A Study to Evaluate Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02742519
• Collaborator: (none)
• Enrollment: 14
• Locations: 6
• Arms: 3
• Duration (Months): 15
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3b, 2-part, Randomized, Double-blind, Placebo-controlled Crossover Study With a Long-term Open-label Period to Investigate Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation
• Study Start Date: May 1, 2016
• Actual Primary Completion Date: Aug 1, 2017
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1-Sequence 1 ivacaftor in Treatment Period 1 →washout→placebo in Treatment Period 2	Drug: ivacaftor; Other Names: VX-770 ; Drug: Placebo
Experimental: Part 1 - Sequence 2 placebo in Treatment Period 1→washout→ivacaftor in Treatment Period 2	Drug: ivacaftor; Other Names: VX-770 ; Drug: Placebo
Experimental: Part 2: ivacaftor open label period	Drug: ivacaftor; Other Names: VX-770

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5) [Baseline Through Week 8 for each treatment period, Up to 24 Weeks]

   LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.

Secondary Outcome Measures

1. Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8 [Baseline and Week 8 of each treatment period, Up to 24 Weeks]

   Serum samples were collected for evaluation of change in immunoreactive trypsinogen levels at Week 8.

2. Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8 [Baseline and Week 8 of each treatment period, Up to 24 Weeks]

   Fecal elastase-1 was used clinically to diagnose pancreatic exocrine insufficiency in participants with cystic fibrosis.

3. Absolute Change From Baseline in Weight at Week 8 [Baseline and Week 8 of each treatment period, Up to 24 Weeks]

4. Absolute Change From Baseline in Body Mass Index (BMI) at Week 8 [Baseline and Week 8 of each treatment period, Up to 24 Weeks]

   BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2).

5. Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to Month 15]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 5 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female with confirmed diagnosis of CF.

• Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D.

• Hematology, serum chemistry, and coagulation at Screening with no clinically significant abnormalities or concomitant diagnosis that would interfere with the LCI and CT scan study assessments, as judged by the investigator.

Exclusion Criteria:

• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1

• Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (in the opinion of the investigator)

• Abnormal liver function, at Screening, defined as ≥3 × upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), and total bilirubin

• History of solid organ or hematological transplantation

• Any clinically significant "non-CF-related" illness within 2 weeks before Day 1

• Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1

• Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer or as determined by the local requirements) before Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Parkville	Victoria	Australia
2		South Brisbane		Australia
3		Subiaco		Australia
4		Westmead		Australia
5		Toronto	Ontario	Canada
6		London		United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 12, 2017
• Statistical Analysis Plan - Aug 14, 2017

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02742519
• Other Study ID Numbers: VX15-770-123; 2015-001267-39
• First Posted: Apr 19, 2016
• Last Update Posted: Nov 19, 2018
• Last Verified: Oct 1, 2018

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

Study Results

Participant Flow

Pre-assignment Detail	Study consisted of 2 parts: Part 1- Double Blind (DB) Crossover Treatment Period and Part 2- Open Label (OL) Period.

Arm/Group Title	Part 1 Sequence 1: Ivacaftor First, Then Placebo	Part 1 Sequence 2: Placebo First, Then Ivacaftor	Part 2: Ivacaftor
Arm/Group Description	Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2. For ivacaftor, the dose was either 50 milligram (mg) or 75 mg, as determined by the participant's body weight on Day 1.	Placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2. For ivacaftor, the dose was either 50 mg or 75 mg, as determined by the participant's body weight on Day 1.	Ivacaftor 50 mg, 75 mg or 150 mg, as determined by the participant's body weight at the beginning of Part 2, administered every 12 hours for up to 32 weeks in open label period.
Period Title: Part 1 Treatment Period 1 (8 Weeks)
STARTED	8	6	0
COMPLETED	8	6	0
NOT COMPLETED	0	0	0
Period Title: Part 1 Treatment Period 1 (8 Weeks)
STARTED	8	6	0
COMPLETED	7	5	0
NOT COMPLETED	1	1	0
Period Title: Part 1 Treatment Period 1 (8 Weeks)
STARTED	0	0	10
COMPLETED	0	0	0
NOT COMPLETED	0	0	10

Baseline Characteristics

Arm/Group Title	Part 1 Sequence 1: Ivacaftor First, Then Placebo	Part 1 Sequence 2: Placebo First, Then Ivacaftor	Total
Arm/Group Description	Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2. For ivacaftor, the dose was either 50 milligram (mg) or 75 mg, as determined by the participant's body weight on Day 1.	Placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2. For ivacaftor, the dose was either 50 mg or 75 mg, as determined by the participant's body weight on Day 1.	Total of all reporting groups
Overall Participants	8	6	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.6 (0.7)	4.2 (1.0)	3.9 (0.9)
Sex: Female, Male (Count of Participants)
Female	4 50%	1 16.7%	5 35.7%
Male	4 50%	5 83.3%	9 64.3%
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	8 100%	6 100%	14 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5)
Description	LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.
Time Frame	Baseline Through Week 8 for each treatment period, Up to 24 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment.

Arm/Group Title	Placebo (Crossover Part)	Ivacaftor (Crossover Part)
Arm/Group Description	Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.	Ivacaftor administered as determined by the participant's body weight on Day 1 orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.
Measure Participants	13	13
Mean (Standard Deviation) [Lung clearance index]	-0.07 (0.93)	-0.53 (1.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Crossover Part), Ivacaftor (Crossover Part)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2121
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8
Description	Serum samples were collected for evaluation of change in immunoreactive trypsinogen levels at Week 8.
Time Frame	Baseline and Week 8 of each treatment period, Up to 24 Weeks

Outcome Measure Data

Analysis Population Description

FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment. Here "Overall Number of Participants Analyzed" signifies those participants who were evaluated for this outcome measure.

Arm/Group Title	Placebo (Crossover Part)	Ivacaftor (Crossover Part)
Arm/Group Description	Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.	Ivacaftor administered as determined by the participant's body weight on Day 1 orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.
Measure Participants	3	4
Mean (Standard Deviation) [Nanogram per milliliter (ng/mL)]	-9.3 (18.4)	-15.5 (6.5)

3. Secondary Outcome

Title	Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8
Description	Fecal elastase-1 was used clinically to diagnose pancreatic exocrine insufficiency in participants with cystic fibrosis.
Time Frame	Baseline and Week 8 of each treatment period, Up to 24 Weeks

Outcome Measure Data

Analysis Population Description

FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment. Here "Overall Number of Participants Analyzed" signifies those participants who were evaluated for this outcome measure.

Arm/Group Title	Placebo (Crossover Part)	Ivacaftor (Crossover Part)
Arm/Group Description	Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.	Ivacaftor administered as determined by the participant's body weight on Day 1 orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.
Measure Participants	11	10
Mean (Standard Deviation) [microgram per gram (mcg/g)]	-17.0 (55.4)	23.1 (37.9)

4. Secondary Outcome

Title	Absolute Change From Baseline in Weight at Week 8
Time Frame	Baseline and Week 8 of each treatment period, Up to 24 Weeks

Outcome Measure Data

Analysis Population Description

FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment.

Arm/Group Title	Placebo (Crossover Part)	Ivacaftor (Crossover Part)
Arm/Group Description	Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.	Ivacaftor administered as determined by the participant's body weight on Day 1 orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.
Measure Participants	13	13
Mean (Standard Deviation) [Kilogram (kg)]	0.9 (1.0)	1.1 (0.9)

5. Secondary Outcome

Title	Absolute Change From Baseline in Body Mass Index (BMI) at Week 8
Description	BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2).
Time Frame	Baseline and Week 8 of each treatment period, Up to 24 Weeks

Outcome Measure Data

Analysis Population Description

FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment.

Arm/Group Title	Placebo (Crossover Part)	Ivacaftor (Crossover Part)
Arm/Group Description	Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.	Ivacaftor administered as determined by the participant's body weight on Day 1 orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.
Measure Participants	13	13
Mean (Standard Deviation) [Kilogram per meter square (kg/m^2)]	0.13 (0.79)	0.32 (0.59)

6. Secondary Outcome

Title	Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	Baseline up to Month 15

Outcome Measure Data

Analysis Population Description

The Safety Set was used which included all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo (Crossover Part)	Ivacaftor (Crossover Part)	Ivacaftor (Open Label Part)
Arm/Group Description	Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.	Ivacaftor administered as determined by the participant's body weight on Day 1 orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.	Ivacaftor administered as determined by the participant's body weight in the beginning of Part 2 orally every 12 hours in for up to 34 weeks in open label period.
Measure Participants	13	13	10
Participants with any AEs	11 137.5%	11 183.3%	6 42.9%
Participants with SAEs	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Baseline up to Month 15
Arm/Group Title	Placebo (Crossover Part)		Ivacaftor (Crossover Part)		Ivacaftor (Open Label Part)
Arm/Group Description	Placebo matched to Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.		Ivacaftor administered orally every 12 hours for 8 weeks in treatment period 1 or treatment period 2.		Ivacaftor administered orally every 12 hours in open label period.
All Cause Mortality
	Placebo (Crossover Part)		Ivacaftor (Crossover Part)		Ivacaftor (Open Label Part)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/10 (0%)
Serious Adverse Events
	Placebo (Crossover Part)		Ivacaftor (Crossover Part)		Ivacaftor (Open Label Part)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Placebo (Crossover Part)		Ivacaftor (Crossover Part)		Ivacaftor (Open Label Part)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/13 (84.6%)		11/13 (84.6%)		6/10 (60%)
Ear and labyrinth disorders
Ear pain	0/13 (0%)		1/13 (7.7%)		0/10 (0%)
Gastrointestinal disorders
Vomiting	1/13 (7.7%)		3/13 (23.1%)		3/10 (30%)
Constipation	1/13 (7.7%)		0/13 (0%)		0/10 (0%)
Diarrhoea	1/13 (7.7%)		0/13 (0%)		0/10 (0%)
Abdominal pain upper	0/13 (0%)		1/13 (7.7%)		0/10 (0%)
General disorders
Pyrexia	1/13 (7.7%)		1/13 (7.7%)		0/10 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	3/13 (23.1%)		3/13 (23.1%)		3/10 (30%)
Upper respiratory tract infection	1/13 (7.7%)		3/13 (23.1%)		1/10 (10%)
Viral upper respiratory tract infection	1/13 (7.7%)		0/13 (0%)		1/10 (10%)
Bacterial disease carrier	1/13 (7.7%)		0/13 (0%)		0/10 (0%)
Otitis media	1/13 (7.7%)		0/13 (0%)		0/10 (0%)
Lower respiratory tract infection	0/13 (0%)		1/13 (7.7%)		0/10 (0%)
Investigations
Haemophilus test positive	0/13 (0%)		1/13 (7.7%)		1/10 (10%)
Streptococcus test positive	0/13 (0%)		0/13 (0%)		1/10 (10%)
Bacterial test positive	0/13 (0%)		1/13 (7.7%)		0/10 (0%)
Pseudomonas test positive	0/13 (0%)		1/13 (7.7%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/13 (7.7%)		0/13 (0%)		0/10 (0%)
Nervous system disorders
Headache	3/13 (23.1%)		1/13 (7.7%)		0/10 (0%)
Lethargy	0/13 (0%)		1/13 (7.7%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Productive cough	3/13 (23.1%)		3/13 (23.1%)		0/10 (0%)
Nasal congestion	1/13 (7.7%)		0/13 (0%)		0/10 (0%)
Rhinorrhoea	1/13 (7.7%)		2/13 (15.4%)		0/10 (0%)
Wheezing	0/13 (0%)		0/13 (0%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Cough	3/13 (23.1%)		2/13 (15.4%)		4/10 (40%)

Limitations/Caveats

Vertex terminated the study early because of enrollment futility.

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.