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A Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation

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ClinicalTrials.gov Identifier: NCT02516410
Recruitment Status : Completed
First Posted : August 5, 2015
Results First Posted : June 12, 2018
Last Update Posted : June 12, 2018
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Brief Summary:
Study to evaluate the efficacy of VX-661 in combination with ivacaftor (IVA, VX-770) through Week 12 in participants with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and with a second CFTR mutation that is not likely to respond to VX-661 and/or IVA therapy (F508del/not responsive [NR]).

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: VX-661 plus ivacaftor combination Drug: Ivacaftor Drug: Placebo (matched to VX-661 plus ivacaftor combination) Drug: Placebo (matched to ivacaftor) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 168 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation and With a Second CFTR Mutation That Is Not Likely to Respond to VX-661 and/or Ivacaftor Therapy (F508del/NR)
Study Start Date : August 2015
Actual Primary Completion Date : June 7, 2016
Actual Study Completion Date : June 7, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis
Drug Information available for: Ivacaftor

Arm Intervention/treatment
Experimental: VX-661/IVA
VX-661 100 milligram (mg) plus IVA 150 mg fixed dose combination (FDC) tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Drug: VX-661 plus ivacaftor combination
Drug: Ivacaftor
Other Names:
  • IVA
  • VX-770

Placebo Comparator: Placebo
Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.
Drug: Placebo (matched to VX-661 plus ivacaftor combination)
Drug: Placebo (matched to ivacaftor)



Primary Outcome Measures :
  1. Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12 [ Time Frame: Baseline, Through Week 12 ]
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.


Secondary Outcome Measures :
  1. Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12 [ Time Frame: Baseline, Through Week 12 ]
    The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

  2. Number of Pulmonary Exacerbation Events [ Time Frame: Baseline through Week 12 ]
    Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported.

  3. Number of Pulmonary Exacerbation Events Per Year [ Time Frame: Baseline through Week 12 ]
    Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Total number of days on study is equal to the Week 12 date or the last dose date (whichever occurs last) minus first dose date plus 1. The total number of years (48 weeks) on study is equal to the total number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.

  4. Absolute Change From Baseline in Body Mass Index (BMI) at Week 12 [ Time Frame: Baseline, Week 12 ]
    BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).

  5. Relative Change From Baseline in Percent Predicted FEV1 Through Week 12 [ Time Frame: Baseline, Through Week 12 ]
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.

  6. Absolute Change From Baseline in Sweat Chloride Through Week 12 [ Time Frame: Baseline, Through Week 12 ]
    Sweat samples were collected using an approved collection device.

  7. Number of Participants With at Least One Pulmonary Exacerbation Through Week 12 [ Time Frame: Baseline through Week 12 ]
    Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported.

  8. Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening) [ Time Frame: Baseline, Week 12 ]
    Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age Z-score (BMI z-score). BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the paediatric population.

  9. Absolute Change From Baseline in Body Weight at Week 12 [ Time Frame: Baseline, Week 12 ]
  10. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 16 ]
    AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or newly developed at or after initial dosing of study drug to Week 16 was considered treatment-emergent.

  11. Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) [ Time Frame: Pre-morning dose on Week 2, Week 4, Week 8 and Week 12 ]
    This outcome was not planned to be assessed in Placebo arm.



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

Inclusion Criteria:

  • Confirmed diagnosis of CF defined as a sweat chloride value greater than or equal to (>=)60 millimole per liter (mmol/L) by quantitative pilocarpine iontophoresis.
  • Heterozygous for the F508del-CFTR mutation and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy, genotype to be confirmed via assessment at the Screening Visit.
  • Forced Expiratory Volume in 1 Second (FEV1) >=40 percent (%) and less than or equal to (<=)90% of predicted normal for age, sex, and height at Screening Visit.

Exclusion Criteria:

  • History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant.
  • 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).
  • History of solid organ or hematological transplantation.
  • Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator within 30 days of screening.
  • Pregnant or nursing females.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02516410


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Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated

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Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT02516410     History of Changes
Other Study ID Numbers: VX14-661-107
2014-004787-37 ( EudraCT Number )
First Posted: August 5, 2015    Key Record Dates
Results First Posted: June 12, 2018
Last Update Posted: June 12, 2018
Last Verified: May 2018

Additional relevant MeSH terms:
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Fibrosis
Cystic 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