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

• ClinicalTrials.gov Identifier: NCT03500263
• Recruitment Status: Completed
• First Posted: April 18, 2018
• Last Update Posted: April 6, 2020
• Sponsor: Proteostasis Therapeutics, Inc.
• Information provided by (Responsible Party): Proteostasis Therapeutics, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: PTI-808; Drug: Placebo; Drug: PTI-801; Drug: PTI-428	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 30, 2018
• Actual Primary Completion Date: March 13, 2019
• Actual Study Completion Date: March 13, 2019

Arms and Interventions

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-808; Active; Drug: PTI-801; 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-808; Active; Drug: PTI-801; 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; 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-808; Active; Drug: PTI-801; 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; Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Other Outcome Measures:

1. Change in sweat chloride over time [ Time Frame: Baseline through Day 21 ]
2. Change in weight over time [ Time Frame: Baseline through Day 21 ]
3. Change in BMI over time [ Time Frame: Baseline through Day 21 ]
4. Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain results over time [ Time Frame: Baseline through Day 21 ]

   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.

5. Change in nasal epithelial mRNA expression over time [ Time Frame: Baseline through Day 21 ]
6. Change in nasal protein expression over time [ Time Frame: Baseline through Day 21 ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United Kingdom

Celerion

Belfast, United Kingdom, BT9 6AD

Western General Hospital

Edinburgh, United Kingdom, EH4 2XU

Queen Elizabeth University Hospital

Glasgow, United Kingdom, G514TF

Medicines Evaluation Unit

Manchester, United Kingdom

Sponsors and Collaborators

Proteostasis Therapeutics, Inc.

More Information

• Responsible Party: Proteostasis Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03500263
• Other Study ID Numbers: PTI-808-02
• First Posted: April 18, 2018
• Last Update Posted: April 6, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases