Evaluation of VX-659/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03633526
• Collaborator: (none)
• Enrollment: 18
• Locations: 6
• Arm: 1
• Actual Duration (Months): 5.5
• Patients Per Site: 3
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study will evaluate the pharmacokinetics (PK), safety, tolerability, efficacy, and pharmacodynamic effect of VX-659, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple combination (TC) in Cystic Fibrosis (CF) subjects with F/F or F/MF genotypes.

The study was discontinued after completion of Part A due to Sponsor's discretion.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: VX-659/TEZ/IVA; Drug: IVA	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-659/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age
• Actual Study Start Date: Aug 3, 2018
• Actual Primary Completion Date: Jan 18, 2019
• Actual Study Completion Date: Jan 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VX-659/TEZ/IVA Participants who received VX-659 120 milligram (mg)/TEZ 50 mg/ IVA 75 mg as fixed-dose combination (FDC) in the morning and IVA 75 mg as a mono tablet in the evening in the triple combination (TC) treatment period.	Drug: VX-659/TEZ/IVA; VX-659/TEZ/IVA FDC tablet.; Other Names: VX-659/VX-661/VX-770 VX-659/tezacaftor/ivacaftor ; Drug: IVA; IVA mono tablet.; Other Names: VX-770 ivacaftor

Outcome Measures

Primary Outcome Measures

1. Maximum Observed Concentration (Cmax) of VX-659, TEZ, and IVA [Day 1 and Day 15]

2. Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, and IVA [Day 8 and Day 15]

3. Area Under the Concentration Versus Time Curve From Time 0 to 6 Hours (AUC0-6h) of VX-659, TEZ, and IVA [Day 1 and Day 15]

Secondary Outcome Measures

1. Maximum Observed Concentration (Cmax) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) [Day 1 and Day 15]

2. Observed Pre-Dose Concentration (Ctrough) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) [Day 8 and Day 15]

3. Area Under the Concentration Versus Time Curve From Time 0 to 6 Hours (AUC0-6h) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) [Day 1 and Day 15]

4. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 6 weeks)]

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

• Homozygous or heterozygous for F508del mutation (F/F or F/MF genotypes)

• Forced expiratory volume in 1 second (FEV1) value ≥40% of predicted mean for age, sex, and height.

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	Children's Hospital Colorado	Aurora	Colorado	United States	80045
2	Ann & Robert Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
3	The Children's Mercy Hospital	Kansas City	Missouri	United States	64108
4	Clinical Research of Charlotte	Charlotte	North Carolina	United States	28277
5	Oregon Health & Science University	Portland	Oregon	United States	97239
6	Texas Children's Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 14, 2018
• Statistical Analysis Plan - Nov 13, 2018

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT03633526
• Other Study ID Numbers: VX18-659-106; 2018-001711-67
• First Posted: Aug 16, 2018
• Last Update Posted: Feb 5, 2020
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor; VX-659

Study Results

Participant Flow

Recruitment Details	A total of 18 participants were enrolled in this study. Two participants were enrolled but were not dosed in triple combination (TC) treatment period. Therefore, results are reported for 16 participants.
Pre-assignment Detail	This study was conducted in participants with cystic fibrosis (CF) 6-11 years of age. The study was terminated before start of Part B at Sponsor's discretion.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Period Title: Overall Study
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.2 (1.4)
Sex: Female, Male (Count of Participants)
Female	5 31.3%
Male	11 68.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 12.5%
Not Hispanic or Latino	14 87.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	16 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Observed Concentration (Cmax) of VX-659, TEZ, and IVA
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included participants who received at least 1 dose of study drug and for whom the primary PK data were considered to be sufficient and interpretable. Here "Number analyzed" signifies those subjects who were evaluable at the specified timepoint.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Measure Participants	16
VX-659: Day 1	1.81 (0.858)
VX-659: Day 15	2.55 (1.21)
TEZ: Day 1	4.53 (1.65)
TEZ: Day 15	5.22 (1.69)
IVA: Day 1	0.536 (0.208)
IVA: Day 15	0.733 (0.256)

2. Primary Outcome

Title	Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, and IVA
Time Frame	Day 8 and Day 15

Outcome Measure Data

Analysis Population Description

PK set. Here "Number analyzed" signifies those participants who were evaluable at specified timepoints.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Measure Participants	16
VX-659: Day 8	0.358 (0.259)
VX-659: Day 15	0.367 (0.283)
TEZ: Day 8	0.897 (0.488)
TEZ: Day 15	0.740 (0.421)
IVA: Day 8	0.289 (0.195)
IVA: Day 15	0.283 (0.241)

3. Primary Outcome

Title	Area Under the Concentration Versus Time Curve From Time 0 to 6 Hours (AUC0-6h) of VX-659, TEZ, and IVA
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK set. Here "Number analyzed" signifies those participants who were evaluable at specified timepoints.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Measure Participants	16
VX-659: Day 1	5.41 (3.65)
VX-659: Day 15	8.55 (4.50)
TEZ: Day 1	15.5 (5.36)
TEZ: Day 15	19.3 (7.26)
IVA: Day 1	1.64 (0.795)
IVA: Day 15	2.95 (1.18)

4. Secondary Outcome

Title	Maximum Observed Concentration (Cmax) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK set. Here "Number analyzed" signifies those subjects who were evaluable at the specified timepoint.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Measure Participants	16
M1-TEZ: Day 1	1.63 (0.553)
M1-TEZ: Day 15	5.04 (1.27)
M1-IVA: Day 1	1.25 (0.449)
M1-IVA: Day 15	1.73 (0.741)

5. Secondary Outcome

Title	Observed Pre-Dose Concentration (Ctrough) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
Time Frame	Day 8 and Day 15

Outcome Measure Data

Analysis Population Description

PK set. Here "Number analyzed" signifies those participants who were evaluable at specified timepoints.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Measure Participants	16
M1-TEZ: Day 8	3.56 (1.33)
M1-TEZ: Day 15	3.35 (1.23)
M1-IVA: Day 8	0.816 (0.491)
M1-IVA: Day 15	0.858 (0.672)

6. Secondary Outcome

Title	Area Under the Concentration Versus Time Curve From Time 0 to 6 Hours (AUC0-6h) of TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK set. Here "Number analyzed" signifies those participants who were evaluable at specified timepoints.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Measure Participants	16
M1-TEZ: Day 1	5.52 (2.87)
M1-TEZ: Day 15	25.2 (7.70)
M1-IVA: Day 1	3.60 (1.87)
M1-IVA: Day 15	6.98 (2.94)

7. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 6 weeks)

Outcome Measure Data

Analysis Population Description

Safety set included all participants who received at least 1 dose of study drug.

Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
Measure Participants	16
Participants with AEs	13 81.3%
Participants with SAEs	1 6.3%

Adverse Events

Time Frame	From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to 6 weeks)
Arm/Group Title	VX-659/TEZ/IVA
Arm/Group Description	Participants who received VX-659 120 mg/TEZ 50 mg/ IVA 75 mg as FDC in the morning and IVA 75 mg as a mono tablet in the evening for 15 days in the TC treatment period.
All Cause Mortality
	VX-659/TEZ/IVA
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Serious Adverse Events
	VX-659/TEZ/IVA
	Affected / at Risk (%)	# Events
Total	1/16 (6.3%)
Skin and subcutaneous tissue disorders
Rash	1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	VX-659/TEZ/IVA
	Affected / at Risk (%)	# Events
Total	13/16 (81.3%)
Gastrointestinal disorders
Abdominal discomfort	1/16 (6.3%)
Post-tussive vomiting	1/16 (6.3%)
Vomiting	2/16 (12.5%)
General disorders
Chills	1/16 (6.3%)
Fatigue	3/16 (18.8%)
Pyrexia	2/16 (12.5%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	1/16 (6.3%)
Injury, poisoning and procedural complications
Ligament sprain	1/16 (6.3%)
Procedural anxiety	1/16 (6.3%)
Investigations
Activated partial thromboplastin time prolonged	1/16 (6.3%)
Alanine aminotransferase increased	1/16 (6.3%)
Bacterial test positive	1/16 (6.3%)
Human rhinovirus test positive	1/16 (6.3%)
International normalised ratio increased	1/16 (6.3%)
Prothrombin time prolonged	1/16 (6.3%)
Pulmonary function test decreased	1/16 (6.3%)
Respirovirus test positive	1/16 (6.3%)
Metabolism and nutrition disorders
Decreased appetite	1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/16 (6.3%)
Nervous system disorders
Headache	6/16 (37.5%)
Respiratory, thoracic and mediastinal disorders
Cough	7/16 (43.8%)
Nasal discharge discolouration	1/16 (6.3%)
Oropharyngeal pain	1/16 (6.3%)
Paranasal sinus hypersecretion	1/16 (6.3%)
Productive cough	2/16 (12.5%)
Sputum increased	2/16 (12.5%)
Skin and subcutaneous tissue disorders
Rash	1/16 (6.3%)
Rash papular	1/16 (6.3%)
Rash vesicular	1/16 (6.3%)
Vascular disorders
Hot flush	1/16 (6.3%)

Limitations/Caveats

The study was terminated before start of Part B due to sponsor discretion.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.