Clinical trial NCT03140527: 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
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer
Cystic Fibrosis
Lead sponsor: Proteostasis Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2017-05-04
Enrollment: 171
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This trial will consist of two parts: Part 1 and Part 2. Part 1 will enroll adult healthy volunteers (HV) into four treatment groups. The first group will enroll HV into a single ascending dose (SAD) treatment group consisting of three cohorts. The second group will enroll HV into a multiple ascending dose (MAD) treatment group consisting of three cohorts. The third group will enroll HV into a food effect (FE) treatment group consisting of one cohort. The fourth group will enroll HV into a drug-drug interactions (DDI) treatment group consisting of one cohort. Approximately 76 subjects will be enrolled in Part 1.

Part 2 Cohorts 1 through 3 will enroll adult subjects with cystic fibrosis (CF) currently on stable ivacaftor/lumacaftor background therapy for a minimum of three months. Part 2 Cohorts 4 and Cohort 5 will enroll adult subjects with CF not currently receiving cystic fibrosis conductance regulator (CFTR) modulator therapy within 30 days prior to Day 1. Part 2 Cohort 6 will enroll adult subjects with cystic fibrosis on stable tezacaftor/ivacaftor background therapy. Approximately 104 subjects will be enrolled in Part 2.

Detailed description: PART 1 The SAD treatment group is comprised of three cohorts where HV will be randomized to either PTI-801 or placebo. The MAD treatment group is comprised of three cohorts where subjects will be randomized to receive either PTI-801 or placebo once daily (QD) for a total of 7 days. HV will participate in a FE treatment group ,the FE treatment group is comprised of one cohort where subjects will be randomized to receive an initial single dose of PTI-801 either after an overnight fast of at least 10 hours (fasted group) or after an overnight fast of at least 10 hours followed by the consumption of a high fat high and high calorie meal (fed group). A set of HV will participate in a DDI treatment group. The DDI treatment group is comprised of one cohort where subjects will receive a 3-drug cocktail consisting of caffeine, bupropion, and midazolam on Day 1. On Day 4, subjects will be randomized to receive either PTI-801 or placebo QD for a total of 12 days. On Day 17, subjects will receive the 3-drug cocktail in combination with PTI-801 or placebo.

PART 2 Part 2 is comprised of a MAD treatment group with three cohorts, a co-administration group with two cohorts and a treatment group with one cohort.

Following the conclusion of the complementary HV MAD Cohort in Part 1, a set of adult subjects diagnosed with CF currently on a stable ivacaftor/lumacaftor background therapy for a minimum of three months will participate in the Part 2 complementary CF MAD cohort. Subjects will be randomized to receive either PTI-801 or placebo QD for a total of 14 days.

Following the conclusion of CF MAD Cohort 1 in Part 2, a set of adult subjects diagnosed with CF not currently receiving or have received background CFTR modulator therapy for a minimum of 30 days prior to Day 1 will participate in the Part 2 CF PTI-801 and PTI-808 co-administration cohort. Subjects will be randomized to receive either PTI-801 co-administered with PTI-808 or placebos QD for a total of 14 days.

Following the conclusion of the CF MAD Cohort 1 in Part 2, a set of adult subjects diagnosed with CF currently on a stable tezacaftor/ivacaftor background therapy for a minimum of one month will participate in the Part 2 complementary CF cohort. Subjects will be randomized to receive either PTI-801 or placebo QD for a total of 14 days.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: baseline to up to 14 days
measure: Part 1 SAD: Apparent terminal half-life (t1/2) of single oral dose
timeFrame: through 72-hours post dose
measure: Part 1 SAD: Time to reach maximum plasma concentration (Tmax) of single oral dose
timeFrame: through 72-hours post dose
measure: Part 1 SAD: Maximum plasma concentration (Cmax) of single oral dose
timeFrame: through 72-hours post dose
measure: Part 1 SAD: Area under the concentration-time curve from time 0 to 24 hours post administration (AUC0-24) of a single oral dose
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: Part 1 SAD: AUC from time 0 to infinity (AUC0-inf)
timeFrame: through 72-hours post dose
measure: Part 1 MAD HV: Apparent terminal half-life (t1/2) of multiple oral doses
timeFrame: through 72-hours post last dose
measure: Part 1 MAD HV: Time to reach maximum plasma concentration (Tmax) of multiple oral doses
timeFrame: through 72-hours post last dose
measure: Part 1 MAD HV: Maximum plasma concentration (Cmax) of multiple oral doses
timeFrame: through 72-hours post last dose
measure: Part 1 MAD HV: Area under the concentration-time curve from time 0 to 24 hours post administration (AUC0-24) of multiple oral doses
timeFrame: through 72-hours post dose
measure: Part 1 MAD HV: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast) of multiple oral doses
timeFrame: through 72-hour post last dose
measure: Part 1 MAD HV: AUC from time 0 to infinity (AUC0-inf) of multiple oral doses
timeFrame: through 72-hour post last dose
measure: Part 1 MAD HV: Cumulative amount of PTI-801 excreted unchanged in urine (Ae) as appropriate of multiple oral doses
timeFrame: through 24-hour post last dose
measure: Part 1 MAD HV: Cumulative amount of PTI-801 unchanged in renal clearance (CLR) as appropriate of multiple oral doses
timeFrame: through 24-hour post last dose
measure: Part 1 FE: Time to reach maximum plasma concentration (Tmax)
timeFrame: through 72-hour post last dose
measure: Part 1 FE :Maximum plasma concentration (Cmax)
timeFrame: through 72-hour post last dose
measure: Part 1 FE: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUCt)
timeFrame: through 72-hour post last dose
measure: Part 1 FE: AUC from time 0 to infinity (AUC0-inf)
timeFrame: through 72-hour post last dose
measure: 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
timeFrame: baseline through 7 days post last dose
measure: Part 1 DDI: Maximum plasma concentration (Cmax) of caffeine, bupropion, and midazolam with and without multiple oral doses of PTI-801
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: 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
timeFrame: baseline through Day 21
Secondary outcomes:
measure: 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
timeFrame: baseline through 7 days post last dose
measure: Part 1 DDI: Apparent terminal half-life (t1/2) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: Part 1 DDI: Time to reach maximum plasma concentration (Tmax) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam
timeFrame: through 72-hours post dose
measure: Part 1 DDI: Maximum plasma concentration (Cmax) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam
timeFrame: through 72-hours post dose
measure: 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
timeFrame: through 72-hours post dose
measure: Part 2 CF: Time to reach maximum plasma concentration (Tmax)
timeFrame: Day 1 through Day 15
measure: Part 2 CF: Maximum plasma concentration (Cmax)
timeFrame: Day 1 through Day 15
measure: Part 2 CF: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast)
timeFrame: Day 1 through Day 15
measure: 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
timeFrame: Day 1 through Day 15
measure: Part 2 CF: change in forced expiratory volume in one second (FEV1) over time
timeFrame: baseline through Day 21
Other outcomes:
measure: Part 1 SAD, MAD HV, and FE: The effect of PTI-801 on the QT interval as measured by holter monitoring
timeFrame: baseline through 7 days post last dose
measure: Part 1: change in nasal epithelial mRNA and protein expression over time
timeFrame: baseline through 7 days post last dose
measure: Part 2 CF: change in sweat chloride over time
timeFrame: baseline through Day 21
measure: Part 2 CF: change in nasal epithelial mRNA and protein expression over time
timeFrame: baseline through Day 21
measure: Part 2 CF: change in weight and BMI over time
timeFrame: baseline through Day 21
measure: Part 2 CF: change in blood glucose over time
timeFrame: baseline through Day 21
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Anchorage
country: United States
facility: Providence Alaska Medical Center
state: Alaska
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Altamonte Springs
country: United States
facility: Central Florida Pulmonary Group
state: Florida
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Miami
country: United States
facility: University of Miami Health System
state: Florida
city: Boise
country: United States
facility: St. Luke's CF Center of Idaho
state: Idaho
city: Chicago
country: United States
facility: Northwestern University Memorial Hospital
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Kansas City
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Children's Lung Specialists
state: Nevada
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Beth Israel
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Toledo
country: United States
facility: Toledo Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: Santiago Reyes, M.D. P.C.
state: Oklahoma
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: San Antonio
country: United States
facility: ICON Early Phase Services
state: Texas
city: Tyler
country: United States
facility: University of Texas Health Science Center at Tyler
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Quebec
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Quebec
city: Copenhagen
country: Denmark
facility: University of Copenhagen Rigshospitalet
city: Berlin
country: Germany
facility: Charite - Campus Virchow-Klinikum
city: Stockholm
country: Sweden
facility: Stockholm CF Center
Study officials:
References: