Safety, Tolerability, and Pharmacokinetics of PTI-808, PTI-801, and PTI-428 Combination Therapy in Subjects With Cystic Fibrosis

Study Overview
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Brief Summary
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The study is a randomized, double-blind, placebo-controlled, study that will be conducted at multiple centers in subjects with Cystic Fibrosis (CF) who are either homozygous for the F508del mutation or heterozygous with at least copy of the F508del mutation.

Detailed Description
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Study PTI-808-02 will enroll up to approximately 32 subjects. Subjects in the first cohort will receive PTI-808 and PTI-801. Following completion of Cohort 1, initiation of enrollment into subsequent cohorts will be based upon review and approval by the Safety Review Committee (SRC).

Official Title
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A Phase 1 / 2, Randomized, Double-Blind, Placebo-Controlled Study Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of PTI-808, PTI-801, and PTI-428 Combination Therapy in Subjects With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: PTI-808
* Drug: Placebo
* Drug: PTI-801
* Drug: PTI-428
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohorts 1,2 and 4: A Confirmed diagnosis of CF with the F508del/F508del CFTR genotype on record, along with clinical findings consistent with CF such as chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities Cohort 3 only: Confirmed diagnosis of CF with at least one copy of the F508del CFTR mutation on record, along with clinical findings consistent with CF, such as chronic sinopulmonary disease or gastrointestinal / nutritional abnormalities Forced expiratory volume in 1 second (FEV1) 40-90% predicted, inclusive Non-smoker and non-tobacco user for a minimum of 30 days prior to screening Cohort 3 only: A sweat chloride value of ≥60 mmol/L based on quantitative pilocarpine iontophoresis (as documented in the subject's medical record or as confirmed at the screening visit) Exclusion Criteria: Currently taking or has taken a CFTR modulator within 30 days prior to initial dose of study drugs Participation in another clinical trial or treatment with an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Study Day 1 History of cancer within the past 5 years History of organ transplantation Hospitalization, sinopulmonary infection, CF exacerbation, or other clinically significant infection or illness (as determined by the investigator) requiring an increase or addition of medication, such as antibiotics or corticosteroids, within 14 days of Day 1 Initiation of any new chronic therapy (e.g., ibuprofen, hypertonic saline, azithromycin, Pulmozyme®, Cayston®, TOBI®) or any change in chronic therapy (excluding pancreatic enzyme replacement therapy) within 28 days prior to Day 1 History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator Pregnant or nursing women

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohorts 1 and 2: PTI-808 Active Co-admin with PTI-801 Active<br>Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21. | Drug: PTI-808<br>* Active<br>Drug: PTI-801<br>* Active<br>|
| Placebo Comparator: Cohorts 1 and 2: PTI-808 Placebo Co-admin with PTI-801 Placebo<br>Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21. | Drug: Placebo<br>* Placebo<br>|
| Active Comparator: Cohort 3 PTI-808 Active + PTI-801 Active + PTI-428 Active<br>Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21. | Drug: PTI-808<br>* Active<br>Drug: PTI-801<br>* Active<br>Drug: PTI-428<br>* Active<br>|
| Placebo Comparator: Cohort 3 PTI-808 placebo + PTI-801 Placebo + PTI-428 Placebo<br>Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21. | Drug: Placebo<br>* Placebo<br>Drug: Placebo<br>* Placebo<br>|
| Active Comparator: Cohort 4 PTI-808 Active + PTI-801 Active + PTI-428 Active<br>Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for 7 days immediately followed by PTI-808 co-administered with PTI-801 or placebos once-a-day for 7 days. A follow-up visit will occur on Day 21. | Drug: PTI-808<br>* Active<br>Drug: PTI-801<br>* Active<br>Drug: PTI-428<br>* Active<br>|
| Placebo Comparator: Cohort 4 PTI-808 Placebo + PTI-801 Placebo + PTI-428 Placebo<br>Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for 7 days immediately followed by PTI-808 co-administered with PTI-801 or placebos once-a-day for 7 days. A follow-up visit will occur on Day 21. | Drug: Placebo<br>* Placebo<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability measured by the number of subjects who experience adverse events and potentially significant clinical laboratory assessments, electrocardiography, physical examinations, vital signs. |  | Baseline through Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apparent terminal half-life (t1/2) of multiple oral doses of PTI-808 + PTI-801 and PTI-428 (cohorts 3 & 4 only) |  | Day 1 through 15 | 
| Time to reach maximum plasma concentration (Tmax) of multiple oral doses of PTI-808 + PTI-801 and PTI-428 (cohorts 3 & 4 only) |  | Day 1 through 15 | 
| Maximum plasma concentration (Cmax) of multiple oral doses of PTI-808 + PTI-801 and PTI-428 (cohorts 3 & 4 only) |  | Day 1 through 15 | 
| Change in FEV1 over time |  | Baseline through Day 21 |