Study Assessing PTI-428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis

Study Overview
=================
Brief Summary
-----------------
This trial will consist of three arms: Part A, Part B, and Part C. Part A has two groups. The first group will enroll adult subjects with cystic fibrosis (CF) into a single ascending dose (SAD) treatment group. The second group will enroll adult subjects with CF, including those on background treatment with ORKAMBI® and those not on a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, into a multiple ascending dose (MAD) treatment group. Part B will enroll adult subjects with CF currently on stable ORKAMBI® background therapy for a minimum of 3 months into a Phase II treatment group consisting of two cohorts. Part C will enroll adult subjects with CF, including those on background treatment with KALYDECO® and those not on a CFTR modulator, into a Phase II treatment group consisting of three cohorts. Approximately 136 subjects will be enrolled.

Detailed Description
-----------------
PART A The SAD treatment group is comprised of 3 cohorts where subjects will be randomized to either PTI-428 or placebo. Following the conclusion of at least 3 SAD treatment groups, a set of adult subjects diagnosed with CF will participate in an assigned MAD treatment group. The MAD treatment group is comprised of 3 cohorts. MAD Cohort 1 will enroll adult subjects with CF currently on stable ORKAMBI® background therapy for a minimum of 3 months at the time of randomization. MAD Cohorts 2 and 3 will enroll adult subjects with CF who are not currently on any background therapies. Subjects in all MAD cohorts will be randomized to either PTI-428 or placebo. Each dose will be administered once daily (QD) for a total of 7 Days. PART B Following the conclusion of MAD Cohort 1, a set of adult subjects diagnosed with CF currently on stable ORKAMBI® background therapy for a minimum of 3 months will participate in Part B. The Part B Phase II treatment group is comprised of 2 cohorts where subjects will be randomized to either PTI-428 or placebo. Each dose will be administered QD for a total of 28 days. PART C Following the conclusion of Part B Phase II, a set of adult subjects diagnosed with CF will participate in Part C. The Part C Phase II treatment group is comprised of 3 cohorts. Part C Cohort 1 will enroll adult subjects with CF who are eligible to take, but not currently taking, ORKAMBI® in accordance with the approved label. Part C Cohort 2 will enroll adult subjects with CF currently on stable KALYDECO® background therapy for a minimum of 3 months at the time of randomization. Part C Cohort 3 will enroll adult subjects with CF who are not currently on any background therapies and are pancreatic sufficient. Each PTI-428 or placebo dose will be administered QD for a total of 28 days.

Official Title
-----------------
A Phase I/II, Multi-center, Randomized, Placebo-Controlled, Study Designed to Assess the Safety, Tolerability, and Pharmacokinetics of PTI-428 in Subjects With Cystic Fibrosis

Conditions
-----------------
Cystic Fibrosis

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of CF. Forced expiratory volume in 1 second (FEV1) 40-90% predicted. Non-smoker and non-tobacco user for a minimum of 30 days prior to screening and for the duration of the study. Exclusion Criteria: Participation in another clinical trial or treatment with an investigational agent within 30 days or 5 half-lives, whichever is longer, prior to Study Day 1. History of cancer within the past five years (excluding cervical CIS with curative therapy for at least one year prior to screening and non-melanoma skin cancer). History of organ transplantation. Any sinopulmonary infection or CF exacerbation requiring a change or addition of medication (including antibiotics) within 1 month of Study Day 1 or any other clinically significant infection as determined by the investigator within 1 month of Day 1. History of alcohol or drug abuse or dependence within 12 months of screening as determined by the Investigator. Male and female of child-bearing potential, unless they are using highly effective methods of contraception during participation in the clinical study and for 4 weeks after termination from study. Pregnant or nursing women.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A<br>Part A consists of two treatment groups, SAD and MAD. Both treatment groups will consist of 3 cohorts. In SAD, subjects will receive a single dose of PTI-428 or placebo. In MAD, subjects will receive once daily dosing of PTI-428 or placebo for 7 days. | Drug: PTI-428<br> <br> Drug: Placebo<br> <br> |
| Placebo Comparator: Part B<br>Part B will consist of 2 cohorts. Subjects will receive once daily dosing of PTI-428 or placebo for 28 days. | Drug: PTI-428<br> <br> Drug: Placebo<br> <br> |
| Placebo Comparator: Part C<br>Part C will consist of 3 cohorts. Subjects will receive once daily dosing of PTI-428 or placebo for 28 days. | Drug: PTI-428<br> <br> Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAD: safety and tolerability as assessed by adverse events, safety labs: hematology, chemistry, and urinalysis, electrocardiograms (ECGs), physical examinations, and vital signs |  | Baseline to Day 7 | 
| MAD: safety and tolerability as assessed by adverse events, pulomonary function tests, safety labs: hematology, chemistry, and urinalysis, electrocardiograms (ECGs), physical examinations, and vital signs |  | Baseline to Day 14 | 
| Part B and Part C Cohorts 2 and 3: safety and tolerability as assessed by adverse events, safety labs: hematology, chemistry, and urinalysis, electrocardiograms (ECGs), physical examinations, and vital signs |  | Baseline to Day 35 | 
| Part C Cohort 1: safety and tolerability as assessed by adverse events, safety labs: hematology, chemistry, and urinalysis, electrocardiograms (ECGs), physical examinations, and vital signs |  | Baseline to Day 49 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAD: apparent terminal half-life (t1/2) of single oral dose |  | Baseline through 72 hours post dose | 
| SAD: time to reach maximum plasma concentration (Tmax) of single oral dose |  | Baseline through 72 hours post dose | 
| SAD: maximum plasma concentration (Cmax) of single oral dose |  | Baseline through 72 hours post dose | 
| SAD: area under the concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of single oral dose |  | Baseline through 72 hours post dose | 
| MAD: t1/2 of multiple oral doses |  | Baseline through 24 hours post Day 7 dose | 
| MAD: Tmax of multiple oral doses |  | Baseline through 24 hours post Day 7 dose | 
| MAD: Cmax of multiple oral doses |  | Baseline through 24 hours post Day 7 dose | 
| MAD: AUC0-t of multiple oral doses |  | Baseline through 24 hours post Day 7 dose | 
| MAD: area under the concentration-time curve from time 0 to infinity (AUC0-∞) of multiple oral doses |  | Baseline through 24 hours post Day 7 dose | 
| Part B and Part C Cohorts 2 and 3: t1/2 of multiple oral doses |  | Baseline through 24 hours post Day 28 dose | 
| Part B and Part C Cohorts 2 and 3: Tmax of multiple oral doses |  | Baseline through 24 hours post Day 28 dose | 
| Part B and Part C Cohorts 2 and 3: Cmax of multiple oral doses |  | Baseline through 24 hours post Day 28 dose | 
| Part B and Part C Cohorts 2 and 3: AUC0-t of multiple oral doses |  | Baseline through 24 hours post Day 28 dose | 
| Part B and Part C Cohorts 2 and 3: AUC0-∞ of multiple oral doses |  | Baseline through 24 hours post Day 28 dose | 
| Part B and Part C Cohorts 2 and 3: change in forced expiratory volume in one second (FEV1) over time |  | Baseline through Day 35 | 
| Part B and Part C Cohorts 2 and 3: change in sweat chloride over time |  | Baseline through Day 35 | 
| Part B and Part C Cohorts 2 and 3: change in weight over time |  | Baseline through Day 35 | 
| Part C Cohort 1: t1/2 of multiple oral doses |  | Baseline through Day 42 | 
| Part C Cohort 1: Tmax of multiple oral doses |  | Baseline through Day 42 | 
| Part C Cohort 1: Cmax of multiple oral doses |  | Baseline through Day 42 | 
| Part C Cohort 1: AUC0-t of multiple oral doses |  | Baseline through Day 42 | 
| Part C Cohort 1: AUC0-∞ of multiple oral doses |  | Baseline through Day 42 | 
| Part C Cohort 1: change in FEV1 over time |  | Baseline through Day 49 | 
| Part C Cohort 1: change in sweat chloride over time |  | Baseline through Day 49 | 
| Part C Cohort 1: change in weight over time |  | Baseline through Day 49 |