A Study Evaluating Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis and F/MF Genotypes

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04353817
• Collaborator: (none)
• Enrollment: 121
• Locations: 34
• Arms: 2
• Actual Duration (Months): 10.9
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of elexacaftor (ELX) / tezacaftor (TEZ) / ivacaftor (IVA) triple combination (TC) in subjects 6 through 11 years of age with cystic fibrosis (CF) who are heterozygous for F508del and a minimal function (MF) mutation (F/MF genotypes).

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: ELX/TEZ/IVA; Drug: IVA; Other: Placebo (matched to ELX/TEZ/IVA); Other: Placebo (matched to IVA)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3b, Randomized, Placebo-controlled Study Evaluating the Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects 6 Through 11 Years of Age Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)
• Actual Study Start Date: Jun 19, 2020
• Actual Primary Completion Date: May 17, 2021
• Actual Study Completion Date: May 17, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.	Other: Placebo (matched to ELX/TEZ/IVA); Placebo matched to ELX/TEZ/IVA for oral administration once daily (qd) in the morning.; Other: Placebo (matched to IVA); Placebo matched to IVA for oral administration qd in the evening.
Experimental: ELX/TEZ/IVA Participants weighing less than (<) 30 kilograms (kg) at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and participants weighing greater than equals to (>=) 30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.	Drug: ELX/TEZ/IVA; Fixed-dose combination tablet for oral administration qd in the morning.; Other Names: VX-445/VX-661/VX-770 elexacaftor/tezacaftor/ivacaftor ; Drug: IVA; Tablet for oral administration qd in the evening.; Other Names: VX-770 ivacaftor

Outcome Measures

Primary Outcome Measures

1. Absolute Change in Lung Clearance Index 2.5 (LCI2.5) [From Baseline Through Week 24]

   The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry.

Secondary Outcome Measures

1. Absolute Change in Sweat Chloride (SwCl) [From Baseline Through Week 24]

   Sweat samples were collected using an approved collection device.

2. Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Day 1 up to Week 28]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 11 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Heterozygous for the F508del mutation (F/MF)

• Forced expiratory volume in 1 second (FEV1) value greater than equal to(≥) 70%

Key Exclusion Criteria:

• Clinically significant cirrhosis with or without portal hypertension

• Lung infection with organisms associated with a more rapid decline in pulmonary status

• Solid organ or hematological transplantation

Other protocol defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Telethon Kids Institute	Nedlands		Australia
2	Queensland Children's Hospital	South Brisbane		Australia
3	The Children's Hospital at Westmead	Westmead		Australia
4	McGill University Health Centre, Glen Site, Montreal Children's Hospital	Montréal		Canada
5	The Hospital for Sick Children	Toronto		Canada
6	British Columbia Children's Hospital	Vancouver		Canada
7	Juliane Marie Center, Rigshospitalet	Copenhagen		Denmark
8	Groupe Hospitaler Pellegrin, CHU De Bordeaux	Bordeaux cedex		France
9	CHU Lyon - Hopital Femme Mere-Enfant	Bron Cedex		France
10	Hopital Necker, Enfants Malades	Paris Cedex 15		France
11	Hopital Robert Debre	Paris		France
12	Centre de Perharidy	Roscoff cedex		France
13	Charite Paediatric Pulmonology Department	Berlin		Germany
14	Universitätsklinikum Essen	Essen		Germany
15	Johann Wolfgang Goethe University	Frankfurt		Germany
16	Justus-Liebig-Universität Gießen Zentrum fur Kinderheilkunde und Jugendmedizin	Gießen		Germany
17	Medizinische Hochschule Hannover	Hannover		Germany
18	Universitaetsklinikum Heidelberg, Zenter fuer Kinder-und Jugendmedizin	Heidelberg		Germany
19	Universitaetsklinkum Koeln, CF-Studienzentrum	Koeln		Germany
20	Hadassah University Hospital Mount Scopus	Jerusalem		Israel
21	Schneider Children's Medical Center	Petah Tikva		Israel
22	Universitair Medisch Centrum Groningen	Groningen		Netherlands
23	Erasmus Medical Center / Sophia Children's Hospital	Rotterdam		Netherlands
24	Hospital Universitari Vall d Hebron	Barcelona		Spain
25	Hospital Virgen de la Arrixaca	Murcia		Spain
26	Inselspital - Universitaetsspital Bern	Bern		Switzerland
27	Kinderspital Zuerich	Zurich		Switzerland
28	University Hospitals Bristol and Weston NHS Foundation Trust, Bristol Royal Hospital	Bristol		United Kingdom
29	Children's Hospital of Wales	Cardiff		United Kingdom
30	Royal Hospital for Sick Children	Edinburgh		United Kingdom
31	Alder Hey Children's NHS Foundation Trust	Liverpool		United Kingdom
32	Great Ormond Street Hospital for Sick Children	London		United Kingdom
33	Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital	London		United Kingdom
34	Southampton General Hospital	Southampton		United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 29, 2020
• Statistical Analysis Plan - May 23, 2021

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT04353817
• Other Study ID Numbers: VX19-445-116; 2019-003554-86
• First Posted: Apr 20, 2020
• Last Update Posted: Jul 26, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor; Elexacaftor

Study Results

Participant Flow

Pre-assignment Detail	This study was conducted in cystic fibrosis (CF) participants aged 6 through 11 years of age.

Arm/Group Title	Placebo	ELX/TEZ/IVA
Arm/Group Description	Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.	Participants weighing less than (<) 30 kilograms (kg) at screening received ELX 100 mg once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and participants weighing greater than equals to (>=) 30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Period Title: Overall Study
STARTED	61	60
COMPLETED	61	59
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo	ELX/TEZ/IVA	Total
Arm/Group Description	Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.	Participants weighing <30 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.	Total of all reporting groups
Overall Participants	61	60	121
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.2 (1.7)	9.1 (1.8)	9.2 (1.7)
Sex: Female, Male (Count of Participants)
Female	35 57.4%	35 58.3%	70 57.9%
Male	26 42.6%	25 41.7%	51 42.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 1.7%	1 0.8%
Not Hispanic or Latino	42 68.9%	48 80%	90 74.4%
Unknown or Not Reported	19 31.1%	11 18.3%	30 24.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.7%	1 0.8%
Asian	0 0%	1 1.7%	1 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 1.7%	1 0.8%
White	42 68.9%	45 75%	87 71.9%
More than one race	0 0%	1 1.7%	1 0.8%
Unknown or Not Reported	19 31.1%	11 18.3%	30 24.8%
Lung Clearance Index2.5 (LCI2.5) (index) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [index]	9.75 (1.95)	10.26 (2.22)	10.01 (2.09)

Outcome Measures

1. Primary Outcome

Title	Absolute Change in Lung Clearance Index 2.5 (LCI2.5)
Description	The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry.
Time Frame	From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants who carry the intended CFTR allele mutation and receive at least 1 dose of study drug.

Arm/Group Title	Placebo	ELX/TEZ/IVA
Arm/Group Description	Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.	Participants weighing <30 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	61	60
Least Squares Mean (Standard Error) [index]	-0.02 (0.16)	-2.29 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ELX/TEZ/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	-2.26
	Confidence Interval	(2-Sided) 95%; -2.71 to -1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Absolute Change in Sweat Chloride (SwCl)
Description	Sweat samples were collected using an approved collection device.
Time Frame	From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	ELX/TEZ/IVA
Arm/Group Description	Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.	Participants weighing <30 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	61	60
Least Squares Mean (Standard Error) [millimole per liter (mmol/L)]	-0.9 (1.5)	-52.1 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ELX/TEZ/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This is the nominal p-value without multiplicity controlled.
	Method	Mixed-effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.2
	Confidence Interval	(2-Sided) 95%; -55.3 to -47.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame	Day 1 up to Week 28

Outcome Measure Data

Analysis Population Description

Safety set included all participants who received at least 1 dose of study drug in the treatment period.

Arm/Group Title	Placebo	ELX/TEZ/IVA
Arm/Group Description	Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.	Participants weighing <30 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	61	60
Participants With TEAEs	57 93.4%	48 80%
Participants With SAEs	9 14.8%	4 6.7%

Adverse Events

Time Frame	Day 1 up to Week 28
Arm/Group Title	Placebo		ELX/TEZ/IVA
Arm/Group Description	Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks.		Participants weighing <30 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
All Cause Mortality
	Placebo		ELX/TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/61 (0%)		0/60 (0%)
Serious Adverse Events
	Placebo		ELX/TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/61 (14.8%)		4/60 (6.7%)
Blood and lymphatic system disorders
Lymphadenitis	1/61 (1.6%)		0/60 (0%)
Congenital, familial and genetic disorders
Phimosis	0/61 (0%)		1/60 (1.7%)
Gastrointestinal disorders
Distal intestinal obstruction syndrome	1/61 (1.6%)		0/60 (0%)
Intussusception	1/61 (1.6%)		0/60 (0%)
General disorders
General physical health deterioration	1/61 (1.6%)		0/60 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	3/61 (4.9%)		0/60 (0%)
Pneumonia pseudomonal	1/61 (1.6%)		0/60 (0%)
Varicella zoster virus infection	0/61 (0%)		1/60 (1.7%)
Investigations
Bacterial test positive	0/61 (0%)		1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Nasal polyps	1/61 (1.6%)		0/60 (0%)
Skin and subcutaneous tissue disorders
Rash	0/61 (0%)		1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	Placebo		ELX/TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/61 (86.9%)		46/60 (76.7%)
Gastrointestinal disorders
Abdominal pain	17/61 (27.9%)		5/60 (8.3%)
Abdominal pain upper	5/61 (8.2%)		4/60 (6.7%)
Diarrhoea	6/61 (9.8%)		4/60 (6.7%)
Nausea	5/61 (8.2%)		1/60 (1.7%)
Steatorrhoea	0/61 (0%)		3/60 (5%)
Vomiting	4/61 (6.6%)		3/60 (5%)
General disorders
Fatigue	5/61 (8.2%)		0/60 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	14/61 (23%)		1/60 (1.7%)
Nasopharyngitis	9/61 (14.8%)		7/60 (11.7%)
Rhinitis	5/61 (8.2%)		3/60 (5%)
Upper respiratory tract infection	5/61 (8.2%)		3/60 (5%)
Investigations
Alanine aminotransferase increased	3/61 (4.9%)		5/60 (8.3%)
Aspartate aminotransferase increased	1/61 (1.6%)		3/60 (5%)
Bacterial test positive	4/61 (6.6%)		0/60 (0%)
Forced expiratory volume decreased	4/61 (6.6%)		0/60 (0%)
Staphylococcus test positive	1/61 (1.6%)		4/60 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/61 (6.6%)		1/60 (1.7%)
Nervous system disorders
Headache	12/61 (19.7%)		18/60 (30%)
Respiratory, thoracic and mediastinal disorders
Cough	26/61 (42.6%)		14/60 (23.3%)
Nasal congestion	3/61 (4.9%)		3/60 (5%)
Nasal polyps	4/61 (6.6%)		0/60 (0%)
Oropharyngeal pain	12/61 (19.7%)		3/60 (5%)
Productive cough	6/61 (9.8%)		7/60 (11.7%)
Rhinorrhoea	7/61 (11.5%)		7/60 (11.7%)
Skin and subcutaneous tissue disorders
Pruritus	0/61 (0%)		4/60 (6.7%)
Rash	3/61 (4.9%)		6/60 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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