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

NCT03140527 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: PTI-801-01
• Study Type: interventional
• Target: 171
• Locations: 5 countries
• Sites: 38

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.

Conditions

Healthy Volunteer; Cystic Fibrosis

Outcome Measures

Primary Outcomes (24)

• 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

  baseline to up to 14 days

• Part 1 SAD: Apparent terminal half-life (t1/2) of single oral dose

  through 72-hours post dose

• Part 1 SAD: Time to reach maximum plasma concentration (Tmax) of single oral dose

  through 72-hours post dose

• Part 1 SAD: Maximum plasma concentration (Cmax) of single oral dose

  through 72-hours post dose

• Part 1 SAD: Area under the concentration-time curve from time 0 to 24 hours post administration (AUC0-24) of a single oral dose

  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

  through 72-hours post dose

• Part 1 SAD: AUC from time 0 to infinity (AUC0-inf)

  using noncompartmental methods as appropriate of single dose

  through 72-hours post dose

• Part 1 MAD HV: Apparent terminal half-life (t1/2) of multiple oral doses

  through 72-hours post last dose

• Part 1 MAD HV: Time to reach maximum plasma concentration (Tmax) of multiple oral doses

  through 72-hours post last dose

• Part 1 MAD HV: Maximum plasma concentration (Cmax) of multiple oral doses

  through 72-hours 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

  through 72-hours post 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

  through 72-hour post last dose

• Part 1 MAD HV: AUC from time 0 to infinity (AUC0-inf) of multiple oral doses

  using noncompartmental methods as appropriate of multiple oral doses

  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

  through 24-hour post last dose

• Part 1 MAD HV: Cumulative amount of PTI-801 unchanged in renal clearance (CLR) as appropriate of multiple oral doses

  through 24-hour post last dose

• Part 1 FE: Time to reach maximum plasma concentration (Tmax)

  through 72-hour post last dose

• Part 1 FE :Maximum plasma concentration (Cmax)

  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)

  through 72-hour post last dose

• Part 1 FE: AUC from time 0 to infinity (AUC0-inf)

  through 72-hour post last 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

  baseline through 7 days post last dose

• Part 1 DDI: Maximum plasma concentration (Cmax) of caffeine, bupropion, and midazolam with and without multiple oral doses of PTI-801

  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 caffeine, bupropion, and midazolam with and without multiple oral doses of PTI-801

  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

  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

  baseline through Day 21

Secondary Outcomes (16)

• 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

  baseline through 7 days post last dose

• Part 1 DDI: Apparent terminal half-life (t1/2) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam

  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

  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

  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

  through 72-hours post dose

Other Outcomes (6)

• Part 1 SAD, MAD HV, and FE: The effect of PTI-801 on the QT interval as measured by holter monitoring

  baseline through 7 days post last dose

• Part 1: change in nasal epithelial mRNA and protein expression over time

  baseline through 7 days post last dose

• Part 2 CF: change in sweat chloride over time

  baseline through Day 21

Study Arms (15)

SAD HV PTI-801 Active - Complete

ACTIVE COMPARATOR

The safety, tolerability, and pharmacokinetic profile of PTI-801 will be evaluated following a single dose of PTI-801. Three cohorts are planned for evaluation where subjects will be randomized to PTI-801 or placebo.The subjects will be followed for 7 days post dose.

Drug: PTI-801

SAD HV PTI-801 Placebo - Complete

PLACEBO COMPARATOR

The safety, tolerability, and pharmacokinetic profile of PTI-801 will be evaluated following a single dose of PTI-801. Three cohorts are planned for evaluation where subjects will be randomized to PTI-801 or placebo.The subjects will be followed for 7 days post dose.

Drug: Placebo

MAD HV PTI-801 Active - Complete

ACTIVE COMPARATOR

Following the conclusion of the respective SAD level dose groups and after sufficient review of study data and approval by the SRC, a second set of healthy adult subjects will participate in an assigned MAD treatment group. The MAD treatment group is comprised of 3 cohorts. Subjects will be randomized to either PTI-801 or placebo. Each dose will be administered once daily (QD) for a total of 7 days. Follow up visits will occur on Days 10, 12 and 14.

Drug: PTI-801

MAD HV PTI-801 Placebo - Complete

PLACEBO COMPARATOR

Following the conclusion of the respective SAD level dose groups and after sufficient review of study data and approval by the SRC, a second set of healthy adult subjects will participate in an assigned MAD treatment group. The MAD treatment group is comprised of 3 cohorts. Subjects will be randomized to either PTI-801 or placebo. Each dose will be administered once daily (QD) for a total of 7 days. Follow up visits will occur on Days 10, 12 and 14.

Drug: Placebo

FE HV PTI-801 Active - Complete

ACTIVE COMPARATOR

Following the conclusion of SAD groups and after sufficient review of study data and approval by the SRC, a third set of healthy adult subjects will participate in the Food Effect cohort. Subjects will be randomized to Fed or Fasted on Days 1 and 12. Follow up visits will occur 7 days post Day 12 dose.

Drug: PTI-801

DDI HV PTI-801 Active - Complete

ACTIVE COMPARATOR

Following the conclusion of HV MAD Cohort 2 and after sufficient review of study data and approval by the SRC, a fourth set of healthy adult subjects will participate in the Drug-Drug Interactions cohort. 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. Subjects will remain in clinic until Day 20. A follow up visit will occur on Day 24.

Drug: PTI-801

DDI HV PTI-801 Placebo - Complete

PLACEBO COMPARATOR

Following the conclusion of HV MAD Cohort 2 and after sufficient review of study data and approval by the SRC, a fourth set of healthy adult subjects will participate in the Drug-Drug Interactions cohort. 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. Subjects will remain in clinic until Day 20. A follow up visit will occur on Day 24.

Drug: Placebo

MAD Cohort 1-3 CF PTI-801 Active - Complete

ACTIVE COMPARATOR

Adult subjects diagnosed with CF currently on stable ivacaftor/lumacaftor background therapy for a minimum of three months will participate in the Part 2 complementary CF MAD cohort. The CF MAD treatment group is comprised of 3 cohorts. Subjects will be randomized to receive either PTI-801 or placebo QD for a total of 14 days. A follow up visit will occur on Day 21.

Drug: PTI-801

MAD Cohort 1-3 CF PTI-801 Placebo - Complete

PLACEBO COMPARATOR

Adult subjects diagnosed with CF currently on stable ivacaftor/lumacaftor background therapy for a minimum of three months will participate in the Part 2 complementary CF MAD cohort. The CF MAD treatment group is comprised of 3 cohorts. Subjects will be randomized to receive either PTI-801 or placebo QD for a total of 14 days. A follow up visit will occur on Day 21.

Drug: Placebo

Cohort 4 CF PTI-801 Active co-admin PTI-808 Active - Complete

ACTIVE COMPARATOR

Adult subjects diagnosed with CF not currently receiving a CFTR modulator therapy within 30 days prior to Day 1 will participate in the Part 2 CF Cohort 4. Subjects will be randomized to receive either PTI-801 co-administered with PTI-808 or placebos QD.

Drug: PTI-801; Drug: PTI-808

Cohort 4 CF PTI-801 Placebo co-admin PTI-808 Placebo- Complete

PLACEBO COMPARATOR

Adult subjects diagnosed with CF not currently receiving a CFTR modulator therapy within 30 days prior to Day 1 will participate in the Part 2 CF Cohort 4. Subjects will be randomized to receive either PTI-801 co-administered with PTI-808 or placebos QD.

Drug: Placebo

Cohort 5 CF PTI-801 Active co-admin with PTI-808 Active

ACTIVE COMPARATOR

Adult subjects diagnosed with CF not currently receiving a CFTR modulator therapy within 30 days prior to Day 1 will participate in the Part 2 CF Cohort 5. Subjects will be randomized to receive either PTI-801 co-administered with PTI-808 or placebos QD.

Drug: PTI-801; Drug: PTI-808

Cohort 5 CF PTI-801 Placebo co-admin with PTI-808 Placebo

PLACEBO COMPARATOR

Adult subjects diagnosed with CF not currently receiving a CFTR modulator therapy within 30 days prior to Day 1 will participate in the Part 2 CF Cohort 5. Subjects will be randomized to receive either PTI-801 co-administered with PTI-808 or placebos QD.

Drug: Placebo

Cohort 6 CF PTI-801 Active

ACTIVE COMPARATOR

Adult subjects diagnosed with CF currently on stable tezacaftor/ivacaftor background therapy for a minimum of one month will participate in the Part 2 complementary CF MAD cohort. Subjects will be randomized to receive either PTI-801 or placebo QD.

Drug: PTI-801

Cohort 6 CF PTI-801 Placebo

PLACEBO COMPARATOR

Adult subjects diagnosed with CF currently on stable tezacaftor/ivacaftor background therapy for a minimum of one month will participate in the Part 2 complementary CF MAD cohort. Subjects will be randomized to receive either PTI-801 or placebo QD.

Drug: Placebo

Interventions

PTI-801 DRUG

Active

Cohort 4 CF PTI-801 Active co-admin PTI-808 Active - Complete; Cohort 5 CF PTI-801 Active co-admin with PTI-808 Active; Cohort 6 CF PTI-801 Active; DDI HV PTI-801 Active - Complete; FE HV PTI-801 Active - Complete; MAD Cohort 1-3 CF PTI-801 Active - Complete; MAD HV PTI-801 Active - Complete; SAD HV PTI-801 Active - Complete

Placebo DRUG

Placebo

Cohort 4 CF PTI-801 Placebo co-admin PTI-808 Placebo- Complete; Cohort 5 CF PTI-801 Placebo co-admin with PTI-808 Placebo; Cohort 6 CF PTI-801 Placebo; DDI HV PTI-801 Placebo - Complete; MAD Cohort 1-3 CF PTI-801 Placebo - Complete; MAD HV PTI-801 Placebo - Complete; SAD HV PTI-801 Placebo - Complete

PTI-808 DRUG

Active

Cohort 4 CF PTI-801 Active co-admin PTI-808 Active - Complete; Cohort 5 CF PTI-801 Active co-admin with PTI-808 Active

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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
• 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

Sponsors & Collaborators

• Proteostasis Therapeutics, Inc.: lead

Study Sites (38)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Providence Alaska Medical Center

Anchorage, Alaska, 99508, United States

Location

Stanford University Medical Center

Stanford, California, 94305, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

Central Florida Pulmonary Group

Altamonte Springs, Florida, 32803, United States

Location

University of Florida College of Medicine

Gainesville, Florida, 32610, United States

Location

University of Miami Health System

Miami, Florida, 33136, United States

Location

St. Luke's CF Center of Idaho

Boise, Idaho, 83712, United States

Location

Northwestern University Memorial Hospital

Chicago, Illinois, 60611, United States

Location

OSF Saint Francis Medical Center

Peoria, Illinois, 61637, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109, United States

Location

Children's Mercy Kansas City

Kansas City, Missouri, 64108, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Children's Lung Specialists

Las Vegas, Nevada, 89107, United States

Location

Columbia University Medical Center

New York, New York, 10001, United States

Location

Mount Sinai Beth Israel

New York, New York, 10003, United States

Location

New York Medical College

Valhalla, New York, 10595, United States

Location

Duke University Health System

Durham, North Carolina, 27710, United States

Location

Akron Children's Hospital

Akron, Ohio, 44308, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Toledo Children's Hospital

Toledo, Ohio, 43606, United States

Location

Santiago Reyes, M.D. P.C.

Oklahoma City, Oklahoma, 73112, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15244, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

ICON Early Phase Services

San Antonio, Texas, 78209, United States

Location

University of Texas Health Science Center at Tyler

Tyler, Texas, 75708, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

St. Paul's Hospital

Vancouver, British Columbia, V6Z1Y6, Canada

Location

Institut Universitaire de Cardiologie et de Pneumologie de Quebec

Québec, G1V 4G5, Canada

Location

University of Copenhagen Rigshospitalet

Copenhagen, 2100, Denmark

Location

Charite - Campus Virchow-Klinikum

Berlin, 10117, Germany

Location

Stockholm CF Center

Stockholm, 141 86, Sweden

Location

MeSH Terms

Conditions

Cystic Fibrosis

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2017
• First Posted: May 4, 2017
• Study Start: April 10, 2017
• Primary Completion: February 27, 2020
• Study Completion: February 27, 2020
• Last Updated: April 30, 2020

Record last verified: 2020-04

Locations

US (33); SE (1); CA (2); DE (1); DK (1)