Cystic Fibrosis
Conditions
Brief summary
A Rollover Safety Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Years and Older With Cystic Fibrosis, Homozygous for F508del.
Interventions
DRUGLUM/IVA
Participants received LUM/IVA every q12h.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Body Mass Index (BMI) | From Parent Study 115B Baseline at Week 96 | BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2). |
| Absolute Change in BMI-for-age Z-score | From Parent Study 115B Baseline at Week 96 | 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. |
| Absolute Change in Weight | From Parent Study 115B Baseline at Week 96 | — |
| Absolute Change in Weight-for-age Z-score | From Parent Study 115B Baseline at Week 96 | 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. |
| Absolute Change From Baseline in Stature (Height) | From Parent Study 115B Baseline at Week 96 | — |
| Absolute Change in Stature-for-age Z-score | From Parent Study 115B Baseline at Week 96 | 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. |
| Time-to-first Pulmonary Exacerbation | From Parent Study 115B Baseline through Week 96 | Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol-defined criteria. |
| Absolute Change in Sweat Chloride | From Parent Study 115B Baseline at Week 96 | Sweat samples were collected using an approved collection device. |
| 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) | Week 96 | 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. |
| Absolute Change in Lung Clearance Index (LCI) 2.5 | From Parent Study 115B Baseline at Week 96 | 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. |
| Absolute Change in Lung Clearance Index (LCI) 5.0 | From Parent Study 115B Baseline at Week 96 | 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. |
| Number of Pulmonary Exacerbations (PEx) | From Parent Study 115B Baseline through Week 96 | Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol-defined criteria. |
Countries
Canada, United States
Participant flow
Recruitment details
This study was planned to have 2 cohorts: Treatment Cohort and Observational Cohort. Only the Treatment Cohort is presented in results as there were no participants enrolled in the Observational Cohort.
Pre-assignment details
This study was conducted in participants with cystic fibrosis (CF) aged 2 years and older who participated in parent study VX15-809-115 Part B (NCT02797132).
Participants by arm
| Arm | Count |
|---|---|
| LUM/IVA 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. | 57 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Commercial drug is available | 5 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal of consent (not due to AE) | 1 |
Baseline characteristics
| Characteristic | LUM/IVA |
|---|---|
| Age, Continuous | 43.2 months STANDARD_DEVIATION 12.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 56 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 57 |
| other Total, other adverse events | 55 / 57 |
| serious Total, serious adverse events | 15 / 57 |
Outcome results
Primary
Safety as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 98
Population: Study 116 safety set included all participants dosed in study 115B who were exposed to any amount of study drug in current study 116 treatment cohort.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LUM/IVA | Safety as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 56 participants |
| LUM/IVA | Safety as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 15 participants |
Secondary
Absolute Change From Baseline in Stature (Height)
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change From Baseline in Stature (Height) | 16.1 centimeter | Standard Deviation 2.3 |
Secondary
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.
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in BMI-for-age Z-score | 0.27 z-score | Standard Deviation 0.73 |
Secondary
Absolute Change in Body Mass Index (BMI)
BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2).
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Body Mass Index (BMI) | 0.30 kg/m^2 | Standard Deviation 1.21 |
Secondary
Absolute Change in Fecal Elastase-1 (FE-1) Levels
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Fecal Elastase-1 (FE-1) Levels | 132.6 microgram per gram (mcg/g) | Standard Deviation 174.2 |
Secondary
Absolute Change in Immunoreactive Trypsinogen (IRT) Serum Levels
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Immunoreactive Trypsinogen (IRT) Serum Levels | -108.5 nanogram per milliliter (ng/mL) | Standard Deviation 306.6 |
Secondary
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.
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 LCI substudy set included all participants who signed the informed consent/assent to the optional LCI substudy and were enrolled and exposed to any amount of study drug in current study 116.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Lung Clearance Index (LCI) 2.5 | -0.20 lung clearance index | Standard Deviation 1.55 |
Secondary
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.
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 LCI substudy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Lung Clearance Index (LCI) 5.0 | 0.11 lung clearance index | Standard Deviation 0.65 |
Secondary
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.
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Stature-for-age Z-score | 0.07 z-score | Standard Deviation 0.39 |
Secondary
Absolute Change in Sweat Chloride
Sweat samples were collected using an approved collection device.
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 Full Analysis Set (FAS) included all participants who were enrolled and exposed to any amount of study drug in current study 116.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Sweat Chloride | -29.6 millimole per liter (mmol/L) | Standard Deviation 12.7 |
Secondary
Absolute Change in Weight
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Weight | 6.0 kg | Standard Deviation 2 |
Secondary
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.
Time frame: From Parent Study 115B Baseline at Week 96
Population: Study 116 FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change in Weight-for-age Z-score | 0.23 z-score | Standard Error 0.56 |
Secondary
Number of Cystic Fibrosis (CF) Related Hospitalizations
Time frame: From Parent Study 115B Baseline through Week 96
Population: Study 115B FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LUM/IVA | Number of Cystic Fibrosis (CF) Related Hospitalizations | 28 hospitalizations |
Secondary
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.
Time frame: Week 96
Population: Study 116 FAS. Here Overall Number of Participants Analyzed signifies those participants who were evaluated for this outcome at Week 96.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | MSSA (Negative) | 31 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | P. Aeruginosa Mucoid (Positive) | 0 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | P. Aeruginosa Mucoid (Negative) | 46 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | P. Aeruginosa Non-Mucoid (Positive) | 1 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | P. Aeruginosa Non-Mucoid (Negative) | 45 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | P. Aeruginosa Small Colony Variant (Positive) | 0 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | Burkholderia (Positive) | 0 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | Burkholderia (Negative) | 46 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | MRSA (Positive) | 4 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | MRSA (Negative) | 42 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | MSSA (Positive) | 15 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | P. Aeruginosa Small Colony Variant (Negative) | 46 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | Stenotrophomonas Maltophilia (Positive) | 2 participants |
| LUM/IVA | Number of Participants With Microbiology Culture Status (Positive or Negative) | Stenotrophomonas Maltophilia (Negative) | 44 participants |
Secondary
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.
Time frame: From Parent Study 115B Baseline through Week 96
Population: Study 115B FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LUM/IVA | Number of Pulmonary Exacerbations (PEx) | 82 pulmonary exacerbation events |
Secondary
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.
Time frame: From Parent Study 115B Baseline through Week 96
Population: Study 115B FAS included all participants who were enrolled and exposed to any amount of study drug in parent study 115B
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LUM/IVA | Time-to-first Pulmonary Exacerbation | 600.0 days |