Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis

NCT03251092 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: PTI-808-01
• Study Type: interventional
• Target: 179
• Locations: 9 countries
• Sites: 48

Brief Summary

Part 1 of this trial will enroll healthy volunteers into a single ascending dose (SAD), multiple ascending dose (MAD), and Food Effect (FE) treatment groups. The SAD treatment group is comprised of at least 3 ascending dose level cohorts where healthy adult subjects will be randomized to receive a single dose of either PTI-808 or placebo and will be followed for 7 days post dose. A safety review committee (SRC) will convene after the completion of each cohort to evaluate safety and pharmacokinetic (PK) data. 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 ascending dose level cohorts where subjects will be randomized to receive either PTI-808 or placebo daily for 7 days and will be followed for 7 days after receiving the last dose. Also following the conclusion of the respective SAD level dose groups, healthy adult subjects will participate in the FE treatment group. Part 2 of this will enroll healthy volunteers to assess the safety, tolerability, and PK of PTI 808 co administered with PTI 801 and PTI 428 to HVs with daily dosing for 7 consecutive days. Part 3 will enroll adult subjects with cystic fibrosis (CF) into a MAD treatment group consisting of 2 cohorts. Subjects will receive PTI-808 co-administered with PTI-801 and PTI-428. PTI-808 will be administered daily for 7 consecutive days followed by PTI-808 + PTI-801 + PTI-428 administered daily for 14 consecutive days. Part 4 will enroll adult subjects with cystic fibrosis (CF) into 28-day cohorts. Subjects will receive PTI-808 co-administered with PTI-801 with or without PTI-428 versus matching placebo.

Conditions

Healthy Volunteer - Complete; Cystic Fibrosis - Complete

Outcome Measures

Primary Outcomes (30)

• Part 1 SAD and MAD: Adverse Events

  Safety and tolerability measure by number of subjects who experience adverse events

  Baseline to up to 14 days

• Part 1 SAD and MAD: Physical Exams

  Safety and tolerability measure by number of subjects who experience potential clinically significant changes in physical examinations

  Baseline to up to 14 days

• Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in vital signs

  Safety and tolerability measure by number of subjects who experience potential clinically significant changes in vital signs

  Baseline to up to 14 days

• Part 1 SAD and MAD: ECGs

  Safety and tolerability measure by number of subjects who experience potential clinically significant changes in ECGs

  Baseline to up to 14 days

• Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in safety labs

  Safety and tolerability measure by number of subjects who experience potential clinically significant changes in safety labs

  Baseline to up to 14 days

• Part 1 SAD and FE: terminal half life

  Apparent terminal half-life (t1/2) of single oral dose

  Through 72 hours post dose

• Part 1 SAD and FE : Tmax

  Time to reach maximum plasma concentration (Tmax) of single oral dose

  Through 72 hours post dose

• Part 1 SAD and FE: Cmax

  Maximum plasma concentration (Cmax) of single oral dose

  Through 72 hours post dose

• Part 1 SAD : AUC

  Area under the concentration-time curve from time 0 to 24 hours post dose (AUC 0-24) of single oral dose

  Through 24 hours post dose

• Part 1 SAD and FE: AUC0

  AUC from time 0 to time of last measurable concentration (AUC0-last) of single oral dose

  Through 72 hours post dose

• Part 1 SAD and FE: AUC0-inf

  AUC from time 0 to infinity (AUC0-inf) of single dose

  Through 72 hours post dose

• Part 1 MAD: t1/2

  t1/2 of multiple oral dose

  Through 72 hours post dose

• Part 1 MAD: Tmax

  Tmax of multiple oral doses

  Through 72 hours post dose

• Part 1 MAD: Cmax

  Cmax of multiple oral doses

  Through 72 hours post last dose

• Part 1 MAD: AUC0-24

  AUC0-24 of multiple oral dose

  Through 24 hours post last dose

• Part 1 MAD: AUC0-last

  AUC0-last of multiple oral doses

  Through 72 hours post last dose

• Part 1 MAD: Urine

  Cumulative amount of PTI-808 excreted unchanged in urine (Ae) as appropriate of multiple oral doses

  Through 24 hours post last dose

• Part 1 MAD: CLR

  Renal clearance (CLR) of multiple oral doses

  Through 24 hours post dose

• Part 2: Physical Exams

  Safety and tolerability measure by number of subjects who experience potential clinically significant changes in physical examinations

  Baseline up to 14 days

• Part 2: ECGs

  Safety and tolerability measure by number of subjects who experience potential clinically significant changes in ECGs

  Baseline up to 14 days

• Part 2: Safety Labs

  Safety and tolerability measure by number of subjects who experience potential clinically significant changes in safety labs

  Baseline up to 14 days

• Part 2: Vitals Signs

  Measure by number of subjects who experience potential clinically significant changes in vital signs

  Baseline up to 14 days

• Part 3 CF: Physical Exams

  Safety and tolerability measured by number of subjects who experience potential clinically significant changes in physical examinations

  Baseline up to 28 days

• Part 3 CF: ECGs

  Safety and tolerability measured by number of subjects who experience potential clinically significant changes in ECGs

  Baseline up to 28 days

• Part 3 CF: Safety Labs

  Safety and tolerability measured by number of subjects who experience potential clinically significant changes in safety labs

  Baseline up to 28 days

• Part 3 CF: Vital Signs

  Measured by number of subjects who experience potential clinically significant changes in vital signs

  Baseline up to 28 days

• Part 4 CF: Physical Exams

  Safety and tolerability measured by number of subjects who experience potential clinically significant changes in physical examinations

  Baseline up to 42 days

• Part 4 CF: ECGs

  Safety and tolerability measured by number of subjects who experience potential clinically significant changes in ECGs

  Baseline up to 42 days

• Part 4 CF: Safety Labs

  Safety and tolerability measured by number of subjects who experience potential clinically significant changes in safety labs

  Baseline up to 42 days

• Part 4 CF: Vital Signs

  Safety and tolerability measured by number of subjects who experience potential clinically significant changes in physical examinations

  Baseline up to 42 days

Secondary Outcomes (14)

• Part 2: Apparent terminal half life (t1/2) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428

  Day 1 through Day 10

• Part 2: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428

  Day 1 through Day 10

• Part 2: Time to reach maximum plasma concentration (Tmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428

  Day 1 through Day 10

• Part 2: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428

  Day 1 through Day 10

• Part 2: AUC from time 0 to infinity (AUC0-inf) of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428

  Day 1 through Day 10

Other Outcomes (7)

• Part 2 Nasal biomarker

  Baseline up to 14 days

• Part 3 CF Sweat Chloride

  Baseline up to 28 days

• Part 3 CF Nasal biomarker

  Baseline up to 28 days

Study Arms (15)

SAD PTI-808 Active

ACTIVE COMPARATOR

Three cohorts of SAD are planned for evaluation where subjects will be randomized to PTI-808 or placebo.

Drug: PTI-808

SAD PTI-808 Placebo

PLACEBO COMPARATOR

Three cohorts of SAD are planned for evaluation where subjects will be randomized to PTI-808 or placebo.

Drug: Placebo

MAD PTI-808 Active

ACTIVE COMPARATOR

Three cohorts of MAD are planned for evaluation where subjects will be randomized to PTI-808 or placebo.

Drug: PTI-808

MAD PTI-808 Placebo

PLACEBO COMPARATOR

Three cohorts of MAD are planned for evaluation where subjects will be randomized to PTI-808 or placebo.

Drug: Placebo

FE PTI-808 Active

ACTIVE COMPARATOR

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-808

FE PTI-808 Placebo

PLACEBO COMPARATOR

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: Placebo

Part 2 PTI-808 + PTI-801 + PTI-428 Active

EXPERIMENTAL

One cohort is planned where subjects will be randomized to either the triple active arm (dosed with PTI 808+PTI 801+PTI 428) OR placebo arm.

Drug: PTI-808; Drug: PTI-428; Drug: PTI-801

Part 2 matching Placebos

PLACEBO COMPARATOR

In all three cohorts in part 2, subjects will be randomized to active drug or placebo. The placebo arm for all cohorts consists of placebo capsules matching PTI-808+PTI-801+PTI-428.

Drug: Placebo

Part 2 dual active arm PTI-801+PTI-428+ PTI-808 placebo

EXPERIMENTAL

One cohort is planned where subjects are randomized to either 808 placebo + dual active arm (dosed with placebo matching PTI 808 plus PTI 801 + PTI 428) OR placebo arm.

Drug: Placebo; Drug: PTI-428; Drug: PTI-801

Part 2 dual active arm PTI-801+PTI-808+PTI-428 placebo

ACTIVE COMPARATOR

One cohort is planned where subjects are randomized to either 428 placebo + dual active arm (dosed with placebo matching PTI 428 plus PTI 808 and PTI 801) OR placebo arm.

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

Part 3 CF MAD PTI-808 + PTI-801 + PTI-428

ACTIVE COMPARATOR

In all cohorts in Part 3, subjects will be will be randomized to receive 7 days of PTI-808 or placebo followed by 14 days of co-administration of PTI-808+PTI-801+PTI-428 or matching placebos. A follow-up will occur on Day 28.

Drug: PTI-808; Drug: PTI-428; Drug: PTI-801

Part 3 CF MAD PTI-808 placebo+PTI-801 placebo+PTI-428 placebo

PLACEBO COMPARATOR

In all cohorts in Part 3, subjects will be randomized to receive 7 days of PTI-808 or placebo followed by 14 days of co-administration of PTI-808+PTI-801+PTI-428 or matching placebos. A follow-up will occur on Day 28.

Drug: Placebo

Part 4 CF PTI-808 + PTI-801 + PTI-428

ACTIVE COMPARATOR

In cohorts 3 \& 4 subjects will be randomized to receive PTI-808 + PTI-801 with or without PTI-428 or matching placebos. A follow-up will occur on Day 42.

Drug: PTI-808; Drug: PTI-428; Drug: PTI-801

Part 4 CF PTI-808 + PTI-801 + PTI-428 placebo

ACTIVE COMPARATOR

In cohorts 3 \& 4, subjects will be randomized to receive PTI-808 + PTI-801 with or without PTI-428 or matching placebos. A follow-up will occur on Day 42.

Drug: PTI-808; Drug: PTI-801

Part 4 CF PTI-808 placebo + PTI-801 placebo + PTI-428 placebo

PLACEBO COMPARATOR

In cohorts 3 \& 4, subjects will be randomized to receive PTI-808 + PTI-801 with or without PTI-428 or matching placebos. A follow-up will occur on Day 42.

Drug: Placebo

Interventions

PTI-808 DRUG

Active

FE PTI-808 Active; MAD PTI-808 Active; Part 2 PTI-808 + PTI-801 + PTI-428 Active; Part 2 dual active arm PTI-801+PTI-808+PTI-428 placebo; Part 3 CF MAD PTI-808 + PTI-801 + PTI-428; Part 4 CF PTI-808 + PTI-801 + PTI-428; Part 4 CF PTI-808 + PTI-801 + PTI-428 placebo; SAD PTI-808 Active

Placebo DRUG

Placebo

FE PTI-808 Placebo; MAD PTI-808 Placebo; Part 2 dual active arm PTI-801+PTI-428+ PTI-808 placebo; Part 2 dual active arm PTI-801+PTI-808+PTI-428 placebo; Part 2 matching Placebos; Part 3 CF MAD PTI-808 placebo+PTI-801 placebo+PTI-428 placebo; Part 4 CF PTI-808 placebo + PTI-801 placebo + PTI-428 placebo; SAD PTI-808 Placebo

PTI-428 DRUG

Active

Part 2 PTI-808 + PTI-801 + PTI-428 Active; Part 2 dual active arm PTI-801+PTI-428+ PTI-808 placebo; Part 3 CF MAD PTI-808 + PTI-801 + PTI-428; Part 4 CF PTI-808 + PTI-801 + PTI-428

PTI-801 DRUG

Active

Part 2 PTI-808 + PTI-801 + PTI-428 Active; Part 2 dual active arm PTI-801+PTI-428+ PTI-808 placebo; Part 2 dual active arm PTI-801+PTI-808+PTI-428 placebo; Part 3 CF MAD PTI-808 + PTI-801 + PTI-428; Part 4 CF PTI-808 + PTI-801 + PTI-428; Part 4 CF PTI-808 + PTI-801 + PTI-428 placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 18 to 55 years old, inclusive, at the time of informed consent
• Body mass index ≥18 and \<30 kg/m2
• Subject must be a non-smoker and non-tobacco user for a minimum of 30 days prior to screening and for the duration of the study.
• Subject understands the full nature and purpose of the study, including possible risks and side effects, and is willing and able to comply with all compulsory study procedures and provides informed consent/permission prior to any study procedures being performed.
• Females of childbearing potential and males capable of fathering a child must meet the contraception requirements

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
• Prolonged QT interval with Fridericia's correction \>450 msec at screening
• Abnormal liver function as defined by aspartate transaminase (AST), alanine transaminase (ALT), or bilirubin \>1.5× the upper limit of the normal range
• Abnormal renal function at screening defined as creatinine clearance \<90 mL/min using the Cockroft-Gault equation
• Clinically significant screening results that would exclude subject from the study (e.g., medical histories, PE, ECGs, vital signs, and laboratory profiles) as deemed by the investigator
• Participation in another clinical study or treatment with an investigational agent within 30 days or five half-lives, whichever is longer, prior to Study Day 1
• History of cancer within the past 5 years (excluding non-melanoma 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)
• Clinically significant infection within 3 months of screening as determined by the investigator
• Known or suspected hypersensitivity or idiosyncratic reaction to study medication or any components thereof
• Has donated blood within 3 months of screening or plans to donate blood within 3 months of study completion
• Pregnant or nursing women
• Any conditions that, in the opinion of the investigator, would make the subject unsuitable for enrollment or could interfere with the subject's participation in or completion of the study

Sponsors & Collaborators

• Proteostasis Therapeutics, Inc.: lead

Study Sites (48)

Banner University of Arizona Medical Center

Tucson, Arizona, 85724, 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

Emory Children's Center

Atlanta, Georgia, 30322, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Michigan Medicine, University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Harper University Hospital

Detroit, Michigan, 48201, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Children's Mercy

Kansas City, Missouri, 64108, United States

Location

Billings Clinic

Billings, Montana, 59101, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

New York Medical College

Valhalla, New York, 10595, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27517, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, 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 Utah

Salt Lake City, Utah, 84132, United States

Location

John Hunter Hospital

Lambton, New South Wales, 2305, Australia

Location

Universitair ziekenhuis Brussel

Brussels, 1090, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

St. Paul's Hospital

Vancouver, British Columbia, V6Z1Y6, Canada

Location

Centre hospitalier de l'Université de Montréal (CHUM)

Montreal, Quebec, H2X3E4, Canada

Location

McGill University Health Centre

Montreal, Quebec, H4A3J1, Canada

Location

Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval

Québec, G1V4G5, Canada

Location

University of Copenhagen Rigshospitalet

Copenhagen, 2100, Denmark

Location

Hôpital Pasteur

Nice, Alpes-Maritimes, 06001, France

Location

Hôpital Haut Lévêque

Pessac, Gironde, 33600, France

Location

Hôpital Guillaume-et-René-Laennec

Nantes, Loire-Atlantique, 44093, France

Location

Hôpital Maison Blanche Maladies respiratoires et allergologie

Reims, Marne, 51092, France

Location

Hospices Civils de Lyon

Lyon, 69495, France

Location

Hôpital Cochin

Paris, 75014, France

Location

Charité Universitätsmedizin Berlin

Berlin, 10117, Germany

Location

University Hospital Cologne

Cologne, 50937, Germany

Location

Universitätsklinikum Essen

Essen, 45239, Germany

Location

Klinikum der J.W. Goethe Universität

Frankfurt, 60590, Germany

Location

Klinikum des Universität München

München, 81377, Germany

Location

Auckland Clinical Studies Ltd.

Grafton, Auckland, 1010, New Zealand

Location

Royal Devon and Exeter Hospital

Exeter, Devon, EX2 5DW, United Kingdom

Location

Western General Hospital

Edinburgh, Scotland, EH42XU, United Kingdom

Location

Birmingham Heartlands Hospital

Birmingham, West Midlands, B9 5SS, United Kingdom

Location

Belfast City Hospital

Belfast, BT9 7AB, United Kingdom

Location

King's College Hospital

London, SE59RS, United Kingdom

Location

University Hospital Southampton

Southampton, SO16 6YD, United Kingdom

Location

Study Officials

• Cassandra Key, MD

  ICON Early Phase Services (Parts 1 & 2)

  PRINCIPAL INVESTIGATOR

• Patrick Flume, MD

  Medical University of South Carolina (Parts 3 & 4)

  PRINCIPAL INVESTIGATOR

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: August 7, 2017
• First Posted: August 16, 2017
• Study Start: July 17, 2017
• Primary Completion: December 23, 2019
• Study Completion: December 23, 2019
• Last Updated: April 22, 2020

Record last verified: 2020-04

Locations

US (22); DE (5); BE (2); NZ (1); FR (6); CA (4); AU (1); DK (1); GB (6)