Study Assessing the Safety, Tolerability, Pharmacokinetics, Food Effect, and Drug-Drug Interactions of PTI-801 in Healthy Volunteers, and Safety, Tolerability, and Pharmacokinetics of PTI-801 in Subjects With Cystic Fibrosis

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03140527
• Date of registration: 27/04/2017
• Prospective Registration: No
• Primary sponsor: Proteostasis Therapeutics, Inc.
• Public title: Study Assessing the Safety, Tolerability, Pharmacokinetics, Food Effect, and Drug-Drug Interactions of PTI-801 in Healthy Volunteers, and Safety, Tolerability, and Pharmacokinetics of PTI-801 in Subjects With Cystic Fibrosis
• Scientific title: A Multi-Center, Randomized, Placebo-Controlled, Phase 1, Two-Part Study Designed to Assess the Safety, Tolerability, Pharmacokinetics, Food Effect, and Drug-Drug Interactions of PTI-801 in Healthy Volunteers, and Safety, Tolerability, and Pharmacokinetics of PTI-801 in Subjects With Cystic Fibrosis
• Date of first enrolment: April 10, 2017
• Target sample size: 171
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03140527
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 1

Countries of recruitment

Canada, Denmark, Germany, Portugal, Sweden, United States

Key inclusion & exclusion criteria

Part 1 Inclusion Criteria:

- Adults age 18 to 55 years old, inclusive, at the time of informed consent.

- Body mass index (BMI) =18 to <30 kg/m2.

- Subject must be a nonsmoker and a nontobacco user for a minimum of 30 days prior to
screening and for the duration of the study.

Part 1 Exclusion Criteria:

- History or current evidence of any clinically significant cardiac,
endocrinologic,hematologic, hepatobiliary, immunologic, metabolic, urologic,
pulmonary, neurologic,dermatologic, psychiatric, renal, or other major disease, as
determined by the investigator.

- Presence of prolonged QT/ Corrected QT Interval (QTc) interval with Fridericia's
correction formula (QTcF) >450 msec at screening.

- Abnormal liver function as defined by aspartate aminotransferase (AST), alanine
aminotransferase (ALT) or bilirubin > upper limit of the normal range.

- Abnormal renal function at screening defined as: Creatinine clearance <80 mL/min using
the Cockcroft-Gault equation.

- 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 5 years (excluding nonmelanoma skin cancer).

- History or current evidence of alcohol or drug abuse or dependence within 12 months of
screening as determined by the investigator.

- Positive urine screen for prohibited drugs (cocaine, cannabinoids, nicotine [urine
cotinine is the detection mechanism for nicotine], opiates, barbiturates,
amphetamines, and benzodiazepines) or positive alcohol test at screening.

- Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface
antigen (HBsAg), or hepatitis C virus antibody (HCVAb).

- Has donated blood within 3 months of screening or plans to donate blood within 3
months of study completion.

Part 1 HV DDI Cohort Additional Exclusion Criteria:

- Concomitant use of known strong or moderate inhibitors or inducers of CYP1A2, CYP2B6,
and CYP3A4 within 14 days or 5 half-lives (whichever is longer) prior to Day 1 and
through the last PK sampling point on Day 20

- Use of grapefruit- or Seville orange-containing products within 48 hours prior to Day
1 and through the last PK sampling point on Day 20

- Use of alcohol- or caffeine-containing products within 48 hours prior to Day 1 and
through the last PK sampling point on Day 20

Part 2 Inclusion Criteria:

- Confirmed diagnosis of CF with the F508del/F508del genotype 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

Part 2 Cohorts 1-3 Additional Inclusion Criterion:

- Stable on ivacaftor/lumacaftor dosing for both label indication and per label dosing
for a minimum of 3 months at the time of dosing

Part 2 Cohort 6 Additional Inclusion Criterion:

- Stable on tezacaftor/ivacaftor dosing for both label indication and per label dosing
for a minimum of 1 month at the time dosing

Part 2 Exclusion Criteria:

- 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 (excluding cervical cancer in situ with
curative therapy for at least one year prior to screening and non-melanoma skin
cancer)

- 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

Part 2 Cohort's 4 and 5 Additional Exclusion Criterion:

- Currently taking or has taken a CFTR modulator within 30 days prior to initial dose of
study drugs



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Cystic Fibrosis

Healthy Volunteer

Intervention(s)

Drug: PTI-801

Drug: PTI-808

Drug: Placebo

Primary Outcome(s)

Part 1 DDI: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast) of caffeine, bupropion, and midazolam with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 1 FE :Maximum plasma concentration (Cmax) [Time Frame: through 72-hour post last dose]

Part 1 MAD HV: Cumulative amount of PTI-801 excreted unchanged in urine (Ae) as appropriate of multiple oral doses [Time Frame: through 24-hour post last dose]

Part 1 SAD and MAD HV: 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 up to 14 days]

Part 1 SAD: Area under the concentration-time curve from time 0 to 24 hours post administration (AUC0-24) of a single oral dose [Time Frame: through 72-hours post dose]

Part 1 FE: Time to reach maximum plasma concentration (Tmax) [Time Frame: through 72-hour post last dose]

Part 1 SAD: Apparent terminal half-life (t1/2) of single oral dose [Time Frame: through 72-hours post dose]

Part 1 DDI: Area under the concentration-time curve from time 0 to infinity (AUCinf) of caffeine, bupropion, and midazolam with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 1 MAD HV: Apparent terminal half-life (t1/2) of multiple oral doses [Time Frame: through 72-hours post last dose]

Part 1 SAD: Time to reach maximum plasma concentration (Tmax) of single oral dose [Time Frame: through 72-hours post dose]

Part 1 SAD: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUC0-last) of a single oral dose [Time Frame: through 72-hours post dose]

Part 1 SAD: Maximum plasma concentration (Cmax) of single oral dose [Time Frame: through 72-hours post dose]

Part 2 CF: 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 through Day 21]

Part 1 DDI: Maximum plasma concentration (Cmax) of caffeine, bupropion, and midazolam with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 1 SAD: AUC from time 0 to infinity (AUC0-inf) [Time Frame: through 72-hours post dose]

Part 1 DDI: 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 through 7 days post last dose]

Part 1 FE: AUC from time 0 to infinity (AUC0-inf) [Time Frame: through 72-hour post last dose]

Part 1 MAD HV: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast) of multiple oral doses [Time Frame: through 72-hour post last dose]

Part 1 FE: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUCt) [Time Frame: through 72-hour post last dose]

Part 1 MAD HV: Cumulative amount of PTI-801 unchanged in renal clearance (CLR) as appropriate of multiple oral doses [Time Frame: through 24-hour post last dose]

Part 1 MAD HV: Area under the concentration-time curve from time 0 to 24 hours post administration (AUC0-24) of multiple oral doses [Time Frame: through 72-hours post dose]

Part 1 MAD HV: Time to reach maximum plasma concentration (Tmax) of multiple oral doses [Time Frame: through 72-hours post last dose]

Part 1 MAD HV: AUC from time 0 to infinity (AUC0-inf) of multiple oral doses [Time Frame: through 72-hour post last dose]

Part 1 MAD HV: Maximum plasma concentration (Cmax) of multiple oral doses [Time Frame: through 72-hours post last dose]

Secondary Outcome(s)

Part 1 DDI: Metabolite over parent ratio of AUClast of the metabolites of caffeine, bupropion, and midazolam after single oral doses of caffeine, bupropion, midazolam, and with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 2 CF: change in forced expiratory volume in one second (FEV1) over time [Time Frame: baseline through Day 21]

Part 1 DDI: Area under the concentration-time curve from time 0 to 24 hours post administration (AUC0-24) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam [Time Frame: through 72-hours post dose]

Part 1 DDI: Maximum plasma concentration (Cmax) of the metabolites of caffeine, bupropion, and midazolam after single oral doses of caffeine, bupropion, midazolam, and with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 1 DDI: AUClast of the metabolites of caffeine, bupropion, and midazolam after single oral doses of caffeine, bupropion, midazolam, and with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 1 DDI: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam [Time Frame: through 72-hours post dose]

Part 1 FE: 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 through 7 days post last dose]

Part 1 DDI: Time to reach maximum plasma concentration (Tmax) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam [Time Frame: through 72-hours post dose]

Part 2 CF: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast) [Time Frame: Day 1 through Day 15]

Part 2 CF: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast) of multiple oral doses of PTI-808 with PTI-801 [Time Frame: Day 1 through Day 15]

Part 1 DDI: Apparent terminal half-life (t1/2) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam [Time Frame: through 72-hours post dose]

Part 1 DDI: Maximum plasma concentration (Cmax) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam [Time Frame: through 72-hours post dose]

Part 1 DDI: Metabolite over parent ratio of Cmax of single oral doses of the metabolites of caffeine, bupropion, and midazolam after single oral doses of caffeine, bupropion, midazolam, and with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 1 DDI: Time to reach maximum plasma concentration (Tmax) of the metabolites of caffeine, bupropion, and midazolam after single oral doses of caffeine, bupropion, midazolam, and with and without multiple oral doses of PTI-801 [Time Frame: through 72-hours post dose]

Part 2 CF: Maximum plasma concentration (Cmax) [Time Frame: Day 1 through Day 15]

Part 2 CF: Time to reach maximum plasma concentration (Tmax) [Time Frame: Day 1 through Day 15]

Secondary ID(s)

PTI-801-01

Source(s) of Monetary Support

Please refer to primary and secondary sponsors