Clinical Trial Results:
A Phase 3, Double-blind, Parallel-group Study to Evaluate the Efficacy and Safety of Tezacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

Trial information Top of page
Trial identification
Sponsor protocol code	VX16-661-115
Additional study identifiers
ISRCTN number	-
US NCT number	NCT03559062
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Vertex Pharmaceuticals Incorporated
Sponsor organisation address	50 Northern Avenue, Boston, Massachusetts, United States,
Public contact	Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
Scientific contact	Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617 341 6777, medicalinfo@vrtx.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	Yes
EMA paediatric investigation plan number(s)	EMEA-001640-PIP01-14
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	Yes
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	01 Feb 2019
Is this the analysis of the primary completion data?	Yes
Primary completion date	21 Dec 2018
Global end of trial reached?	Yes
Global end of trial date	21 Dec 2018
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the efficacy of tezacaftor (TEZ) in combination with ivacaftor (IVA) in subjects with cystic fibrosis (CF) aged 6 through 11 years, homozygous or heterozygous for F508del.
Protection of trial subjects	The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	17 May 2018
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Australia: 14
Country: Number of subjects enrolled	Germany: 15
Country: Number of subjects enrolled	France: 8
Country: Number of subjects enrolled	Switzerland: 8
Country: Number of subjects enrolled	United Kingdom: 8
Country: Number of subjects enrolled	Denmark: 6
Country: Number of subjects enrolled	Belgium: 5
Country: Number of subjects enrolled	Ireland: 4
Country: Number of subjects enrolled	Poland: 1
Worldwide total number of subjects	69
EEA total number of subjects	47
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	69
Adolescents (12-17 years)	0
Adults (18-64 years)	0
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	A total of 69 subjects were randomized, out of which 67 subjects received study drug and were included in subject disposition and baseline characteristics section.
Period 1
Period 1 title	Overall Period
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Carer, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Placebo
Arm description	Subjects with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks.
Arm type	Blinding arm
Investigational medicinal product name	Placebo (matched to TEZ/IVA)
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received placebo matched to TEZ/IVA once daily in the morning.
Investigational medicinal product name	Placebo (matched to IVA)
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received placebo matched to IVA once daily in the evening.
Arm title	TEZ/IVA
Arm description	Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.
Arm type	Experimental
Investigational medicinal product name	TEZ/IVA
Investigational medicinal product code	VX-661/VX-770
Other name	Tezacaftor/Ivacaftor fixed dose combination
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received TEZ/IVA once daily in the morning.
Investigational medicinal product name	IVA
Investigational medicinal product code	VX-770
Other name	Ivacaftor
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received IVA once daily in the evening.
Investigational medicinal product name	Placebo (matched to IVA)
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received placebo matched to IVA once daily in the morning.
Arm title	Ivacaftor
Arm description	Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.
Arm type	Blinding arm
Investigational medicinal product name	IVA
Investigational medicinal product code	VX-770
Other name	Ivacaftor
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received IVA every 12 hours.
Investigational medicinal product name	Placebo (matched to TEZ/IVA)
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	Subjects received placebo matched to TEZ/IVA once daily in the morning.
Number of subjects in period 1 [1] Placebo TEZ/IVA Ivacaftor Started 10 54 3 Completed 10 53 3 Not completed 0 1 0      Other - 1 -
Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 69 subjects were randomized, out of which 67 subjects received study drug and were included in subject disposition and baseline characteristics section.

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Placebo
Reporting group description	Subjects with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks.
Reporting group title	TEZ/IVA
Reporting group description	Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.
Reporting group title	Ivacaftor
Reporting group description	Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.
Reporting group values Placebo TEZ/IVA Ivacaftor Total Number of subjects 10 54 3 67 Age categorical Units: Subjects Age continuous Units: years     arithmetic mean (standard deviation) 9.0 ( 1.7 ) 8.5 ( 1.7 ) 9.0 ( 1.7 ) - Gender categorical Units: Subjects     Female 6 29 2 37     Male 4 25 1 30

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Placebo
Reporting group description	Subjects with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks.
Reporting group title	TEZ/IVA
Reporting group description	Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.
Reporting group title	Ivacaftor
Reporting group description	Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.

End points Top of page

Primary: Absolute Change in Lung Clearance Index 2.5 Top of page
End point title	Absolute Change in Lung Clearance Index 2.5 [1] [2]
End point description
End point type	Primary
End point timeframe	From baseline through Week 8
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The study was designed to perform within treatment group comparison. Because single group within treatment comparisons cannot be reported in the EudraCT database, no statistical analyses are reported. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is applicable for only TEZ/IVA.
End point values TEZ/IVA Number of subjects analysed 54 Units: Lung clearance index     least squares mean (standard error) -0.51 ( 0.11 )
No statistical analyses for this end point

Primary: Absolute Change in Lung Clearance Index 2.5 Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From first dose of study drug up to safety follow-up visit
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	21.1
Reporting groups
Reporting group title	Placebo
Reporting group description	Subjects with genotype F/F received placebo matched to TEZ/IVA FDC in the morning and placebo matched to IVA in the evening for 8 weeks.
Reporting group title	TEZ/IVA
Reporting group description	Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.
Reporting group title	Ivacaftor
Reporting group description	Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.
Serious adverse events Placebo TEZ/IVA Ivacaftor Total subjects affected by serious adverse events      subjects affected / exposed 0 / 10 (0.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      number of deaths (all causes) 0 0 0      number of deaths resulting from adverse events
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Placebo TEZ/IVA Ivacaftor Total subjects affected by non serious adverse events      subjects affected / exposed 8 / 10 (80.00%) 31 / 54 (57.41%) 2 / 3 (66.67%) Investigations Alanine aminotransferase increased      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 2 0 0 Aspartate aminotransferase increased      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Injury, poisoning and procedural complications Thermal burn      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Arthropod bite      subjects affected / exposed 0 / 10 (0.00%) 0 / 54 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 Nervous system disorders Headache      subjects affected / exposed 1 / 10 (10.00%) 8 / 54 (14.81%) 0 / 3 (0.00%)      occurrences all number 1 11 0 Gastrointestinal disorders Vomiting      subjects affected / exposed 0 / 10 (0.00%) 4 / 54 (7.41%) 0 / 3 (0.00%)      occurrences all number 0 4 0 Abdominal pain      subjects affected / exposed 0 / 10 (0.00%) 3 / 54 (5.56%) 0 / 3 (0.00%)      occurrences all number 0 3 0 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 1 / 10 (10.00%) 9 / 54 (16.67%) 0 / 3 (0.00%)      occurrences all number 1 10 0 Sputum increased      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Rhinorrhoea      subjects affected / exposed 0 / 10 (0.00%) 3 / 54 (5.56%) 1 / 3 (33.33%)      occurrences all number 0 4 1 Productive cough      subjects affected / exposed 1 / 10 (10.00%) 7 / 54 (12.96%) 0 / 3 (0.00%)      occurrences all number 1 9 0 Nasal congestion      subjects affected / exposed 0 / 10 (0.00%) 3 / 54 (5.56%) 0 / 3 (0.00%)      occurrences all number 0 3 0 Throat irritation      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Skin and subcutaneous tissue disorders Rash      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Blister      subjects affected / exposed 0 / 10 (0.00%) 0 / 54 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 Musculoskeletal and connective tissue disorders Arthritis      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Infections and infestations Infective pulmonary exacerbation of cystic fibrosis      subjects affected / exposed 2 / 10 (20.00%) 3 / 54 (5.56%) 0 / 3 (0.00%)      occurrences all number 4 3 0 Bacterial disease carrier      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Gastroenteritis      subjects affected / exposed 0 / 10 (0.00%) 4 / 54 (7.41%) 0 / 3 (0.00%)      occurrences all number 0 5 0 Nasopharyngitis      subjects affected / exposed 1 / 10 (10.00%) 5 / 54 (9.26%) 0 / 3 (0.00%)      occurrences all number 1 5 0 Otitis media      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 2 0 0 Rhinitis      subjects affected / exposed 1 / 10 (10.00%) 0 / 54 (0.00%) 0 / 3 (0.00%)      occurrences all number 1 0 0 Impetigo      subjects affected / exposed 0 / 10 (0.00%) 0 / 54 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1 Upper respiratory tract infection      subjects affected / exposed 0 / 10 (0.00%) 0 / 54 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 2 Viral upper respiratory tract infection      subjects affected / exposed 0 / 10 (0.00%) 0 / 54 (0.00%) 1 / 3 (33.33%)      occurrences all number 0 0 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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