A Rollover Safety Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

Study Overview
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Brief Summary
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A Rollover Safety Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous for F508del.

Official Title
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A Phase 3, Rollover Study to Evaluate the Safety of Long-term Treatment With Lumacaftor/Ivacaftor Combination Therapy in Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: LUM/IVA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects entering the Treatment Cohort must meet the following criteria: Completed 24 weeks of LUM/IVA treatment and the Safety Follow-up Visit in Study VX15-809-115 Part B (Study 115B, NCT02797132) Willing to remain on a stable CF medication regimen through the Safety Follow-up Visit Subjects entering the Observational Cohort must meet 1 of the following criteria: Completed 24 weeks of LUM/IVA treatment and the Safety Follow-up Visit in Study 115B, but do not want to enroll in the Treatment Cohort. Received at least 4 weeks of LUM/IVA treatment and completed visits up to Week 24 and the Safety Follow-up Visit, if required, of Study 115B but are not taking LUM/IVA at the end of the Study 115B Treatment Period (i.e., Week 24) because of a drug interruption and either did not receive Vertex approval to enroll in the Treatment Cohort or do not want to enroll in the Treatment Cohort. Permanently discontinued LUM/IVA in Study 115B after receiving at least 4 weeks of treatment and remained in the study from the time of treatment discontinuation through the Week 24 Visit and Safety Follow-up Visit, if required. Exclusion Criteria (Treatment Cohort Only): Prematurely discontinued LUM/IVA treatment in Study 115B. History of any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering LUM/IVA to the subject History of drug intolerance or other serious reactions to LUM/IVA in Study 115B that would pose an additional risk to the subject in the opinion of investigator, and which should be discussed with the Vertex medical monitor. Subjects with a history of allergy or hypersensitivity to LUM/IVA. Liver function test (LFT) abnormality meeting criteria for LUM/IVA treatment interruption at the completion of Study 115B, for which no convincing alternative etiology is identified. QTc value at the completion of Study 115B that would pose an additional risk to the subject in the opinion of investigator, and which should be discussed with the Vertex medical monitor History of poor compliance with LUM/IVA and/or procedures in Study 115B as deemed by the investigator. Participation in an investigational drug trial (including studies investigating LUM and/or IVA) other than Study 115B.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LUM/IVA<br>LUM/IVA granules or tablets were administered orally every 12 hours (Participants aged 2 through 5 years received LUM 100 mg/IVA 125 mg granules or LUM 150 mg/IVA 188 mg granules based on body weight. Participants ≥6 years of age were to receive LUM 200 mg/IVA 250 mg tablets). Doses were adjusted upward for changes in weight and age. | Drug: LUM/IVA<br>* Participants received LUM/IVA every q12h.<br>* Other names: lumacaftor/ivacaftor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Day 1 up to Week 98 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Sweat Chloride | Sweat samples were collected using an approved collection device. | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change in Body Mass Index (BMI) | BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2). | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change in BMI-for-age Z-score | BMI was defined as weight in kilograms divided by height in m^2. z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change in Weight |  | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change in Weight-for-age Z-score | Z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change From Baseline in Stature (Height) |  | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change in Stature-for-age Z-score | Z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. | From Parent Study 115B Baseline at Week 96 | 
| Time-to-first Pulmonary Exacerbation | Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol-defined criteria. | From Parent Study 115B Baseline through Week 96 | 
| Number of Pulmonary Exacerbations (PEx) | Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol-defined criteria. | From Parent Study 115B Baseline through Week 96 | 
| Number of Cystic Fibrosis (CF) Related Hospitalizations |  | From Parent Study 115B Baseline through Week 96 | 
| Absolute Change in Fecal Elastase-1 (FE-1) Levels |  | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change in Immunoreactive Trypsinogen (IRT) Serum Levels |  | From Parent Study 115B Baseline at Week 96 | 
| Number of Participants With Microbiology Culture Status (Positive or Negative) | Following microbial tests were performed: Burkholderia, Methicillin Resistant Staphylococcus Aureus (MRSA), Methicillin Susceptible Staphylococcus Aureus (MSSA), Pseudomonas Aeruginosa Mucoid (P. Aeruginosa Mucoid), P. Aeruginosa Non-Mucoid, P. Aeruginosa Small Colony Variant and Stenotrophomonas Maltophilia. | Week 96 | 
| Absolute Change in Lung Clearance Index (LCI) 2.5 | LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. | From Parent Study 115B Baseline at Week 96 | 
| Absolute Change in Lung Clearance Index (LCI) 5.0 | LCI 5.0 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/20th of its starting value. | From Parent Study 115B Baseline at Week 96 |