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

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ClinicalTrials.gov Identifier: NCT02718495
Recruitment Status : Completed
First Posted : March 24, 2016
Last Update Posted : March 21, 2019
Sponsor:
Information provided by (Responsible Party):
Proteostasis Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE March 10, 2016
First Posted Date  ICMJE March 24, 2016
Last Update Posted Date March 21, 2019
Actual Study Start Date  ICMJE July 19, 2016
Actual Primary Completion Date November 28, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2017)
  • SAD: safety and tolerability as assessed by adverse events, safety labs: hematology, chemistry, and urinalysis, electrocardiograms (ECGs), physical examinations, and vital signs [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to Day 49 ]
Original Primary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
  • SAD: Safety and tolerability measured by number of subjects who experience adverse events and potential clinically significant changes in safety labs, electrocardiograms (ECGs), physical examinations, and vital signs. [ Time Frame: baseline to 7 days ]
  • MAD: Safety and tolerability measured by number of subjects who experience adverse events and potential clinically significant changes in pulmonary function tests, safety labs, ECGs, physical examinations, and vital signs. [ Time Frame: baseline to 14 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2017)
  • SAD: apparent terminal half-life (t1/2) of single oral dose [ Time Frame: Baseline through 72 hours post dose ]
  • SAD: time to reach maximum plasma concentration (Tmax) of single oral dose [ Time Frame: Baseline through 72 hours post dose ]
  • SAD: maximum plasma concentration (Cmax) of single oral dose [ Time Frame: 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 [ Time Frame: Baseline through 72 hours post dose ]
  • MAD: t1/2 of multiple oral doses [ Time Frame: Baseline through 24 hours post Day 7 dose ]
  • MAD: Tmax of multiple oral doses [ Time Frame: Baseline through 24 hours post Day 7 dose ]
  • MAD: Cmax of multiple oral doses [ Time Frame: Baseline through 24 hours post Day 7 dose ]
  • MAD: AUC0-t of multiple oral doses [ Time Frame: 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 [ Time Frame: Baseline through 24 hours post Day 7 dose ]
  • Part B and Part C Cohorts 2 and 3: t1/2 of multiple oral doses [ Time Frame: Baseline through 24 hours post Day 28 dose ]
  • Part B and Part C Cohorts 2 and 3: Tmax of multiple oral doses [ Time Frame: Baseline through 24 hours post Day 28 dose ]
  • Part B and Part C Cohorts 2 and 3: Cmax of multiple oral doses [ Time Frame: Baseline through 24 hours post Day 28 dose ]
  • Part B and Part C Cohorts 2 and 3: AUC0-t of multiple oral doses [ Time Frame: Baseline through 24 hours post Day 28 dose ]
  • Part B and Part C Cohorts 2 and 3: AUC0-∞ of multiple oral doses [ Time Frame: 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 [ Time Frame: Baseline through Day 35 ]
  • Part B and Part C Cohorts 2 and 3: change in sweat chloride over time [ Time Frame: Baseline through Day 35 ]
  • Part B and Part C Cohorts 2 and 3: change in weight over time [ Time Frame: Baseline through Day 35 ]
  • Part C Cohort 1: t1/2 of multiple oral doses [ Time Frame: Baseline through Day 42 ]
  • Part C Cohort 1: Tmax of multiple oral doses [ Time Frame: Baseline through Day 42 ]
  • Part C Cohort 1: Cmax of multiple oral doses [ Time Frame: Baseline through Day 42 ]
  • Part C Cohort 1: AUC0-t of multiple oral doses [ Time Frame: Baseline through Day 42 ]
  • Part C Cohort 1: AUC0-∞ of multiple oral doses [ Time Frame: Baseline through Day 42 ]
  • Part C Cohort 1: change in FEV1 over time [ Time Frame: Baseline through Day 49 ]
  • Part C Cohort 1: change in sweat chloride over time [ Time Frame: Baseline through Day 49 ]
  • Part C Cohort 1: change in weight over time [ Time Frame: Baseline through Day 49 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2016)
  • SAD: apparent terminal half-life (t1/2) of single oral dose [ Time Frame: through 72-hours post dose ]
  • SAD: time to reach maximum plasma concentration (Tmax) of single oral dose [ Time Frame: through 72-hours post dose ]
  • SAD: maximum plasma concentration (Cmax) of single oral dose [ Time Frame: 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 [ Time Frame: through 72-hours post dose ]
  • MAD: Apparent terminal half-life (t1/2) of multiple oral doses [ Time Frame: through 72 hours post day 7 dose ]
  • MAD: Time to reach maximum plasma concentration (Tmax) of multiple oral doses [ Time Frame: through 72 hours post day 7 dose ]
  • MAD: Maximum plasma concentration (Cmax) of multiple oral doses [ Time Frame: through 72 hours post day 7 dose ]
  • MAD: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of multiple oral doses [ Time Frame: through 72 hours post day 7 dose ]
  • MAD: area under the concentration-time curve from time 0 to infinity (AUC0-∞) of multiple oral doses [ Time Frame: through 72 hours post day 7 dose ]
Current Other Pre-specified Outcome Measures
 (submitted: April 27, 2017)
  • SAD: change in nasal epithelial CFTR mRNA and protein expression [ Time Frame: Baseline through Day 7 ]
  • MAD: change in nasal epithelial CFTR mRNA and protein expression [ Time Frame: Baseline through Day 14 ]
  • MAD: change in sweat chloride over time [ Time Frame: Baseline through Day 14 ]
  • Part B and Part C Cohorts 2 and 3: change in nasal epithelial CFTR mRNA and protein expression [ Time Frame: Baseline through Day 35 ]
  • Part B and Part C Cohorts 2 and 3: change in CFQ-R over time [ Time Frame: Baseline through Day 28 ]
  • Part C Cohort 1: change in nasal epithelial CFTR mRNA and protein expression [ Time Frame: Baseline through Day 49 ]
  • Part C Cohort 1: change in CFQ-R over time [ Time Frame: Baseline through Day 42 ]
  • Part C Cohort 3: change in fecal elastase over time [ Time Frame: Baseline through Day 35 ]
  • Part C Cohort 3: change in fecal calprotectin over time [ Time Frame: Baseline through Day 35 ]
Original Other Pre-specified Outcome Measures
 (submitted: March 18, 2016)
  • SAD: Change from baseline in cystic fibrosis transmembrane conductance regulator (CFTR) expression. [ Time Frame: baseline to 7 days ]
  • MAD: Change from baseline in CFTR expression. [ Time Frame: baseline to 14 days ]
  • MAD: Change from baseline in sweat chloride concentration. [ Time Frame: baseline to 14 days ]
 
Descriptive Information
Brief Title  ICMJE Study Assessing PTI-428 Safety, Tolerability, and Pharmacokinetics in Subjects With Cystic Fibrosis
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE
  • Drug: PTI-428
  • Drug: Placebo
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: PTI-428
    • Drug: Placebo
  • 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.
    Interventions:
    • Drug: PTI-428
    • Drug: Placebo
  • 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.
    Interventions:
    • Drug: PTI-428
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 9, 2018)
56
Original Estimated Enrollment  ICMJE
 (submitted: March 18, 2016)
36
Actual Study Completion Date  ICMJE November 28, 2017
Actual Primary Completion Date November 28, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Denmark,   France,   Germany,   United States
Removed Location Countries Czechia,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT02718495
Other Study ID Numbers  ICMJE PTI-428-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Proteostasis Therapeutics, Inc.
Study Sponsor  ICMJE Proteostasis Therapeutics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Proteostasis Therapeutics, Inc.
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP