Clinical trial NCT03251092: Study Designed to Assess the Safety, Tolerability and PK of PTI-808 in Healthy Volunteers and in Adults With Cystic Fibrosis
Official title: A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of PTI-808 in Healthy Adult Subjects and in Adults With Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Healthy Volunteer - Complete
Cystic Fibrosis - Complete
Lead sponsor: Proteostasis Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2017-08-16
Enrollment: 179
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Part 4 - Part 4 will assess the safety, tolerability, PK, and the effects of PTI-808 co-administered with PTI-801 with or without PTI-428 over a 28-day treatment period in CF subjects who are either homozygous for the F508del CFTR genotype or are heterozygous for the F508del CFTR genotype. Subjects will be randomized to receive treatment with PTI-808 co-administered with PTI-801 with or without PTI-428 versus matching placebo.

Eligibility 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

Part 4 CF Inclusion Criteria:

1. Confirmed diagnosis of CF with either the F508del CFTR homozygous genotype on record or for heterozygote subjects, only one copy of the F508del CFTR mutation on record
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 4 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 28 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 of 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 14 days prior to the screening visit

Primary outcomes:
measure: Part 1 SAD and MAD: Adverse Events
timeFrame: Baseline to up to 14 days
measure: Part 1 SAD and MAD: Physical Exams
timeFrame: Baseline to up to 14 days
measure: Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in vital signs
timeFrame: Baseline to up to 14 days
measure: Part 1 SAD and MAD: ECGs
timeFrame: Baseline to up to 14 days
measure: Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in safety labs
timeFrame: Baseline to up to 14 days
measure: Part 1 SAD and FE: terminal half life
timeFrame: Through 72 hours post dose
measure: Part 1 SAD and FE : Tmax
timeFrame: Through 72 hours post dose
measure: Part 1 SAD and FE: Cmax
timeFrame: Through 72 hours post dose
measure: Part 1 SAD : AUC
timeFrame: Through 24 hours post dose
measure: Part 1 SAD and FE: AUC0
timeFrame: Through 72 hours post dose
measure: Part 1 SAD and FE: AUC0-inf
timeFrame: Through 72 hours post dose
measure: Part 1 MAD: t1/2
timeFrame: Through 72 hours post dose
measure: Part 1 MAD: Tmax
timeFrame: Through 72 hours post dose
measure: Part 1 MAD: Cmax
timeFrame: Through 72 hours post last dose
measure: Part 1 MAD: AUC0-24
timeFrame: Through 24 hours post last dose
measure: Part 1 MAD: AUC0-last
timeFrame: Through 72 hours post last dose
measure: Part 1 MAD: Urine
timeFrame: Through 24 hours post last dose
measure: Part 1 MAD: CLR
timeFrame: Through 24 hours post dose
measure: Part 2: Physical Exams
timeFrame: Baseline up to 14 days
measure: Part 2: ECGs
timeFrame: Baseline up to 14 days
measure: Part 2: Safety Labs
timeFrame: Baseline up to 14 days
measure: Part 2: Vitals Signs
timeFrame: Baseline up to 14 days
measure: Part 3 CF: Physical Exams
timeFrame: Baseline up to 28 days
measure: Part 3 CF: ECGs
timeFrame: Baseline up to 28 days
measure: Part 3 CF: Safety Labs
timeFrame: Baseline up to 28 days
measure: Part 3 CF: Vital Signs
timeFrame: Baseline up to 28 days
measure: Part 4 CF: Physical Exams
timeFrame: Baseline up to 42 days
measure: Part 4 CF: ECGs
timeFrame: Baseline up to 42 days
measure: Part 4 CF: Safety Labs
timeFrame: Baseline up to 42 days
measure: Part 4 CF: Vital Signs
timeFrame: Baseline up to 42 days
Secondary outcomes:
measure: Part 2: Apparent terminal half life (t1/2) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428
timeFrame: Day 1 through Day 10
measure: Part 2: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428
timeFrame: Day 1 through Day 10
measure: Part 2: Time to reach maximum plasma concentration (Tmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428
timeFrame: Day 1 through Day 10
measure: Part 2: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428
timeFrame: Day 1 through Day 10
measure: 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
timeFrame: Day 1 through Day 10
measure: 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
timeFrame: Day 1 through Day 22
measure: Part 3 CF: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428
timeFrame: Day 1 through Day 22
measure: Part 3 CF: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428
timeFrame: Day 1 through Day 22
measure: Part 3 CF: FEV1
timeFrame: Baseline through Day 28
measure: Part 4 CF: Time to reach maximum plasma concentration (Tmax) of multiple oral doses of PTI 808 + PTI 801 co-administered with or without PTI 428
timeFrame: Day 1 through Day 28
measure: Part 4 CF: Maximum plasma concentration (Cmax) of multiple oral doses of PTI 808 + PTI 801 co-administered with or without PTI 428
timeFrame: Day 1 through 28
measure: Part 4 CF: AUC0-last of multiple oral doses when PTI 808 + PTI 801 is coadministered with or without PTI 428 in adults with CF
timeFrame: Day 1 through 28
measure: Part 4 CF: FEV1
timeFrame: Baseline through Day 42
measure: Part 4 CF Sweat Chloride
timeFrame: Baseline through Day 42
Other outcomes:
measure: Part 2 Nasal biomarker
timeFrame: Baseline up to 14 days
measure: Part 3 CF Sweat Chloride
timeFrame: Baseline up to 28 days
measure: Part 3 CF Nasal biomarker
timeFrame: Baseline up to 28 days
measure: Part 4 CF Weight and BMI
timeFrame: Baseline up to 42 days
measure: Part 4 CF Blood Glucose
timeFrame: Baseline up to 42 days
measure: Part 4 CF disease-specific health related quality of life
timeFrame: Baseline up to 42 days
measure: Part 4 CF Nasal biomarker
timeFrame: Baseline up to 42 days
Locations:
city: Tucson
country: United States
facility: Banner University of Arizona Medical Center
state: Arizona
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: Atlanta
country: United States
facility: Emory Children's Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
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: Michigan Medicine, University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Harper University Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy
state: Missouri
city: Billings
country: United States
facility: Billings Clinic
state: Montana
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
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: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Lambton
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Brussels
country: Belgium
facility: Universitair ziekenhuis Brussel
city: Leuven
country: Belgium
facility: UZ Leuven
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Montréal
country: Canada
facility: Centre hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
city: Copenhagen
country: Denmark
facility: University of Copenhagen Rigshospitalet
city: Nice
country: France
facility: Hôpital Pasteur
state: Alpes-Maritimes
city: Pessac
country: France
facility: Hôpital Haut Lévêque
state: Gironde
city: Nantes
country: France
facility: Hôpital Guillaume-et-René-Laennec
state: Loire-Atlantique
city: Reims
country: France
facility: Hôpital Maison Blanche Maladies respiratoires et allergologie
state: Marne
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Paris
country: France
facility: Hôpital Cochin
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Cologne
country: Germany
facility: University Hospital Cologne
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universität
city: München
country: Germany
facility: Klinikum des Universität München
city: Grafton
country: New Zealand
facility: Auckland Clinical Studies Ltd.
state: Auckland
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: Devon
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
state: Scotland
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: West Midlands
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
Study officials:
affiliation: ICON Early Phase Services (Parts 1 & 2)
name: Cassandra Key, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina (Parts 3 & 4)
name: Patrick Flume, MD
role: PRINCIPAL_INVESTIGATOR
References: