Clinical trial NCT02718495: Study Assessing PTI-428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cystic Fibrosis
Lead sponsor: Proteostasis Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2016-03-24
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: SAD: safety and tolerability as assessed by adverse events, safety labs: hematology, chemistry, and urinalysis, electrocardiograms (ECGs), physical examinations, and vital signs
timeFrame: Baseline to Day 7
measure: 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
timeFrame: Baseline to Day 14
measure: 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
timeFrame: Baseline to Day 35
measure: 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
timeFrame: Baseline to Day 49
Secondary outcomes:
measure: SAD: apparent terminal half-life (t1/2) of single oral dose
timeFrame: Baseline through 72 hours post dose
measure: SAD: time to reach maximum plasma concentration (Tmax) of single oral dose
timeFrame: Baseline through 72 hours post dose
measure: SAD: maximum plasma concentration (Cmax) of single oral dose
timeFrame: Baseline through 72 hours post dose
measure: SAD: area under the concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of single oral dose
timeFrame: Baseline through 72 hours post dose
measure: MAD: t1/2 of multiple oral doses
timeFrame: Baseline through 24 hours post Day 7 dose
measure: MAD: Tmax of multiple oral doses
timeFrame: Baseline through 24 hours post Day 7 dose
measure: MAD: Cmax of multiple oral doses
timeFrame: Baseline through 24 hours post Day 7 dose
measure: MAD: AUC0-t of multiple oral doses
timeFrame: Baseline through 24 hours post Day 7 dose
measure: MAD: area under the concentration-time curve from time 0 to infinity (AUC0-∞) of multiple oral doses
timeFrame: Baseline through 24 hours post Day 7 dose
measure: Part B and Part C Cohorts 2 and 3: t1/2 of multiple oral doses
timeFrame: Baseline through 24 hours post Day 28 dose
measure: Part B and Part C Cohorts 2 and 3: Tmax of multiple oral doses
timeFrame: Baseline through 24 hours post Day 28 dose
measure: Part B and Part C Cohorts 2 and 3: Cmax of multiple oral doses
timeFrame: Baseline through 24 hours post Day 28 dose
measure: Part B and Part C Cohorts 2 and 3: AUC0-t of multiple oral doses
timeFrame: Baseline through 24 hours post Day 28 dose
measure: Part B and Part C Cohorts 2 and 3: AUC0-∞ of multiple oral doses
timeFrame: Baseline through 24 hours post Day 28 dose
measure: Part B and Part C Cohorts 2 and 3: change in forced expiratory volume in one second (FEV1) over time
timeFrame: Baseline through Day 35
measure: Part B and Part C Cohorts 2 and 3: change in sweat chloride over time
timeFrame: Baseline through Day 35
measure: Part B and Part C Cohorts 2 and 3: change in weight over time
timeFrame: Baseline through Day 35
measure: Part C Cohort 1: t1/2 of multiple oral doses
timeFrame: Baseline through Day 42
measure: Part C Cohort 1: Tmax of multiple oral doses
timeFrame: Baseline through Day 42
measure: Part C Cohort 1: Cmax of multiple oral doses
timeFrame: Baseline through Day 42
measure: Part C Cohort 1: AUC0-t of multiple oral doses
timeFrame: Baseline through Day 42
measure: Part C Cohort 1: AUC0-∞ of multiple oral doses
timeFrame: Baseline through Day 42
measure: Part C Cohort 1: change in FEV1 over time
timeFrame: Baseline through Day 49
measure: Part C Cohort 1: change in sweat chloride over time
timeFrame: Baseline through Day 49
measure: Part C Cohort 1: change in weight over time
timeFrame: Baseline through Day 49
Other outcomes:
measure: SAD: change in nasal epithelial CFTR mRNA and protein expression
timeFrame: Baseline through Day 7
measure: MAD: change in nasal epithelial CFTR mRNA and protein expression
timeFrame: Baseline through Day 14
measure: MAD: change in sweat chloride over time
timeFrame: Baseline through Day 14
measure: Part B and Part C Cohorts 2 and 3: change in nasal epithelial CFTR mRNA and protein expression
timeFrame: Baseline through Day 35
measure: Part B and Part C Cohorts 2 and 3: change in CFQ-R over time
timeFrame: Baseline through Day 28
measure: Part C Cohort 1: change in nasal epithelial CFTR mRNA and protein expression
timeFrame: Baseline through Day 49
measure: Part C Cohort 1: change in CFQ-R over time
timeFrame: Baseline through Day 42
measure: Part C Cohort 3: change in fecal elastase over time
timeFrame: Baseline through Day 35
measure: Part C Cohort 3: change in fecal calprotectin over time
timeFrame: Baseline through Day 35
Locations:
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Altamonte Springs
country: United States
facility: Central Florida Pulmonary Group
state: Florida
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Boise
country: United States
facility: St. Luke's Cystic Fibrosis Center of Idaho
state: Idaho
city: Chicago
country: United States
facility: Northwestern University Memorial Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Overland Park
country: United States
facility: Quintiles Overland Park Phase 1 Unit
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Childrens Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: Universiy of Michigan Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Las Vegas
country: United States
facility: Children's Lung Specialists
state: Nevada
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Vancouver
country: Canada
facility: St. Paul's Hospital Pacific Lung Research Center
state: British Columbia
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Institut de Recherches Cliniques de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Quebec
state: Quebec
city: Copenhagen
country: Denmark
facility: University of Copenhagen Rigshospitalet
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin - Hôpital des Enfants
city: Paris
country: France
facility: Hôpital Cochin
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum
city: Frankfurt
country: Germany
facility: Universitaetsklinikum Frankfurt-Zentrum der Inneren Medizin
Study officials:
References: