A Study to Evaluate the Safety and Efficacy of VX-371 in... | NCT02709109

ID	Type	Description	Link
2015-004841-13	EudraCT Number

Name	Class
Vertex Pharmaceuticals Incorporated	INDUSTRY

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Sequence 1: VX-371 + Hypertonic Saline (HS), then HS	Experimental	Participants received 85 microgram (mcg) VX-371 diluted in 3 milliliter (mL) 4.2 percent (%) HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 milligram (mg)/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their cystic fibrosis (CF) standard of care.	Drug: VX-371 + HS Drug: Hypertonic saline Drug: Orkambi
Sequence 2: HS, then VX-371 + HS	Experimental	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.	Drug: VX-371 + HS Drug: Hypertonic saline Drug: Orkambi
Sequence 3: VX-371 + Placebo, then Placebo	Experimental	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.

Name	Type	Description	Arm Group Labels	Other Names
VX-371 + HS	Drug		Sequence 1: VX-371 + Hypertonic Saline (HS), then HS Sequence 2: HS, then VX-371 + HS
Hypertonic saline

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included abnormal clinically significant findings for spirometry, clinical laboratory parameters, standard 12-lead electrocardiograms (ECGs), vital signs and ophthalmologic examinations. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 112 days (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs.	Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days)
Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Study Baseline was defined as the most recent non-missing measurement before the first dose of inhaled study drug in the study. Day 28 measurements after treatment discontinuation from the treatment period in which discontinuation occurred were included in the analysis.	Study baseline, Day 28

Secondary Outcomes

Measure	Description	Time Frame
Plasma Concentrations of VX-371		Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2
Urine Concentrations of VX-371		Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Willing and able to use the delivery device as directed by the study manual.
Confirmed diagnosis of CF, defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis.
Homozygous for the F508del CFTR mutation. If the CFTR screening genotype result is not received before randomization, a previous CFTR genotype lab report may be used to establish eligibility.
Percent predicted forced expiratory volume at one second (FEV1) of ≥40 to <90 percentage points adjusted for age, sex, and height according to the Global Lung Initiative (GLI) at the Screening Visit.
Willing to discontinue physician-prescribed saline use.
Female subjects of childbearing potential with a negative serum pregnancy test at the Screening Visit.

Exclusion Criteria:

History of any comorbidity, which in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject.
An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
A 12 lead ECG demonstrating QTcF >450 msec at the Screening Visit.
History of solid organ or hematological transplantation.
Used diuretics or renin-angiotensin aldosterone system antihypertensive drugs in the 28 days prior to Screening or an anticipated need for any of these medications during the study.
Ongoing or prior participation in an investigational drug study within 30 days of the Screening Visit.
Inability to withhold short-acting, long-acting, or once-daily, long-acting bronchodilator use for 4, 12, or 24 hours prior to clinic visit, respectively.
History of significant intolerance to inhaled saline, or intolerance to the single dose of saline at Screening
Known hypersensitivity or history of intolerance to Orkambi.
Pregnant and nursing females.
Subjects who have participated in Parion Sciences Study NCT02343445.

Name	Affiliation	Role
Alison Church, MD	Parion Sciences	Study Chair

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Sequence 1: VX-371 + HS, Then HS	Participants received 85 microgram (mcg) VX-371 diluted in 3 milliliter (mL) 4.2 percent (%) HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 milligram (mg)/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their cystic fibrosis (CF) standard of care.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jul 22, 2016	Jul 8, 2021

Arm/Group Information

ID	Title	Description
BG000	Sequence 1: VX-371 + HS, Then HS	Participants received 85 mcg VX-371 diluted in 3 milliliter (mL) 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.
BG001	Sequence 2: HS, Then VX-371 + HS	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.
BG002	Sequence 3: VX-371 + Placebo, Then Placebo	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.
BG003	Sequence 4: Placebo, Then VX-371 + Placebo	Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care.
BG004	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included abnormal clinically significant findings for spirometry, clinical laboratory parameters, standard 12-lead electrocardiograms (ECGs), vital signs and ophthalmologic examinations. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 112 days (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs.

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

Posted

Count of Participants

Participants

Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days)

ID	Title	Description
OG000	VX-371 + Hypertonic Saline	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
OG001	Hypertonic Saline	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
OG002	VX-371 + Placebo	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
OG003	Placebo	Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

Units	Counts
Participants	OG00089 OG00190 OG00246 OG003

Title

Denominators

Categories

Participants With TEAEs

Title	Measurements
	OG00065 OG00166 OG00232 OG003

Primary

Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Study Baseline was defined as the most recent non-missing measurement before the first dose of inhaled study drug in the study. Day 28 measurements after treatment discontinuation from the treatment period in which discontinuation occurred were included in the analysis.

The full analysis set (FAS) included all randomized participants who carried the intended homozygous F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation and received at least 1 dose of inhaled study drug. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure.

Posted

Least Squares Mean

Standard Error

percentage points

Study baseline, Day 28

ID	Title	Description
OG000	VX-371 + Hypertonic Saline	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
OG001	Hypertonic Saline	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
OG002	VX-371 + Placebo

Secondary

Plasma Concentrations of VX-371

The Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of VX-371. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at specified time points.

Posted

Mean

Standard Deviation

Picograms per milliliter (pg/mL)

Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2

ID	Title	Description
OG000	VX-371 + Hypertonic Saline	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
OG001	VX-371 + Placebo	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

Units	Counts
Participants	OG000

Secondary

Urine Concentrations of VX-371

The PK analysis set included all participants who received at least 1 dose of VX-371. Here, "overall number of participants analyzed" signifies participants evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at specified time points.

Posted

Mean

Standard Deviation

pg/mL

Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2

ID	Title	Description
OG000	VX-371 + Hypertonic Saline	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.
OG001	VX-371 + Placebo	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Infective pulmonary exacerbation of cystic	Infections and infestations	MedDRA version 19.0	Non-systematic Assessment	EG0003 affected89 at risk EG0013 affected90 at risk EG0025 affected46 at risk EG0033 affected42 at risk
Cystic fibrosis related diabetes	Congenital, familial and genetic disorders	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0010 affected90 at risk EG0020 affected46 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0010 affected90 at risk EG0020 affected46 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0010 affected90 at risk EG0020 affected46 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0010 affected90 at risk EG0020 affected46 at risk EG003
Testicular torsion	Reproductive system and breast disorders	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0010 affected90 at risk EG0020 affected46 at risk EG003
Bronchospasm	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0010 affected90 at risk EG0020 affected46 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0000 affected89 at risk EG0012 affected90 at risk EG0021 affected46 at risk EG003
Cystic fibrosis respiratory infection	Surgical and medical procedures	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0010 affected90 at risk EG0020 affected46 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0000 affected89 at risk EG0011 affected90 at risk EG0020 affected46 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG00020 affected89 at risk EG00113 affected90 at risk EG00213 affected46 at risk EG0035 affected42 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0008 affected89 at risk EG0016 affected90 at risk EG0024 affected46 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0007 affected89 at risk EG0015 affected90 at risk EG0022 affected46 at risk EG003
Respiration abnormal	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0007 affected89 at risk EG0016 affected90 at risk EG0023 affected46 at risk EG003
Wheezing	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0006 affected89 at risk EG0012 affected90 at risk EG0020 affected46 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0005 affected89 at risk EG0016 affected90 at risk EG0025 affected46 at risk EG003
Sputum increased	Respiratory, thoracic and mediastinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0005 affected89 at risk EG0012 affected90 at risk EG0025 affected46 at risk EG003
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	MedDRA version 19.0	Non-systematic Assessment	EG0008 affected89 at risk EG00112 affected90 at risk EG0026 affected46 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA version 19.0	Non-systematic Assessment	EG0000 affected89 at risk EG0015 affected90 at risk EG0022 affected46 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA version 19.0	Non-systematic Assessment	EG0003 affected89 at risk EG0015 affected90 at risk EG0020 affected46 at risk EG003
Pulmonary function test decreased	Investigations	MedDRA version 19.0	Non-systematic Assessment	EG0000 affected89 at risk EG0010 affected90 at risk EG0023 affected46 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0005 affected89 at risk EG0014 affected90 at risk EG0022 affected46 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0002 affected89 at risk EG0013 affected90 at risk EG0023 affected46 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0016 affected90 at risk EG0021 affected46 at risk EG003
Headache	Nervous system disorders	MedDRA version 19.0	Non-systematic Assessment	EG0006 affected89 at risk EG0018 affected90 at risk EG0022 affected46 at risk EG003
Pyrexia	General disorders	MedDRA version 19.0	Non-systematic Assessment	EG0001 affected89 at risk EG0015 affected90 at risk EG0025 affected46 at risk EG003

Facility	Status	City	State	ZIP	Country	Contacts
		Little Rock	Arkansas		United States

ID	Term
D010182	Pancreatic Diseases
D004066	Digestive System Diseases
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D007232	Infant, Newborn, Diseases

ID	Term
D012462	Saline Solution, Hypertonic
C000599212	lumacaftor, ivacaftor drug combination

ID	Term
D006982	Hypertonic Solutions
D012996	Solutions
D004364	Pharmaceutical Preparations

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	VX-371 + Hypertonic Saline	Participants received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	89	8	89	49	89
EG001	Hypertonic Saline	Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	90	4	90	55	90
EG002	VX-371 + Placebo	Participants received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	46	6	46	26	46
EG003	Placebo	Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days in either treatment period 1 or 2.	42	3	42	20	42