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

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ClinicalTrials.gov Identifier: NCT03251092
Recruitment Status : Recruiting
First Posted : August 16, 2017
Last Update Posted : October 11, 2018
Sponsor:
Information provided by (Responsible Party):
Proteostasis Therapeutics, Inc.

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 3 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.


Condition or disease Intervention/treatment Phase
Healthy Volunteer - Complete Cystic Fibrosis Drug: PTI-808 Drug: Placebo Drug: PTI-428 Drug: PTI-801 Phase 1

Detailed Description:

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.

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.

Following the conclusion of the respective SAD level dose groups the food effect portion of the study will be initiated and subjects will be randomized to receive an initial single dose of PTI-808 either after an overnight fast of at least 10 hours (fasted group) or after an overnight fast of at least 10 hours followed the consumption of a high fat high calorie meal (fed group). After a 10 day washout period, subjects will cross over to the opposite group and receive a second dose of PTI-808. Subjects will be followed for up to 7 days following dosing.

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 - Part 3 will enroll adult subjects with CF to assess the safety, tolerability, and PK of multiple ascending doses of PTI-808 co-administered with PTI-801 and PTI-428. Subjects will receive 7 days of PTI-808 or placebo followed by 14 days of PTI-808 or placebo co-administered with PTI-801+PTI-428 or matching placebos.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of PTI 808 in Healthy Adult Subjects and in Adults With Cystic Fibrosis
Actual Study Start Date : July 17, 2017
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

Arm Intervention/treatment
Active Comparator: SAD PTI-808 Active
Three cohorts of SAD are planned for evaluation where subjects will be randomized to PTI-808 or placebo.
Drug: PTI-808
Active

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

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

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

Active Comparator: FE PTI-808 Active
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
Active

Placebo Comparator: FE PTI-808 Placebo
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
Placebo

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

Drug: PTI-428
Active

Drug: PTI-801
Active

Placebo Comparator: Part 2 matching Placebos
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
Placebo

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

Drug: PTI-428
Active

Drug: PTI-801
Active

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

Drug: Placebo
Placebo

Drug: PTI-801
Active

Active Comparator: Part 3 CF MAD PTI-808 + PTI-801 + PTI-428
In all three 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
Active

Drug: PTI-428
Active

Drug: PTI-801
Active

Placebo Comparator: Part 3 CF MAD PTI-808 placebo+PTI-801 placebo+PTI-428 placebo
In all three 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
Placebo




Primary Outcome Measures :
  1. Part 1 SAD and MAD: Adverse Events [ Time Frame: Baseline to up to 14 days ]
    Safety and tolerability measure by number of subjects who experience adverse events

  2. Part 1 SAD and MAD: Physical Exams [ Time Frame: Baseline to up to 14 days ]
    Safety and tolerability measure by number of subjects who experience potential clinically significant changes in physical examinations

  3. Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in vital signs [ Time Frame: Baseline to up to 14 days ]
    Safety and tolerability measure by number of subjects who experience potential clinically significant changes in vital signs

  4. Part 1 SAD and MAD: ECGs [ Time Frame: Baseline to up to 14 days ]
    Safety and tolerability measure by number of subjects who experience potential clinically significant changes in ECGs

  5. Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in safety labs [ Time Frame: Baseline to up to 14 days ]
    Safety and tolerability measure by number of subjects who experience potential clinically significant changes in safety labs

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

  7. Part 1 SAD and FE : Tmax [ Time Frame: Through 72 hours post dose ]
    Time to reach maximum plasma concentration (Tmax) of single oral dose

  8. Part 1 SAD and FE: Cmax [ Time Frame: Through 72 hours post dose ]
    Maximum plasma concentration (Cmax) of single oral dose

  9. Part 1 SAD : AUC [ Time Frame: Through 24 hours post dose ]
    Area under the concentration-time curve from time 0 to 24 hours post dose (AUC 0-24) of single oral dose

  10. Part 1 SAD and FE: AUC0 [ Time Frame: Through 72 hours post dose ]
    AUC from time 0 to time of last measurable concentration (AUC0-last) of single oral dose

  11. Part 1 SAD and FE: AUC0-inf [ Time Frame: Through 72 hours post dose ]
    AUC from time 0 to infinity (AUC0-inf) of single dose

  12. Part 1 MAD: t1/2 [ Time Frame: Through 72 hours post dose ]
    t1/2 of multiple oral dose

  13. Part 1 MAD: Tmax [ Time Frame: Through 72 hours post dose ]
    Tmax of multiple oral doses

  14. Part 1 MAD: Cmax [ Time Frame: Through 72 hours post last dose ]
    Cmax of multiple oral doses

  15. Part 1 MAD: AUC0-24 [ Time Frame: Through 24 hours post last dose ]
    AUC0-24 of multiple oral dose

  16. Part 1 MAD: AUC0-last [ Time Frame: Through 72 hours post last dose ]
    AUC0-last of multiple oral doses

  17. Part 1 MAD: Urine [ Time Frame: Through 24 hours post last dose ]
    Cumulative amount of PTI-808 excreted unchanged in urine (Ae) as appropriate of multiple oral doses

  18. Part 1 MAD: CLR [ Time Frame: Through 24 hours post dose ]
    Renal clearance (CLR) of multiple oral doses

  19. Part 2: Physical Exams [ Time Frame: Baseline up to 14 days ]
    Safety and tolerability measure by number of subjects who experience potential clinically significant changes in physical examinations

  20. Part 2: ECGs [ Time Frame: Baseline up to 14 days ]
    Safety and tolerability measure by number of subjects who experience potential clinically significant changes in ECGs

  21. Part 2: Safety Labs [ Time Frame: Baseline up to 14 days ]
    Safety and tolerability measure by number of subjects who experience potential clinically significant changes in safety labs

  22. Part 2: Vitals Signs [ Time Frame: Baseline up to 14 days ]
    Measure by number of subjects who experience potential clinically significant changes in vital signs

  23. Part 3 CF: Physical Exams [ Time Frame: Baseline up to 28 days ]
    Safety and tolerability measured by number of subjects who experience potential clinically significant changes in physical examinations

  24. Part 3 CF: ECGs [ Time Frame: Baseline up to 28 days ]
    Safety and tolerability measured by number of subjects who experience potential clinically significant changes in ECGs

  25. Part 3 CF: Safety Labs [ Time Frame: Baseline up to 28 days ]
    Safety and tolerability measured by number of subjects who experience potential clinically significant changes in safety labs

  26. Part 3 CF: Vital Signs [ Time Frame: Baseline up to 28 days ]
    Measure by number of subjects who experience potential clinically significant changes in vital signs


Secondary Outcome Measures :
  1. Part 2: Apparent terminal half life (t1/2) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 [ Time Frame: Day 1 through Day 10 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in healthy adults

  2. Part 2: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 [ Time Frame: Day 1 through Day 10 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in healthy adults

  3. Part 2: Time to reach maximum plasma concentration (Tmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 [ Time Frame: Day 1 through Day 10 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in healthy adults

  4. Part 2: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428 [ Time Frame: Day 1 through Day 10 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in healthy adults

  5. 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 [ Time Frame: Day 1 through Day 10 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in healthy adults

  6. Part 3 CF: Time to reach maximum plasma concentration (Tmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 [ Time Frame: Day 1 through Day 22 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in adults with CF

  7. Part 3 CF: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 [ Time Frame: Day 1 through Day 22 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in adults with CF

  8. Part 3 CF: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428 [ Time Frame: Day 1 through Day 22 ]
    Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 is co administered with PTI 801 and PTI 428 in adults with CF

  9. Part 3 CF: FEV1 [ Time Frame: Baseline through Day 28 ]
    Change in forced expiratory volume in one second (FEV1) over time


Other Outcome Measures:
  1. Part 2 Nasal biomarker [ Time Frame: Baseline up to 14 days ]
    change in nasal epithelial mRNA and protein over time

  2. Part 3 CF Sweat Chloride [ Time Frame: Baseline up to 28 days ]
    Change in sweat chloride concentrations over time

  3. Part 3 CF Nasal biomarker [ Time Frame: Baseline up to 28 days ]
    Change in nasal epithelial mRNA and protein expression over time



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Part 1 and Part 2 Inclusion Criteria:

  1. Adults aged 18 to 55 years old, inclusive, at the time of informed consent
  2. Body mass index ≥18 and <30 kg/m2
  3. 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.
  4. 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.
  5. Females of childbearing potential and males capable of fathering a child must meet the contraception requirements

Part 1 & Part 2 Exclusion Criteria:

  1. 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
  2. Prolonged QT interval with Fridericia's correction >450 msec at screening
  3. Abnormal liver function as defined by aspartate transaminase (AST), alanine transaminase (ALT), or bilirubin >1.5× the upper limit of the normal range
  4. Abnormal renal function at screening defined as creatinine clearance <90 mL/min using the Cockroft-Gault equation
  5. 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
  6. 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
  7. History of cancer within the past 5 years (excluding non-melanoma skin cancer)
  8. History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
  9. 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
  10. Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (HCVAb)
  11. Clinically significant infection within 3 months of screening as determined by the investigator
  12. Known or suspected hypersensitivity or idiosyncratic reaction to study medication or any components thereof
  13. Has donated blood within 3 months of screening or plans to donate blood within 3 months of study completion
  14. Pregnant or nursing women
  15. 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
  16. Use of prohibited medications within 14 days prior to dosing of study drug

Part 3 CF Inclusion Criteria:

  1. Confirmed diagnosis of CF with the F508del/F508del genotype
  2. Forced expiratory volume in 1 second (FEV1) 40-90% predicted, inclusive
  3. Non-smoker and non-tobacco user for a minimum of 30 days prior to screening

Part 3 CF Exclusion Criteria:

  1. 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
  2. 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)
  3. History of organ transplantation
  4. 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
  5. 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
  6. History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
  7. Pregnant or nursing women
  8. Currently taking or has taken a CFTR modulator within 30 days prior to initial dose of study drugs

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03251092


Contacts
Contact: Proteostasis Clinical Trials 1-866-223-3262 pticlinicaltrials@proteostasis.com

Locations
United States, Arizona
Banner University of Arizona Medical Center Recruiting
Tucson, Arizona, United States, 85724
United States, California
Stanford University Medical Center Recruiting
Stanford, California, United States, 94305
United States, Colorado
National Jewish Health Recruiting
Denver, Colorado, United States, 80206
United States, Florida
Central Florida Pulmonary Group Recruiting
Altamonte Springs, Florida, United States, 32803
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
United States, Missouri
Children's Mercy Recruiting
Kansas City, Missouri, United States, 64108
United States, Montana
Billings Clinic Recruiting
Billings, Montana, United States, 59101
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
United States, New Hampshire
Dartmouth Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03756
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
United States, Texas
ICON Early Phase Services Active, not recruiting
San Antonio, Texas, United States, 78209
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Denmark
University of Copenhagen Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Germany
University Hospital Cologne Recruiting
Cologne, Germany, 50937
Sponsors and Collaborators
Proteostasis Therapeutics, Inc.
Investigators
Principal Investigator: Cassandra Key, MD ICON Early Phase Services (Parts 1 & 2)
Principal Investigator: Patrick Flume, MD Medical University of South Carolina (Part 3)

Additional Information:
Responsible Party: Proteostasis Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03251092     History of Changes
Other Study ID Numbers: PTI-808-01
First Posted: August 16, 2017    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Fibrosis
Cystic Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases