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

Cystic Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03140527
• Other study ID #: PTI-801-01
• Status: Completed
• Phase: Phase 1
• Start date: April 10, 2017
• Est. completion date: February 27, 2020

Study information

• Verified date: April 2020
• Source: Proteostasis Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 171
• Est. completion date: February 27, 2020
• Est. primary completion date: February 27, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Healthy Volunteer

Intervention

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

Locations

Country	Name	City	State
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Quebec	Quebec
Canada	St. Paul's Hospital	Vancouver	British Columbia
Denmark	University of Copenhagen Rigshospitalet	Copenhagen
Germany	Charite - Campus Virchow-Klinikum	Berlin
Sweden	Stockholm CF Center	Stockholm
United States	Akron Children's Hospital	Akron	Ohio
United States	Central Florida Pulmonary Group	Altamonte Springs	Florida
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	St. Luke's CF Center of Idaho	Boise	Idaho
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University Memorial Hospital	Chicago	Illinois
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	National Jewish Health	Denver	Colorado
United States	Duke University Health System	Durham	North Carolina
United States	University of Florida College of Medicine	Gainesville	Florida
United States	University of Iowa	Iowa City	Iowa
United States	Children's Mercy Kansas City	Kansas City	Missouri
United States	Children's Lung Specialists	Las Vegas	Nevada
United States	University of Miami Health System	Miami	Florida
United States	Columbia University Medical Center	New York	New York
United States	Mount Sinai Beth Israel	New York	New York
United States	Santiago Reyes, M.D. P.C.	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of Utah	Salt Lake City	Utah
United States	ICON Early Phase Services	San Antonio	Texas
United States	Stanford University Medical Center	Stanford	California
United States	Toledo Children's Hospital	Toledo	Ohio
United States	University of Texas Health Science Center at Tyler	Tyler	Texas
United States	New York Medical College	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
Proteostasis Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  Germany,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Part 1: change in nasal epithelial mRNA and protein expression over time		baseline through 7 days post last dose
Other	Part 2 CF: change in sweat chloride over time		baseline through Day 21
Other	Part 2 CF: change in nasal epithelial mRNA and protein expression over time		baseline through Day 21
Other	Part 2 CF: change in weight and BMI over time		baseline through Day 21
Other	Part 2 CF: change in blood glucose over time		baseline through Day 21
Primary	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
Primary	Part 1 SAD: Apparent terminal half-life (t1/2) of single oral dose		through 72-hours post dose
Primary	Part 1 SAD: Time to reach maximum plasma concentration (Tmax) of single oral dose		through 72-hours post dose
Primary	Part 1 SAD: Maximum plasma concentration (Cmax) of single oral dose		through 72-hours post dose
Primary	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
Primary	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
Primary	Part 1 SAD: AUC from time 0 to infinity (AUC0-inf)	using noncompartmental methods as appropriate of single dose	through 72-hours post dose
Primary	Part 1 MAD HV: Apparent terminal half-life (t1/2) of multiple oral doses		through 72-hours post last dose
Primary	Part 1 MAD HV: Time to reach maximum plasma concentration (Tmax) of multiple oral doses		through 72-hours post last dose
Primary	Part 1 MAD HV: Maximum plasma concentration (Cmax) of multiple oral doses		through 72-hours post last dose
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Part 1 FE: Time to reach maximum plasma concentration (Tmax)		through 72-hour post last dose
Primary	Part 1 FE :Maximum plasma concentration (Cmax)		through 72-hour post last dose
Primary	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
Primary	Part 1 FE: AUC from time 0 to infinity (AUC0-inf)		through 72-hour post last dose
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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		through 72-hours post dose
Secondary	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		through 72-hours post dose
Secondary	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		through 72-hours post dose
Secondary	Part 1 DDI: Time to reach maximum plasma concentration (Tmax) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam		through 72-hours post dose
Secondary	Part 1 DDI: Maximum plasma concentration (Cmax) of multiple oral doses of PTI-801 with and without caffeine, bupropion, and midazolam		through 72-hours post dose
Secondary	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		through 72-hours post dose
Secondary	Part 2 CF: Time to reach maximum plasma concentration (Tmax)		Day 1 through Day 15
Secondary	Part 2 CF: Maximum plasma concentration (Cmax)		Day 1 through Day 15
Secondary	Part 2 CF: Area under the concentration-time curve from time 0 to time of last measurable concentration (AUClast)		Day 1 through Day 15
Secondary	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		Day 1 through Day 15
Secondary	Part 2 CF: change in forced expiratory volume in one second (FEV1) over time		baseline through Day 21

External Links

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