLQLVWUDWLRQmust be interruptedLPPHGLDWHO\DQGWKH9HUWH[PHGLFDOPRQLWRU
PXVWEHQRWLILHGLIDQ\RIWKHIROORZLQJFULWHULDDUHPHW
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LGHQWLILHGUHJDUGOHVVRIZKHWKHU$/7RU$67OHYHOVKDYHLPSURYHGWKHsubject must be 
discontinued from the studyLQFRQVXOWDWLRQZLWKWKH9HUWH[PHGLFDOPRQLWRUVHH6HFWLRQ
6XEMHFWVGLVFRQWLQXHGIRUHOHYDWHGWUDQVDPLQDVHVVKRXOGEHIROORZHGXQWLOWKHLUWUDQVDPLQDVHV
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GUXJWUHDWPHQWLQFRQVXOWDWLRQZLWKWKH9HUWH[PHGLFDOPRQLWRU
Additional Evaluations: 
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FOLQLFDOO\DSSURSULDWHRULIWKHRQJRLQJUHYLHZRIWKHGDWDVXJJHVWVWKDWDPRUHGHWDLOHG
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11.5.3
Physical Examinations and Vital Signs
$SK\VLFDOH[DPLQDWLRQRIDOOERG\V\VWHPVDQGYLWDOVLJQVDVVHVVPHQWZLOOEHSHUIRUPHGDW
6FUHHQLQJVHH7DEOH$WRWKHUYLVLWVV\PSWRPGLUHFWHGSK\VLFDOH[DPLQDWLRQVDQG
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KHDOWKFDUHSURYLGHU
$SK\VLFDOH[DPLQDWLRQLQFOXGHVDUHYLHZRIWKHIROORZLQJV\VWHPVKHDGQHFNWK\URLG
H\HVHDUVQRVHWKURDW((17UHVSLUDWRU\FDUGLRYDVFXODUO\PSKQRGHVDEGRPHQVNLQ
PXVFXORVNHOHWDODQGQHXURORJLFDO%UHDVWDQRUHFWDODQGJHQLWDOH[DPLQDWLRQVZLOOEHSHUIRUPHG
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11.5.4
Electrocardiograms
1RWDSSOLFDEOH
11.5.5
Contraception and Pregnancy
1RWDSSOLFDEOH
11.5.6
Ophthalmologic Examinations
6XEMHFWVZLOOXQGHUJRDQ2(DWDOOWLPHSRLQWVLQGLFDWHGLQ7DEOH7DEOHDQG7DEOH
7KH2(ZLOOEHFRQGXFWHGE\DOLFHQVHGRSKWKDOPRORJLVWRURSWRPHWULVWSUHIHUDEO\DSHGLDWULF
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12
STATISTICAL AND ANALYTICAL PLANS
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12.1
Sample Size and Power
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Table 12-1 
Sample Size Calculation Corresponding to Different Values of Treatment 
Effect on Lung Clearance Index Change-From-Predose
Treatment Effect (points) on LCI
Change From Study Baseline
Standard Deviation of Paired 
Treatment Difference in LCI Change 
From Study Baseline
N 
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12.2
Analysis Sets
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7KHSafety SetLVGHILQHGDVDOOVXEMHFWVZKRUHFHLYHGDWOHDVWGRVHRIVWXG\GUXJ$OO
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12.3
Statistical Analysis
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12.3.1
General Considerations
7KHIROORZLQJVXPPDULHVZLOOEHSHUIRUPHGIRU3DUW
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DQGPD[LPXPYDOXH
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Baseline:)RUWKLVFURVVRYHUVWXG\W\SHVRIEDVHOLQHVWXG\EDVHOLQHDQGSHULRGEDVHOLQHZLOO
EHGHILQHGIRU3DUWVDQG
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12.3.2
Background Characteristics
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12.3.2.1
Subject Disposition
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12.3.2.2
Demographics and Baseline Characteristics
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12.3.2.3
Prior and Concomitant Medications
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12.3.2.4
Study Drug Exposure and Compliance
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12.3.3
Part 1 Efficacy Analysis 
12.3.3.1
Analysis of Primary Variable
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12.3.5.1
Adverse Events
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12.3.5.2
Clinical Laboratory Assessments
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12.3.5.3
Vital Signs
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12.3.5.4
Physical Examination
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12.3.5.5
Other Safety Analysis
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12.3.6
Interim and IDMC Analyses
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13
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
13.1
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting
13.1.1
Adverse Events
13.1.1.1
Definition of an Adverse Event
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13.1.1.2
Clinically Significant Assessments
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13.1.1.3
Documentation of Adverse Events
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13.1.1.4
Adverse Event Severity
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Table 13-1 
Grading of AE Severity
Classification
Definition
Mild (Grade 1)
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Moderate (Grade 2)
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Severe (Grade 3)
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Life-threatening (Grade 4)
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13.1.1.5
Adverse Event Causality
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Table 13-2 
Classifications for AE Causality
Classification
Definition
Related
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Possibly related
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Unlikely related
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Not related
7KHHYHQWLVUHODWHGWRDQHWLRORJ\RWKHUWKDQWKHLQYHVWLJDWLRQDOVWXG\GUXJWKH
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13.1.1.6
Study Drug Action Taken
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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classification
Definition
Dose not changed
6WXG\GUXJGRVHQRWFKDQJHGLQUHVSRQVHWRDQ$(
Dose reduced
6WXG\GUXJGRVHUHGXFHGLQUHVSRQVHWRDQ$(
Drug interrupted
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Drug withdrawn
6WXG\GUXJDGPLQLVWUDWLRQSHUPDQHQWO\GLVFRQWLQXHGLQUHVSRQVHWRDQ$(
Not applicable
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WUHDWPHQWKDGEHHQFRPSOHWHGEHIRUHWKH$(EHJDQDQGQRRSSRUWXQLW\WRGHFLGH
ZKHWKHUWRFRQWLQXHLQWHUUXSWRUZLWKGUDZWUHDWPHQWLVSRVVLEOH
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13.1.1.7
Adverse Event Outcome
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Table 13-4 
Classifications for Outcome of an AE 
Classification
Definition
Recovered/Resolved
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Recovered/ Resolved 
With Sequelae
5HVROXWLRQRIDQ$(ZLWKUHVLGXDOVLJQVRUV\PSWRPV
Not Recovered/Not 
Resolved (Continuing)
(LWKHULQFRPSOHWHLPSURYHPHQWRUQRLPSURYHPHQWRIDQ$(VXFKWKDWLWUHPDLQV
RQJRLQJ
Fatal
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UHODWHGWRWKH$(
Unknown
2XWFRPHRIDQ$(LVQRWNQRZQHJDVXEMHFWORVWWRIROORZXS
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13.1.1.8
Treatment Given
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13.1.2
Serious Adverse Events
13.1.2.1
Definition of a Serious Adverse Event
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13.2
Administrative Requirements
13.2.1
Ethical Considerations
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13.2.2
Subject Information and Informed Consent
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13.2.3
Investigator Compliance
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13.2.4
Access to Records
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13.2.5
Subject Privacy
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13.2.6
Record Retention
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13.2.7
Study Termination
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13.3
Data Quality Assurance
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13.4
Monitoring
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13.5
Electronic Data Capture 
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Table 7-.1 
Sample Size Calculation Corresponding to Different 
Values of Treatment Effect on Lung Clearance Index 
Change-From-Predose
Treatment Effect (points) on LCI
Change From Study Baseline
Standard Deviation of Paired 
Treatment Difference in LCI 
Change From Study Baseline
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Table 3-1 
Study VX15-770-123: Screening
Event/Assessment
Screening Period 
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Table 3-3 
Study VX15-770-123: Early Termination of Treatment Visit, Safety Follow-up 
Visit, and Follow-up Telephone Contact 
Event/Assessment
Early Termination of 
Treatment Visit
Safety Follow-up Visit
4 weeks (±7 days)
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Drug 20
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Week 144 Visit
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Page 23 of 29


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Table 10-4 Visit Window Mapping Rules (within Period)
Assessments
Period - Visit
Analysis Visit
Target Study Day
Visit Window 
(in study days)
x /DEV
o &KHPLVWU\
o +HPDWRORJ\
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If only Day of AE start date is missing:  
,IWKH$(VWDUW\HDUDQGPRQWKDUHWKHVDPHDVWKDWIRUWKHILUVWGRVHGDWHWKHQ
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PLVVLQJWKHQLPSXWHWKH$(VWDUWGD\DVWKHGD\RIILUVWGRVHGDWHRWKHUZLVHLPSXWHWKH
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If Day and Month of AE start date are missing: 
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x
,IWKHIXOORUSDUWLDO$(HQGGDWHLV127EHIRUHWKHILUVWGRVHGDWHRU$(HQGGDWHLV
PLVVLQJWKHQLPSXWHWKH$(VWDUW0RQWKDQG'D\DVWKH0RQWKDQG'D\RIILUVWGRVH
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If Year of AE start date is missing: 
Page 24 of 29


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Page 25 of 29


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Table 11-5 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT EVENT
Parameter
Threshold Criteria
Comments
Clinical Chemistry
&3.
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Page 26 of 29


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Page 27 of 29


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Page 28 of 29


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Page 29 of 29