Cystic Fibrosis
Conditions
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.
Interventions
DRUGPTI-428
DRUGPlacebo
Sponsors
Proteostasis Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| 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 |
| 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 |
| 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 |
| 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 |
Secondary
| Measure | Time frame |
|---|---|
| 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: 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 |
| 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: 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 |
Other
| Measure | Time frame |
|---|---|
| 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 |
| SAD: change in nasal epithelial CFTR mRNA and protein expression | Baseline through Day 7 |
| MAD: change in sweat chloride over time | Baseline through Day 14 |
| MAD: change in nasal epithelial CFTR mRNA and protein expression | Baseline through Day 14 |
| Part B and Part C Cohorts 2 and 3: change in CFQ-R over time | Baseline through Day 28 |
| Part B and Part C Cohorts 2 and 3: change in nasal epithelial CFTR mRNA and protein expression | Baseline through Day 35 |
Countries
Canada, Denmark, France, Germany, United States
Outcome results
None listed