Cystic Fibrosis - Complete, Healthy Volunteer - Complete
Conditions
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.
Sponsors
Proteostasis Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 4 CF: Vital Signs | Baseline up to 42 days | Safety and tolerability measured by number of subjects who experience potential clinically significant changes in physical examinations |
| Part 1 SAD : AUC | 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 |
| Part 1 SAD and FE: AUC0 | Through 72 hours post dose | AUC from time 0 to time of last measurable concentration (AUC0-last) of single oral dose |
| Part 1 SAD and FE: AUC0-inf | Through 72 hours post dose | AUC from time 0 to infinity (AUC0-inf) of single dose |
| Part 1 MAD: t1/2 | Through 72 hours post dose | t1/2 of multiple oral dose |
| Part 1 MAD: Tmax | Through 72 hours post dose | Tmax of multiple oral doses |
| Part 1 MAD: Cmax | Through 72 hours post last dose | Cmax of multiple oral doses |
| Part 1 MAD: AUC0-24 | Through 24 hours post last dose | AUC0-24 of multiple oral dose |
| Part 1 MAD: AUC0-last | Through 72 hours post last dose | AUC0-last of multiple oral doses |
| Part 1 MAD: Urine | Through 24 hours post last dose | Cumulative amount of PTI-808 excreted unchanged in urine (Ae) as appropriate of multiple oral doses |
| Part 1 MAD: CLR | Through 24 hours post dose | Renal clearance (CLR) of multiple oral doses |
| Part 2: Physical Exams | Baseline up to 14 days | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in physical examinations |
| Part 2: ECGs | Baseline up to 14 days | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in ECGs |
| Part 2: Safety Labs | Baseline up to 14 days | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in safety labs |
| Part 2: Vitals Signs | Baseline up to 14 days | Measure by number of subjects who experience potential clinically significant changes in vital signs |
| Part 3 CF: Physical Exams | Baseline up to 28 days | Safety and tolerability measured by number of subjects who experience potential clinically significant changes in physical examinations |
| Part 3 CF: ECGs | Baseline up to 28 days | Safety and tolerability measured by number of subjects who experience potential clinically significant changes in ECGs |
| Part 3 CF: Safety Labs | Baseline up to 28 days | Safety and tolerability measured by number of subjects who experience potential clinically significant changes in safety labs |
| Part 3 CF: Vital Signs | Baseline up to 28 days | Measured by number of subjects who experience potential clinically significant changes in vital signs |
| Part 4 CF: Physical Exams | Baseline up to 42 days | Safety and tolerability measured by number of subjects who experience potential clinically significant changes in physical examinations |
| Part 4 CF: ECGs | Baseline up to 42 days | Safety and tolerability measured by number of subjects who experience potential clinically significant changes in ECGs |
| Part 4 CF: Safety Labs | Baseline up to 42 days | Safety and tolerability measured by number of subjects who experience potential clinically significant changes in safety labs |
| Part 1 SAD and MAD: Adverse Events | Baseline to up to 14 days | Safety and tolerability measure by number of subjects who experience adverse events |
| Part 1 SAD and MAD: Physical Exams | Baseline to up to 14 days | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in physical examinations |
| Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in vital signs | Baseline to up to 14 days | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in vital signs |
| Part 1 SAD and MAD: ECGs | Baseline to up to 14 days | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in ECGs |
| Part 1 SAD and MAD: The number of subjects who experience potential clinically significant changes in safety labs | Baseline to up to 14 days | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in safety labs |
| Part 1 SAD and FE: terminal half life | Through 72 hours post dose | Apparent terminal half-life (t1/2) of single oral dose |
| Part 1 SAD and FE : Tmax | Through 72 hours post dose | Time to reach maximum plasma concentration (Tmax) of single oral dose |
| Part 1 SAD and FE: Cmax | Through 72 hours post dose | Maximum plasma concentration (Cmax) of single oral dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 3 CF: FEV1 | Baseline through Day 28 | Change in forced expiratory volume in one second (FEV1) over time |
| 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 | Day 1 through Day 28 | Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 + PTI 801 is co administered with or with out PTI 428 in adults with CF |
| Part 4 CF: Maximum plasma concentration (Cmax) of multiple oral doses of PTI 808 + PTI 801 co-administered with or without PTI 428 | Day 1 through 28 | Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 + PTI 801 is co administered with or with out PTI 428 in adults with CF |
| 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 | Day 1 through 28 | Evaluate the PK profile of PTI 808, PTI 801, and PTI 428 when PTI 808 + PTI 801 is co administered with or without PTI 428 in adults with CF |
| Part 4 CF: FEV1 | Baseline through Day 42 | Change in forced expiratory volume in one second (FEV1) over time |
| Part 4 CF Sweat Chloride | Baseline through Day 42 | Change in sweat chloride concentrations over time |
| 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 | 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 |
| 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 | 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 |
| 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 | 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 |
| 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 | 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 |
| 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 | 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 |
| 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 | 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 |
| Part 3 CF: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 | 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 |
| Part 3 CF: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428 | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Part 2 Nasal biomarker | Baseline up to 14 days | change in nasal epithelial mRNA and protein over time |
| Part 3 CF Nasal biomarker | Baseline up to 28 days | Change in nasal epithelial mRNA and protein expression over time |
| Part 4 CF Weight and BMI | Baseline up to 42 days | Change in weight and BMI over time |
| Part 4 CF Blood Glucose | Baseline up to 42 days | Change in blood glucose over time |
| Part 4 CF disease-specific health related quality of life | Baseline up to 42 days | Change in disease-specific health related quality of life over time |
| Part 4 CF Nasal biomarker | Baseline up to 42 days | Change in nasal epithelial mRNA and protein expression over time |
| Part 3 CF Sweat Chloride | Baseline up to 28 days | Change in sweat chloride concentrations over time |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, New Zealand, United Kingdom, United States
Outcome results
None listed