Study of VX-809 Alone and in Combination With VX-770 in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutation

• ClinicalTrials.gov Identifier: NCT01225211
• Recruitment Status: Completed
• First Posted: October 20, 2010
• Results First Posted: October 5, 2015
• Last Update Posted: October 5, 2015
• Sponsor: Vertex Pharmaceuticals Incorporated
• Information provided by (Responsible Party): Vertex Pharmaceuticals Incorporated

Tracking Information

• First Submitted Date: October 15, 2010
• First Posted Date: October 20, 2010
• Results First Submitted Date: August 1, 2015
• Results First Posted Date: October 5, 2015
• Last Update Posted Date: October 5, 2015
• Study Start Date: October 2010
• Actual Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 2, 2015)

• Cohort 1: Safety and Tolerability Based on Adverse Events (AEs) [ Time Frame: Cohort 1: Day 1 up to 28 days after last dose (Last dose = Day 21) ]
  AE: any untoward medical occurrence in a participant during study; irrespective of relationship with treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after informed consent. AE includes serious AEs (SAEs) as well as Non-SAEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Number of participants with AEs and SAEs are reported. AE that started at/after initial dosing of study drug, or increased in severity after initial dosing of study drug is considered treatment-emergent. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 14) and combination therapy period (Period 2: Day 15 to Day 21).
• Cohort 2 and 3: Safety and Tolerability Based on Adverse Events (AEs) [ Time Frame: Cohort 2 and 3: Day 1 up to 28 days after last dose (Last dose = Day 56) ]
  Detailed description is provided in Outcome Measure 1. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 28) and combination therapy period (Period 2: Day 29 to Day 56).
• Cohort 4: Safety and Tolerability Assessed by Number of Participants With AEs and SAEs [ Time Frame: Cohort 4: Day 1 up to 28 days after last dose (Last dose = Day 56) ]
  AEs and SAEs are defined in Outcome Measure 1.
• Cohort 1: Absolute Change From Day 14 in Sweat Chloride at Day 21 [ Time Frame: Cohort 1: Day 14, Day 21 ]
• Cohort 2 And 3: Absolute Change From Day 28 in Sweat Chloride at Day 56 [ Time Frame: Cohort 2 and 3: Day 28, Day 56 ]
• Cohort 4: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 56 [ Time Frame: Cohort 4: Baseline, Day 56 ]
  FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Hankinson method.

Original Primary Outcome Measures (submitted: October 19, 2010)

• Safety and tolerability [ Time Frame: Through Day 35 ]
  Assessments will be measured based on adverse events, plasma samples (hematology, clinical chemistry, coagulation), urinalysis, electrocardiograms, and vital signs
• Change in sweat chloride when VX-770 is administered in combination with VX-809 [ Time Frame: From Day 15 to Day 21 ]

Current Secondary Outcome Measures (submitted: September 2, 2015)

• Cohort 1: Absolute Change From Baseline in Sweat Chloride at Day 14 [ Time Frame: Cohort 1: Baseline, Day 14 ]
• Cohort 2 And 3: Absolute Change From Baseline in Sweat Chloride at Day 14 [ Time Frame: Cohort 2: Baseline, Day 14 ]
• Cohort 4: Absolute Change From Baseline in Sweat Chloride at Day 56 [ Time Frame: Cohort 4: Baseline, Day 56 ]
• Cohort 1: Absolute Change From Day 14 in FEV1 at Day 21 [ Time Frame: Cohort 1: Day 14, Day 21 ]
  FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
• Cohort 1: Absolute Change From Day 14 in ppFEV1 at Day 21 [ Time Frame: Cohort 1: Day 14, Day 21 ]
  FEV1 and ppFEV1 are defined in Outcome Measure 6.
• Cohort 2 and 3: Absolute Change From Day 28 in ppFEV1 at Day 56 [ Time Frame: Cohort 2 and 3: Day 28, Day 56 ]
  FEV1 and ppFEV1 are defined in Outcome Measure 6.
• Cohort 2 and 3: Relative Change From Day 28 in ppFEV1 at Day 56 [ Time Frame: Cohort 2 and 3: Day 28, Day 56 ]
  FEV1 and ppFEV1 are defined in Outcome Measure 6.
• Cohort 2 and 3: Absolute Change From Baseline in ppFEV1 at Day 28 and 56 [ Time Frame: Cohort 2 and 3: Baseline, Day 28 and 56 ]
  FEV1 and ppFEV1 are defined in Outcome Measure 6.
• Cohort 2 and 3: Relative Change From Baseline in FEV1 at Day 28 and 56 [ Time Frame: Cohort 2 and 3: Baseline, Day 28 and 56 ]
  FEV1 and ppFEV1 are defined in Outcome Measure 6.
• Cohort 4: Relative Change From Baseline in Percent Predicted FEV1 at Day 56 [ Time Frame: Cohort 4: Baseline, Day 56 ]
  FEV1 and ppFEV1 are defined in Outcome Measure 6.
• Cohort 2 and 3: Absolute Change From Day 28 in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Day 56 [ Time Frame: Cohort 2 and 3: Day 28, Day 56 ]
  The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for subjects 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.
• Cohort 4: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 56 [ Time Frame: Cohort 4: Baseline, Day 56 ]
  CFQ-R respiratory domain is defined in Outcome Measure 17.
• Cohort 4: Absolute Change From Baseline in Body Mass Index (BMI) at Day 56 [ Time Frame: Cohort 4: Baseline, Day 56 ]
  BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).
• Cohort 4: Absolute Change From Baseline in Weight at Day 56 [ Time Frame: Cohort 4: Baseline, Day 56 ]

Original Secondary Outcome Measures (submitted: October 19, 2010)

• Change in percent predicted Forced expiratory volume in 1 second (FEV1) [ Time Frame: Through Day 28 ]
• Change in sweat chloride from baseline to Day 14 at increasing doses of VX-809 administered alone [ Time Frame: From Baseline to Day 14 ]
• PK parameters, including exposure, concentration and half-life, of VX-809 and metabolite in plasma in the presence and absence of VX-770 [ Time Frame: Through Day 28 ]
  Blood samples drawn during the study will be analyzed to measure the PK parameters, such as concentration, exposure and half-life of VX-809 and its metabolite.
• PK parameters, including exposure, concentration and half-life, of VX-770 and metabolites in plasma in the presence of VX-809 [ Time Frame: Through Day 28 ]
  Blood samples drawn during the study will be analyzed to measure the PK parameters, such as concentration, exposure and half-life of VX-770 and its metabolites.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of VX-809 Alone and in Combination With VX-770 in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutation
• Official Title: A Phase 2, Multicenter, Double-Blinded, Placebo-Controlled, Multiple-Dose Study to Evaluate Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Lumacaftor Monotherapy, and Lumacaftor and Ivacaftor Combination Therapy in Subjects With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation
• Brief Summary: The purpose of this study is to evaluate of the safety, efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) effects of lumacaftor (VX-809) alone and when coadministered with ivacaftor (VX-770) in participants with cystic fibrosis, homozygous or heterozygous for the F508del-CFTR mutation.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Cystic Fibrosis

Intervention

• Drug: Lumacaftor
  Tablet
  Other Name: VX-809, LUM
• Drug: Ivacaftor
  Tablet.
  Other Name: VX-770, IVA
• Drug: Lumacaftor Placebo
  Matching placebo tablet.
• Drug: Ivacaftor Placebo
  Matching placebo tablet.

Study Arms

• Placebo Comparator: Cohort 1: Placebo
  Participants homozygous (HO) for the F508del-CF transmembrane conductance regulator gene (CFTR) mutation received lumacaftor matched placebo once daily (qd) (Day 1 through Day 14), followed by lumacaftor matched placebo qd in combination with ivacaftor matched placebo every 12 hours (q12h) (Day 15 through Day 21).
  Interventions:

  • Drug: Lumacaftor Placebo
  • Drug: Ivacaftor Placebo
• Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h
  Participants homozygous for the F508del-CFTR mutation received 200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor (IVA) q12h (Day 15 through Day 21).
  Interventions:

  • Drug: Lumacaftor
  • Drug: Ivacaftor
• Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h
  Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21).
  Interventions:

  • Drug: Lumacaftor
  • Drug: Ivacaftor
• Placebo Comparator: Cohort 2 and 3: Placebo (HO and HE)
  Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56).
  Interventions:

  • Drug: Lumacaftor Placebo
  • Drug: Ivacaftor Placebo
• Experimental: Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO)
  Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
  Interventions:

  • Drug: Lumacaftor
  • Drug: Ivacaftor
• Experimental: Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO)
  Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
  Interventions:

  • Drug: Lumacaftor
  • Drug: Ivacaftor
• Experimental: Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE)
  Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
  Interventions:

  • Drug: Lumacaftor
  • Drug: Ivacaftor
• Experimental: Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO)
  Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56).
  Interventions:

  • Drug: Lumacaftor
  • Drug: Ivacaftor
• Placebo Comparator: Cohort 4: Placebo
  Participants heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 1 through Day 56).
  Interventions:

  • Drug: Lumacaftor Placebo
  • Drug: Ivacaftor Placebo
• Experimental: Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h
  Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56).
  Interventions:

  • Drug: Lumacaftor
  • Drug: Ivacaftor

Publications *

• Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3.
• Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, Marigowda G, Waltz D, Boyle MP; VX09-809-102 Study Group. Lumacaftor/Ivacaftor Treatment of Patients with Cystic Fibrosis Heterozygous for F508del-CFTR. Ann Am Thorac Soc. 2017 Feb;14(2):213-219. doi: 10.1513/AnnalsATS.201609-689OC.
• Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D; VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014 Jul;2(7):527-38. doi: 10.1016/S2213-2600(14)70132-8. Epub 2014 Jun 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 2, 2015): 312
• Original Estimated Enrollment (submitted: October 19, 2010): 160
• Actual Study Completion Date: April 2014
• Actual Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female participants with confirmed diagnosis of CF
• Must have the F508del-CFTR mutation on at least 1 allele.
• FEV1 greater than equal (>=) 40% of predicted normal for age, gender, and height (Knudson standards)(Cohort 1, 2, and 3); FEV1 40-90% of predicted normal for age, gender, and height (Hankinson standards (Cohort 4)
• Participant of child-bearing potential and who are sexually active must meet the contraception requirements

Exclusion Criteria:

• History of any illness or condition 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 (e.g., cirrhosis with portal hypertension).
• An acute illness including acute upper or lower respiratory infection, pulmonary exacerbation or changes in therapy (including antibiotics) for pulmonary disease within 14 days (Cohort 1, 2, and 3) or 28 days (Cohort 4) before receiving the first dose of study drug.
• History of solid organ or hematological transplantation.
• History of alcohol abuse or drug addiction in the past year, including cannabis, cocaine, and opiates.
• Ongoing participation in another therapeutic clinical study, or prior participation in an investigational drug study without appropriate washout
• Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use an acceptable method of non-hormonal contraception
• Participants enrolled in Cohort 1 or Cohort 2 will not be eligible for Cohort 3
• Ongoing or prior participation in an investigational drug study within 30 days of the Screening Visit
• Heterozygous participants who participated in Cohort 2 and meet the eligibility criteria for Cohort 4 may participate in Cohort 4
• Evidence of lens opacity or cataract as determined by the ophthalmologic examination (Cohort 4 only)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, France, Germany, New Zealand, United Kingdom, United States
• Removed Location Countries: Ireland

Administrative Information

• NCT Number: NCT01225211
• Other Study ID Numbers: VX09-809-102; 2010-020413-90 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Vertex Pharmaceuticals Incorporated
• Original Responsible Party: George Spencer-Green, MD, Vertex Pharmaceuticals Incorporated
• Current Study Sponsor: Vertex Pharmaceuticals Incorporated
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Vertex Pharmaceuticals Incorporated
• Verification Date: September 2015