A Study to Evaluate the Safety and Efficacy of VX-371 in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation

• ClinicalTrials.gov Identifier: NCT02709109
• Recruitment Status: Completed
• First Posted: March 15, 2016
• Results First Posted: July 29, 2021
• Last Update Posted: July 29, 2021
• Sponsor: Parion Sciences
• Collaborator: Vertex Pharmaceuticals Incorporated
• Information provided by (Responsible Party): Parion Sciences

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety and efficacy of treatment with VX-371 in hypertonic saline compared to hypertonic saline alone in subjects with cystic fibrosis (CF) who are ≥12 years of age, homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation, and being treated with Orkambi

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: VX-371 + HS; Drug: Hypertonic saline; Drug: Placebo; Drug: Orkambi; Drug: VX-371	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 147 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, Crossover Study to Evaluate the Safety and Efficacy of VX-371 in Subjects Aged 12 Years or Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, and Being Treated With Orkambi
• Study Start Date: February 2016
• Actual Primary Completion Date: September 2017
• Actual Study Completion Date: September 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sequence 1: VX-371 + Hypertonic Saline (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.	Drug: VX-371 + HS; Drug: Hypertonic saline; Drug: Orkambi; Other Name: lumacaftor/ivacaftor
Experimental: 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.	Drug: VX-371 + HS; Drug: Hypertonic saline; Drug: Orkambi; Other Name: lumacaftor/ivacaftor
Experimental: 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.	Drug: Placebo; Drug: Orkambi; Other Name: lumacaftor/ivacaftor; Drug: VX-371
Experimental: 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.	Drug: Placebo; Drug: Orkambi; Other Name: lumacaftor/ivacaftor; Drug: VX-371

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days) ]
   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.
2. Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 [ Time Frame: Study baseline, 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.

Secondary Outcome Measures :

1. Plasma Concentrations of VX-371 [ Time Frame: 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 ]
2. Urine Concentrations of VX-371 [ Time Frame: 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 Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Arkansas

Little Rock, Arkansas, United States

United States, California

Oakland, California, United States

United States, Florida

Gainesville, Florida, United States

Miami, Florida, United States

Orlando, Florida, United States

United States, Illinois

Chicago, Illinois, United States

Glenview, Illinois, United States

United States, Kansas

Kansas City, Kansas, United States

United States, Louisiana

New Orleans, Louisiana, United States

United States, Massachusetts

Worcester, Massachusetts, United States

United States, Michigan

Detroit, Michigan, United States

Grand Rapids, Michigan, United States

United States, Minnesota

Minneapolis, Minnesota, United States

United States, Mississippi

Jackson, Mississippi, United States

United States, New Hampshire

Lebanon, New Hampshire, United States

United States, New Mexico

Albuquerque, New Mexico, United States

United States, New York

Albany, New York, United States

Hawthorne, New York, United States

Syracuse, New York, United States

United States, North Carolina

Charlotte, North Carolina, United States

United States, Ohio

Cleveland, Ohio, United States

United States, Pennsylvania

Pittsburgh, Pennsylvania, United States

United States, Texas

Austin, Texas, United States

Dallas, Texas, United States

Fort Worth, Texas, United States

Tyler, Texas, United States

United States, Virginia

Charlottesville, Virginia, United States

Richmond, Virginia, United States

United States, Wisconsin

Madison, Wisconsin, United States

Milwaukee, Wisconsin, United States

France

Bron Cedex, France

Pierre-Bénite, France

Roscoff Cedex, France

Strasbourg Cedex 2, France

Ireland

Dublin, Ireland

United Kingdom

Birmingham, United Kingdom

Bristol, United Kingdom

London, United Kingdom

Manchester, United Kingdom

Southampton, United Kingdom

Sponsors and Collaborators

Parion Sciences

Vertex Pharmaceuticals Incorporated

Investigators

• Study Chair: Alison Church, MD; Parion Sciences

  Study Documents (Full-Text)

Documents provided by Parion Sciences:

Study Protocol  [PDF] July 22, 2016

Statistical Analysis Plan  [PDF] July 27, 2017

More Information

• Responsible Party: Parion Sciences
• ClinicalTrials.gov Identifier: NCT02709109
• Other Study ID Numbers: VX15-371-101; 2015-004841-13 ( EudraCT Number )
• First Posted: March 15, 2016
• Results First Posted: July 29, 2021
• Last Update Posted: July 29, 2021
• Last Verified: July 2021

• 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; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Ivacaftor; Chloride Channel Agonists; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action