A Phase 2a, Two-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

Subjects who meet all of the following inclusion criteria will be eligible.
1. Subject (or subject's legally appointed and authorized representative) will sign and date an informed consent form (ICF) and, where appropriate, assent form.
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions laboratory tests, contraceptive guidelines, and other study procedures.
3. Willing and able to use the nebulization device as directed by the instructions for use.
4. The subject must have evidence supportive of a PCD diagnosis, based on the following:
A. Subjects *12 to <18 years of age must meet 2 or more of the following PCD clinical criteria:
* Unexplained neonatal respiratory distress (at term birth) with need for respiratory support with CPAP and/or oxygen for >24 hours.
* Any organ laterality defect confirmed by historical chest imaging * situs inversustotalis, situs ambiguous, or heterotaxy.
* Daily, year-round wet or productive cough starting in first year of life or bronchiectasis on historical chest imaging.
* Daily, year-round nasal congestion starting in first year of life or pansinusitis on historical sinus imaging.
B. Subjects *18 years of age must have bronchiectasis on historical chest imaging.
C. All subjects must ALSO have documentation of at least 1 of the following historical tests:
* For patients with no laterality defect, nNO level, measured with a chemiluminescent NO analyzer, during plateau <77 nL/min on 2 occasions, at least 2 months apart, with CF excluded by sweat chloride or genetic testing.
* For patients with a laterality defect, nNO level, measured with a chemiluminescent NO analyzer, during plateau <77 nL/min on at least 1 occasion
* Diagnostic ciliary ultrastructural defect on transmission electron micrograph (TEM).
* 2 loss of function and/or known mutations in a single PCD-associated gene.
Prior to randomization, all subjects must have a confirmed diagnosis of PCD (including central review, as required) based on one of the following:
* 2 loss of function and/or known mutations in a single PCD-associated gene identified by the central genetic testing laboratory from the specimen obtained at the Screening Visit; previous genotype results cannot be used to determine eligibility for randomization.
* Diagnostic ciliary ultrastructural defect on transmission electron micrograph. A previously prepared TEM specimen will be reviewed centrally; a new specimen will not be obtained.
* Laterality defect that includes dextrocardia plus bronchiectasis in more than 1 lobe on historical chest imaging.
5. Subjects with ppFEV1 of *40 to <90 percentage points adjusted for age, sex, and height according to the Global Lung Function Initiative (GLI) predicted values at the Screening Visit, taken 4 hours or more after last dose of short-acting bronchodilators (*-agonists and/or anticholinergics)
6. Non-smoker for the past 90 days prior to the Screening Visit and less than a 5 pack-year lifetime history of smoking, and willing to not smoke while enrolled in the study.
7. Stable regimen of medications and chest physiotherapy for the 28 days prior to Day 1, and no anticipated need for changes during the study period (other than stopping inhaled HS).
8. If currently using daily inhaled HS, must be able to discontinue its use for the duration of the study.
9. If taking daily chronic or chronic cycling antibiotics, has been on a consistent regimen for at least 4 months prior to the Screening Visit. The cycling regimen of antibiotics can be either intermittent monotherapy (e.g., 28 days on/28 days off) or continuous alternating therapy (e.g., 28-day cycles of 2 alternating antibiotics).
10. Clinically stable (as deemed by the investigator) for at least 14 days prior to the Screening Visit with no evidence of significant new or acute respiratory exacerbations, excluding symptoms of allergic (perennial or seasonal) or non-allergic rhinitis.
11. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit. Females of childbearing potential must have a negative urine pregnancy test at the Day 1, Day 57 and Day 85 visits before receiving the first dose of study drug in each Treatment Period, respectively. Subjects of childbearing potential and who are sexually active must meet the contraception requirements outlined in Section 11.6.5.1.

Subjects who meet any of the following exclusion criteria will not be eligible.
1. Diagnosis of CF, including at least 1 of the following:
a. Documented sweat chloride test *60 mM by quantitative pilocarpine iontophoresis
b. Abnormal nasal potential difference (NPD) test
c. 2 CF-causing mutations in the CFTR gene
2. Subjects with only 1 mutation in the CFTR gene and a sweat chloride test *60 mM by quantitative pilocarpine iontophoresis.
3. History of any organ transplantation or lung resection or chest wall surgery.
4. Significant congenital heart defects, other than a laterality defect, at the discretion of the investigator.
5. Diagnosis of Cri du chat syndrome (chromosome 5p deletion syndrome).
6. 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.
7. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This may include, but is not limited to history of clinically significant and uncontrolled adrenal, neurologic, gastrointestinal, renal, hepatic, cardiovascular (including hyper/hypotension and tachy/bradycardia), psychological, pulmonary (other than PCD), metabolic, endocrine, or hematological/coagulation disorder or disease, or scoliosis of such severity that it impacts pulmonary function or any other major disorder or disease, in the opinion of the investigator.
8. Use of diuretics (including amiloride) or renin-angiotensin antihypertensive drugs (e.g., spironolactone, angiotensin converting enzyme [ACE] and/or neural endopeptidase (NEP)-inhibitors, or angiotensin receptor blockers [ARBs]) or trimethoprim or drospirenone in the 28 days before Day 1 or anticipate need for these medications during the study.
9. Had symptoms of acute upper or lower respiratory tract infection or had an acute pulmonary exacerbation requiring treatment or was treated with systemic antibiotics for ear or sinus disease within 28 days before Day 1 (topical otic antibiotics allowed).
10. History of significant intolerance to inhaled HS, as determined by the investigator.
11. History of drug or alcohol abuse, in the opinion of the investigator.
12. Known hypersensitivity to any of the study drugs or amiloride.
13. Used ivacaftor within 28 days prior to Day 1 or anticipate need for ivacaftor during the study.
14. Pregnant and/or nursing females.
15. Any clinically significant laboratory abnormalities at the Screening Visit as judged by the investigator, or any of the following:
a. Plasma or serum potassium > upper limit of normal (ULN)
b. Abnormal renal function, defined as creatinine clearance rate <50 mL/min using the Bedside Schwartz equation (for subjects 12 to 17 years of age) or <50 mL/min using the Cockcroft-Gault equation (for subjects *18 years of age).
c. Abnormal liver function, defined as *3 × ULN for alanine aminotransferase (ALT), or aspartate aminotransferase (AST), or >2 x ULN for total bilirubin, unless accounted for by Gilbert's syndrome (benign indirect hyperbilirubinemia)
d. Hemoglobin concentration <10.0 g/dL
16. Unwilling or unable to follow the contraception guidelines as outlined in Section 11.6.5.1.
17. History of at least 2 sputum or throat swab cultures yielding B. cepacia complex or M. abscessus or M. avium within the previous 2 years.
18. Has had surgery within 3 months of Day 1 that required general anesthesia and hospitalization.
19. Has previously participated in an investigational study involving administration of any investigational compound or use of an investigational device within 28 days prior to the Screening Visit (Note: Participation in a past or concurrent observational study is acceptable).
20. Has any surgical or medical condition which in the judgment of the investigator might interfere with the absorption, distribution, metabolism, or excretion of the study drug or with safety evaluations.
21. Has any other condition or circumstances that, in the opinion of the investigator, should disqualify this subject for this study.
22. The subject or a close relative of the subject is the investigator or a sub-investigator, research assistant, pharmacist, study coordinator, or other staff directly involved in the conduct of the study.;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.
1. Unable to swallow tablets.
2. 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.
3. Known hypersensitivity to ivacaftor.