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

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Placebo; Drug: PTI-428

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital Pacific Lung Research Center
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • Institut de recherches cliniques de Montreal
    • Quebec City, Quebec, Canada, G1V 4G5
      • Institut Universitaire De Cardiologie Et De Pneumologie De Québec
• Denmark
  • Copenhagen, Denmark, 2100
    • University of Copenhagen Rigshospitalet
• France
  • Bordeaux, France, 33076
    • Groupe Hospitalier Pellegrin - Hopital des enfants
  • Paris, France, 75014
    • Hopital Cochin
• Germany
  • Berlin, Germany, 10117
    • Charité - Campus Virchow-Klinikum
  • Frankfurt, Germany, 60590
    • Universitaetsklinikum Frankfurt-Zentrum der Inneren Medizin
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Florida
    • Altamonte Springs, Florida, United States, 32803
      • Central Florida Pulmonary Group
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Cystic Fibrosis Center of Idaho
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Memorial Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center Research Institute, Inc.
    • Overland Park, Kansas, United States, 66211
      • Quintiles Overland Park Phase 1 Unit
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Childrens Hospital Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Universiy of Michigan Health System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nevada
    • Las Vegas, Nevada, United States, 89107
      • Children's Lung Specialists
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Drexel University College of Medicine
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part A; 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: Placebo; Drug: PTI-428
Placebo Comparator: Part B; Part B will consist of 2 cohorts. Subjects will receive once daily dosing of PTI-428 or placebo for 28 days.	Drug: Placebo; Drug: PTI-428
Placebo Comparator: Part C; Part C will consist of 3 cohorts. Subjects will receive once daily dosing of PTI-428 or placebo for 28 days.	Drug: Placebo; Drug: PTI-428

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Other Outcome Measures

Outcome Measure	Time Frame
SAD: change in nasal epithelial CFTR mRNA and protein expression	Baseline through Day 7
MAD: change in nasal epithelial CFTR mRNA and protein expression	Baseline through Day 14
MAD: change in sweat chloride over time	Baseline through Day 14
Part B and Part C Cohorts 2 and 3: change in nasal epithelial CFTR mRNA and protein expression	Baseline through Day 35
Part B and Part C Cohorts 2 and 3: change in CFQ-R over time	Baseline through Day 28
Part C Cohort 1: change in nasal epithelial CFTR mRNA and protein expression	Baseline through Day 49
Part C Cohort 1: change in CFQ-R over time	Baseline through Day 42
Part C Cohort 3: change in fecal elastase over time	Baseline through Day 35
Part C Cohort 3: change in fecal calprotectin over time	Baseline through Day 35

Collaborators and Investigators

• Sponsor: Proteostasis Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2016
• Primary Completion (Actual): November 28, 2017
• Study Completion (Actual): November 28, 2017

Study Registration Dates

• First Submitted: March 10, 2016
• First Submitted That Met QC Criteria: March 18, 2016
• First Posted (Estimate): March 24, 2016

Study Record Updates

• Last Update Posted (Actual): March 21, 2019
• Last Update Submitted That Met QC Criteria: March 19, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: PTI-428-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES