Safety, Tolerability, and Pharmacokinetics of PTI-808, PTI-801, and PTI-428 Combination Therapy in Subjects With Cystic Fibrosis

A Phase 1 / 2, Randomized, Double-Blind, Placebo-Controlled Study Designed to Evaluate the Safety, Tolerability, and Pharmacokinetics of PTI-808, PTI-801, and PTI-428 Combination Therapy in Subjects With Cystic Fibrosis

The study is a randomized, double-blind, placebo-controlled, study that will be conducted at multiple centers in subjects with Cystic Fibrosis (CF) who are either homozygous for the F508del mutation or heterozygous with at least copy of the F508del mutation.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Placebo; Drug: PTI-801; Drug: PTI-808; Drug: PTI-428

Detailed Description

Study PTI-808-02 will enroll up to approximately 32 subjects. Subjects in the first cohort will receive PTI-808 and PTI-801. Following completion of Cohort 1, initiation of enrollment into subsequent cohorts will be based upon review and approval by the Safety Review Committee (SRC).

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Belfast, United Kingdom, BT9 6AD
    • Celerion
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital
  • Glasgow, United Kingdom, G514TF
    • Queen Elizabeth University Hospital
  • Manchester, United Kingdom
    • Medicines Evaluation Unit

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:

• Cohorts 1,2 and 4: A Confirmed diagnosis of CF with the F508del/F508del CFTR genotype on record, along with clinical findings consistent with CF such as chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities
• Cohort 3 only: Confirmed diagnosis of CF with at least one copy of the F508del CFTR mutation on record, along with clinical findings consistent with CF, such as chronic sinopulmonary disease or gastrointestinal / nutritional abnormalities
• Forced expiratory volume in 1 second (FEV1) 40-90% predicted, inclusive
• Non-smoker and non-tobacco user for a minimum of 30 days prior to screening
• Cohort 3 only: A sweat chloride value of ≥60 mmol/L based on quantitative pilocarpine iontophoresis (as documented in the subject's medical record or as confirmed at the screening visit)

Exclusion Criteria:

• Currently taking or has taken a CFTR modulator within 30 days prior to initial dose of study drugs
• Participation in another clinical trial or treatment with an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Study Day 1
• History of cancer within the past 5 years
• History of organ transplantation
• Hospitalization, sinopulmonary infection, CF exacerbation, or other clinically significant infection or illness (as determined by the investigator) requiring an increase or addition of medication, such as antibiotics or corticosteroids, within 14 days of Day 1
• Initiation of any new chronic therapy (e.g., ibuprofen, hypertonic saline, azithromycin, Pulmozyme®, Cayston®, TOBI®) or any change in chronic therapy (excluding pancreatic enzyme replacement therapy) within 28 days prior to Day 1
• History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
• Pregnant or nursing women

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohorts 1 and 2: PTI-808 Active Co-admin with PTI-801 Active; Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21.	Drug: PTI-801; Active; Drug: PTI-808; Active
Placebo Comparator: Cohorts 1 and 2: PTI-808 Placebo Co-admin with PTI-801 Placebo; Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21.	Drug: Placebo; Placebo
Active Comparator: Cohort 3 PTI-808 Active + PTI-801 Active + PTI-428 Active; Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21.	Drug: PTI-801; Active; Drug: PTI-808; Active; Drug: PTI-428; Active
Placebo Comparator: Cohort 3 PTI-808 placebo + PTI-801 Placebo + PTI-428 Placebo; Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for a total of 14 days. A follow up visit will occur on Day 21.	Drug: Placebo; Placebo
Active Comparator: Cohort 4 PTI-808 Active + PTI-801 Active + PTI-428 Active; Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for 7 days immediately followed by PTI-808 co-administered with PTI-801 or placebos once-a-day for 7 days. A follow-up visit will occur on Day 21.	Drug: PTI-801; Active; Drug: PTI-808; Active; Drug: PTI-428; Active
Placebo Comparator: Cohort 4 PTI-808 Placebo + PTI-801 Placebo + PTI-428 Placebo; Subjects will be randomized to receive either PTI-808 co-administered with PTI-801 and PTI-428 or placebos once-a-day for 7 days immediately followed by PTI-808 co-administered with PTI-801 or placebos once-a-day for 7 days. A follow-up visit will occur on Day 21.	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability measured by the number of subjects who experience adverse events and potentially significant clinical laboratory assessments, electrocardiography, physical examinations, vital signs.	Baseline through Day 21

Secondary Outcome Measures

Outcome Measure	Time Frame
Apparent terminal half-life (t1/2) of multiple oral doses of PTI-808 + PTI-801 and PTI-428 (cohorts 3 & 4 only)	Day 1 through 15
Time to reach maximum plasma concentration (Tmax) of multiple oral doses of PTI-808 + PTI-801 and PTI-428 (cohorts 3 & 4 only)	Day 1 through 15
Maximum plasma concentration (Cmax) of multiple oral doses of PTI-808 + PTI-801 and PTI-428 (cohorts 3 & 4 only)	Day 1 through 15
Change in FEV1 over time	Baseline through Day 21

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in sweat chloride over time		Baseline through Day 21
Change in weight over time		Baseline through Day 21
Change in BMI over time		Baseline through Day 21
Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain results over time	Disease-specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms. Developed specifically for use in patients with a diagnosis of cystic fibrosis. Scaling of items: 5 distinct 4-point Likert scales (e.g., always/often/ sometime/never) Scoring: Scores for each HRQoL domain; after recoding, each item is summed to generate a domain score and standardized. Scores range from 0 to 100, with higher scores indicating better health.	Baseline through Day 21
Change in nasal epithelial mRNA expression over time		Baseline through Day 21
Change in nasal protein expression over time		Baseline through Day 21

Collaborators and Investigators

• Sponsor: Proteostasis Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2018
• Primary Completion (Actual): March 13, 2019
• Study Completion (Actual): March 13, 2019

Study Registration Dates

• First Submitted: April 9, 2018
• First Submitted That Met QC Criteria: April 13, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): April 6, 2020
• Last Update Submitted That Met QC Criteria: March 31, 2020
• Last Verified: March 1, 2020

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-808-02

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No