Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of treatment with VX-371 with and without ivacaftor, and the effect of VX-371 with and without ivacaftor on quality of life (QOL) in subjects with primary ciliary dyskinesia (PCD).

Official Title
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A Phase 2a, 2-part,Randomized, Double-blind, Placebo-controlled, Incomplete Block Crossover Study to Evaluate the Safety and Efficacy of VX-371 Solution for Inhalation With and Without Oral Ivacaftor in Subjects With Primary Ciliary Dyskinesia

Conditions
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Primary Ciliary Dyskinesia

Intervention / Treatment
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* Drug: VX-371
* Drug: Hypertonic Saline
* Drug: Placebo (0.17% saline)
* Drug: VX-371 + HS
* Drug: Ivacaftor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject must have evidence supportive of a PCD diagnosis. Subjects with percent predicted FEV1 of ≥40 to <90 percentage points Non-smoker for at least 90 days prior to the Screening Visit and less than a 5 pack-year lifetime history of smoking Stable regimen of medications and chest physiotherapy for the 28 days prior to Day 1 If currently using daily inhaled HS, must be able to discontinue its use for the duration of the study. If taking daily chronic or chronic cycling antibiotics, has been on a consistent regimen for at least 4 months prior to the Screening Visit. Clinically stable (as deemed by the investigator) for at least 14 days prior to the Screening Visit Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit. Subjects of childbearing potential and who are sexually active must meet the contraception requirements. Exclusion Criteria: Diagnosis of CF based on results of sweat chloride or nasal potential difference (NPD) tests or presence of 2 CF-causing mutations in CFTR gene. History of any organ transplantation or lung resection or chest wall surgery. Significant congenital heart defects, other than a laterality defect, at the discretion of the investigator Diagnosis of Cri du chat syndrome (chromosome 5p deletion syndrome). Inability to withhold short-acting bronchodilator use for 4 hours prior to clinic visit and long-acting bronchodilator use the night before the first and last clinic visit of each treatment period. Use of diuretics (including amiloride) or renin-angiotensin antihypertensive drugs Symptoms of acute upper or lower respiratory tract infection, acute pulmonary exacerbation, or treatment or was treated with systemic antibiotics for ear or sinus disease within 28 days before Day 1 (topical otic antibiotics allowed). History of significant intolerance to inhaled HS Pregnant and/or nursing females Any clinically significant laboratory abnormalities History of chronic B. cepacia complex or M. abscessus or M. avium Surgery that required general anesthesia and hospitalization within 3 months of Day 1 Additional Exclusion Criteria for Part B: In addition to the exclusion criteria above, subjects who participate in Part B and meet any of the following exclusion criteria will not be eligible to continue into Part B Unable to swallow tablets. Concomitant use of strong or moderate inhibitors or inducers of cytochrome P450 (CYP) 3A, including consumption of certain herbal medications (e.g., St. John's Wort), and grapefruit/grapefruit juice. Known hypersensitivity to ivacaftor.

Ages Eligible for Study
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Minimum Age: 12 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: VX-371 in Hypertonic Saline (HS), Then HS<br>Participants received 85 microgram (mcg) VX-371 diluted in 3 milliliter (mL) 4.2 percent (%) HS twice daily through oral nebulized inhalation from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2. | Drug: Hypertonic Saline<br> <br> Drug: VX-371 + HS<br> <br> |
| Experimental: Part A: HS, Then VX-371 in HS<br>Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through 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 (from Day 57 through Day 85) in treatment period 2. | Drug: Hypertonic Saline<br> <br> Drug: VX-371 + HS<br> <br> |
| Experimental: Part A: VX-371, Then Placebo<br>Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2. | Drug: VX-371<br> <br> Drug: Placebo (0.17% saline)<br> <br> |
| Experimental: Part A: Placebo, Then VX-371<br>Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily from Day 1 through Day 29 in treatment period 1 followed by a 28 day washout period (from Day 29 through 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 (from Day 57 through Day 85) in treatment period 2. | Drug: VX-371<br> <br> Drug: Placebo (0.17% saline)<br> <br> |
| Experimental: Part B: VX-371 in HS + Ivacaftor<br>Participants who were on 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3. | Drug: VX-371 + HS<br> <br> Drug: Ivacaftor<br> <br> |
| Experimental: Part B: HS + Ivacaftor<br>Participants who were on 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3. | Drug: Hypertonic Saline<br> <br> Drug: Ivacaftor<br> <br> |
| Experimental: Part B: VX-371 + Ivacaftor<br>Participants who were on 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3. | Drug: VX-371<br> <br> Drug: Ivacaftor<br> <br> |
| Placebo Comparator: Part B: Placebo + Ivacaftor<br>Participants who were on 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (from Day 57 through Day 85) in treatment period 2 continued their inhaled study drug regimen from Treatment Period 2 and also received ivacaftor 150 mg tablet twice daily for 28 days (from Day 85 through Day 113) in treatment period 3. | Drug: Placebo (0.17% saline)<br> <br> Drug: Ivacaftor<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | An 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 pulse oximetry 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 84 days that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs. | Part A: From first dose of study drug up 84 days | 
| Part B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | An 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 pulse oximetry examinations. 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 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. | Part B: Day 85 up to 28 days after last dose of study drug (56 days) | 
| Part A: Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 29 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The study baseline is defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of study drug in the study. | Part A: Study Baseline, Day 29 of each treatment period | 
| Part B: Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 29 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The study baseline is defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of study drug in the study. | Study Baseline, Day 29 of Part B | 
| Part B: Absolute Change From Part B Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 29 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Part B baseline was defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of ivacaftor in Part B and after the last dose in Period 2. | Part B Baseline, Day 29 of Part B | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Change From Study Baseline in Quality of Life-Primary Ciliary Dyskinesia (QOL-PCD) (Adult Version) Lower Respiratory Symptoms Domain Score at Day 29 | QOL- PCD adult version has following 10 domains: lower respiratory symptoms, emotional functioning, treatment burden, role, social functioning, vitality, health perception, upper respiratory symptoms, physical functioning and hearing symptoms. The total numbers of items in the lower respiratory symptoms domain are 6 in the questionnaire for adults. All items are scored using a 4-point Likert scale. Scaled score calculated as: [Sum of scores - (n*1)] / [(n*4) - (n*1)]*100. Where 'n' is the number of questions in domain. The total score range is from 0-100, where higher score indicates greater improvement. Change from study baseline >0 indicated improvement. The study baseline is defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of study drug in the study. | Study Baseline, Day 29 of Part A | 
| Part B: Change From Study Baseline in Quality of Life-Primary Ciliary Dyskinesia (QOL-PCD) (Adult Version) Lower Respiratory Symptoms Domain Score at Day 29 | QOL- PCD adult version has following 10 domains: lower respiratory symptoms, emotional functioning, treatment burden, role, social functioning, vitality, health perception, upper respiratory symptoms, physical functioning and hearing symptoms. The total numbers of items in the lower respiratory symptoms domain are 6 in the questionnaire for adults. All items are scored using a 4-point Likert scale. Scaled score calculated as: [Sum of scores - (n*1)] / [(n*4) - (n*1)]*100. Where 'n' is the number of questions in domain. The total score range is from 0-100, where higher score indicates greater improvement. Change from study baseline >0 indicated improvement. The study baseline is defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of study drug in the study. | Study Baseline, Day 29 of Part B | 
| Part B: Change From Part B Baseline in Quality of Life-Primary Ciliary Dyskinesia (QOL-PCD) (Adult Version) Lower Respiratory Symptoms Domain Score at Day 29 | QOL- PCD adult version has following 10 domains: lower respiratory symptoms, emotional functioning, treatment burden, role, social functioning, vitality, health perception, upper respiratory symptoms, physical functioning and hearing symptoms. The total numbers of items in the lower respiratory symptoms domain are 6 in the questionnaire for adults. All items are scored using a 4-point Likert scale. Scaled score calculated as: [Sum of scores - (n*1)] / [(n*4) - (n*1)]*100. Where 'n' is the number of questions in domain. The total score range is from 0-100, where higher score indicates greater improvement. Change from Part B baseline >0 indicated improvement. Part B baseline was defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of ivacaftor in Part B and after the last dose in Period 2. | Part B Baseline, Day 29 of Part B | 
| Part A: Change From Study Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score for Participants Aged Greater Than or Equals to (>=) 16 Years at Day 29 | SGRQ measured health-related quality of life among participants with respiratory diseases. It is a 40 items questionnaire grouped into three domains (Symptoms, Activity, and Impacts). Total scores range from 0 to 100. Higher score reflected worse quality of life. The study baseline is defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of study drug in the study. | Study Baseline, Day 29 of Part A | 
| Part B: Change From Study Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score for Participants Aged >=16 Years at Day 29 | SGRQ measured health-related quality of life among participants with respiratory diseases. It is a 40 items questionnaire grouped into three domains (Symptoms, Activity, and Impacts). Total scores range from 0 to 100. Higher score reflected worse quality of life. The study baseline is defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of study drug in the study. | Study Baseline, Day 29 of Part B | 
| Part B: Change From Part B Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score for Participants Aged >=16 Years at Day 29 | SGRQ measured health-related quality of life among participants with respiratory diseases. It is a 40 items questionnaire grouped into three domains (Symptoms, Activity, and Impacts). Total scores range from 0 to 100. Higher score reflected worse quality of life. Part B baseline was defined as the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of ivacaftor in Part B and after the last dose in Period 2. | Part B Baseline, Day 29 of Part B |