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

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

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

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Placebo; Drug: VX-371 + HS; Drug: Hypertonic saline; Drug: Orkambi; Drug: VX-371

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 2

Contacts and Locations

Study Locations

• 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
• United States
  • Arkansas
    • Little Rock, Arkansas, United States
  • California
    • Oakland, California, United States
  • Florida
    • Gainesville, Florida, United States
    • Miami, Florida, United States
    • Orlando, Florida, United States
  • Illinois
    • Chicago, Illinois, United States
    • Glenview, Illinois, United States
  • Kansas
    • Kansas City, Kansas, United States
  • Louisiana
    • New Orleans, Louisiana, United States
  • Massachusetts
    • Worcester, Massachusetts, United States
  • Michigan
    • Detroit, Michigan, United States
    • Grand Rapids, Michigan, United States
  • Minnesota
    • Minneapolis, Minnesota, United States
  • Mississippi
    • Jackson, Mississippi, United States
  • New Hampshire
    • Lebanon, New Hampshire, United States
  • New Mexico
    • Albuquerque, New Mexico, United States
  • New York
    • Albany, New York, United States
    • Hawthorne, New York, United States
    • Syracuse, New York, United States
  • North Carolina
    • Charlotte, North Carolina, United States
  • Ohio
    • Cleveland, Ohio, United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States
  • Texas
    • Austin, Texas, United States
    • Dallas, Texas, United States
    • Fort Worth, Texas, United States
    • Tyler, Texas, United States
  • Virginia
    • Charlottesville, Virginia, United States
    • Richmond, Virginia, United States
  • Wisconsin
    • Madison, Wisconsin, United States
    • Milwaukee, Wisconsin, United States

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: lumacaftor/ivacaftor; Drug: VX-371

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Parion Sciences
• Collaborators: Vertex Pharmaceuticals Incorporated
• Investigators: Study Chair: Alison Church, MD, Parion Sciences

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: February 29, 2016
• First Submitted That Met QC Criteria: March 9, 2016
• First Posted (Estimate): March 15, 2016

Study Record Updates

• Last Update Posted (Actual): July 29, 2021
• Last Update Submitted That Met QC Criteria: July 8, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor
• Other Study ID Numbers: VX15-371-101; 2015-004841-13 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No