Cystic Fibrosis - Complete Clinical Trial
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
| Verified date | April 2020 |
| Source | Proteostasis Therapeutics, Inc. |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 179 |
| Est. completion date | December 23, 2019 |
| Est. primary completion date | December 23, 2019 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 18 Years to 99 Years |
| Eligibility |
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 |
| Country | Name | City | State |
|---|---|---|---|
| Australia | John Hunter Hospital | Lambton | New South Wales |
| Belgium | Universitair ziekenhuis Brussel | Brussels | |
| Belgium | UZ Leuven | Leuven | |
| Canada | Centre hospitalier de l'Université de Montréal (CHUM) | Montréal | Quebec |
| Canada | McGill University Health Centre | Montréal | Quebec |
| Canada | Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval | Québec | |
| Canada | St. Paul's Hospital | Vancouver | British Columbia |
| Denmark | University of Copenhagen Rigshospitalet | Copenhagen | |
| France | Hospices Civils de Lyon | Lyon | |
| France | Hôpital Guillaume-et-René-Laennec | Nantes | Loire-Atlantique |
| France | Hôpital Pasteur | Nice | Alpes-Maritimes |
| France | Hôpital Cochin | Paris | |
| France | Hôpital Haut Lévêque | Pessac | Gironde |
| France | Hôpital Maison Blanche Maladies respiratoires et allergologie | Reims | Marne |
| Germany | Charité Universitätsmedizin Berlin | Berlin | |
| Germany | University Hospital Cologne | Cologne | |
| Germany | Universitätsklinikum Essen | Essen | |
| Germany | Klinikum der J.W. Goethe Universität | Frankfurt | |
| Germany | Klinikum des Universität München | München | |
| New Zealand | Auckland Clinical Studies Ltd. | Grafton | Auckland |
| United Kingdom | Belfast City Hospital | Belfast | |
| United Kingdom | Birmingham Heartlands Hospital | Birmingham | West Midlands |
| United Kingdom | Western General Hospital | Edinburgh | Scotland |
| United Kingdom | Royal Devon and Exeter Hospital | Exeter | Devon |
| United Kingdom | King's College Hospital | London | |
| United Kingdom | University Hospital Southampton | Southampton | |
| United States | Central Florida Pulmonary Group | Altamonte Springs | Florida |
| United States | Michigan Medicine, University of Michigan | Ann Arbor | Michigan |
| United States | Emory Children's Center | Atlanta | Georgia |
| United States | Johns Hopkins University | Baltimore | Maryland |
| United States | Billings Clinic | Billings | Montana |
| United States | Boston Children's Hospital | Boston | Massachusetts |
| United States | Massachusetts General Hospital | Boston | Massachusetts |
| United States | University of North Carolina at Chapel Hill | Chapel Hill | North Carolina |
| United States | Medical University of South Carolina | Charleston | South Carolina |
| United States | Northwestern Memorial Hospital | Chicago | Illinois |
| United States | National Jewish Health | Denver | Colorado |
| United States | Harper University Hospital | Detroit | Michigan |
| United States | Children's Mercy | Kansas City | Missouri |
| United States | Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire |
| United States | University of Minnesota | Minneapolis | Minnesota |
| United States | University of Nebraska Medical Center | Omaha | Nebraska |
| United States | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania |
| 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 | Banner University of Arizona Medical Center | Tucson | Arizona |
| United States | New York Medical College | Valhalla | New York |
| Lead Sponsor | Collaborator |
|---|---|
| Proteostasis Therapeutics, Inc. |
United States, Australia, Belgium, Canada, Denmark, France, Germany, New Zealand, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Part 2 Nasal biomarker | change in nasal epithelial mRNA and protein over time | Baseline up to 14 days | |
| Other | Part 3 CF Sweat Chloride | Change in sweat chloride concentrations over time | Baseline up to 28 days | |
| Other | Part 3 CF Nasal biomarker | Change in nasal epithelial mRNA and protein expression over time | Baseline up to 28 days | |
| Other | Part 4 CF Weight and BMI | Change in weight and BMI over time | Baseline up to 42 days | |
| Other | Part 4 CF Blood Glucose | Change in blood glucose over time | Baseline up to 42 days | |
| Other | Part 4 CF disease-specific health related quality of life | Change in disease-specific health related quality of life over time | Baseline up to 42 days | |
| Other | Part 4 CF Nasal biomarker | Change in nasal epithelial mRNA and protein expression over time | Baseline up to 42 days | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | Part 1 SAD and FE: terminal half life | Apparent terminal half-life (t1/2) of single oral dose | Through 72 hours post dose | |
| Primary | Part 1 SAD and FE : Tmax | Time to reach maximum plasma concentration (Tmax) of single oral dose | Through 72 hours post dose | |
| Primary | Part 1 SAD and FE: Cmax | Maximum plasma concentration (Cmax) of single oral dose | Through 72 hours post dose | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | Part 1 SAD and FE: AUC0-inf | AUC from time 0 to infinity (AUC0-inf) of single dose | Through 72 hours post dose | |
| Primary | Part 1 MAD: t1/2 | t1/2 of multiple oral dose | Through 72 hours post dose | |
| Primary | Part 1 MAD: Tmax | Tmax of multiple oral doses | Through 72 hours post dose | |
| Primary | Part 1 MAD: Cmax | Cmax of multiple oral doses | Through 72 hours post last dose | |
| Primary | Part 1 MAD: AUC0-24 | AUC0-24 of multiple oral dose | Through 24 hours post last dose | |
| Primary | Part 1 MAD: AUC0-last | AUC0-last of multiple oral doses | Through 72 hours post last dose | |
| Primary | 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 | |
| Primary | Part 1 MAD: CLR | Renal clearance (CLR) of multiple oral doses | Through 24 hours post dose | |
| Primary | 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 | |
| Primary | Part 2: ECGs | Safety and tolerability measure by number of subjects who experience potential clinically significant changes in ECGs | Baseline up to 14 days | |
| Primary | 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 | |
| Primary | Part 2: Vitals Signs | Measure by number of subjects who experience potential clinically significant changes in vital signs | Baseline up to 14 days | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | Part 3 CF: Vital Signs | Measured by number of subjects who experience potential clinically significant changes in vital signs | Baseline up to 28 days | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | |
| Primary | 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 | Part 2: Apparent terminal half life (t1/2) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 | 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 | Day 1 through Day 10 | |
| Secondary | Part 2: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 | 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 | Day 1 through Day 10 | |
| Secondary | Part 2: Time to reach maximum plasma concentration (Tmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 | 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 | Day 1 through Day 10 | |
| Secondary | Part 2: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428 | 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 | Day 1 through Day 10 | |
| Secondary | 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 | 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 | Day 1 through Day 10 | |
| Secondary | 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 | 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 | Day 1 through Day 22 | |
| Secondary | Part 3 CF: Maximum plasma concentration (Cmax) of multiple oral doses PTI 808 is co administered with PTI 801 and PTI 428 | 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 | Day 1 through Day 22 | |
| Secondary | Part 3 CF: AUC0-last of multiple oral doses when PTI 808 is co administered with PTI 801 and PTI 428 | 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 | Day 1 through Day 22 | |
| Secondary | Part 3 CF: FEV1 | Change in forced expiratory volume in one second (FEV1) over time | Baseline through Day 28 | |
| Secondary | 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 | 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 | Day 1 through Day 28 | |
| Secondary | Part 4 CF: Maximum plasma concentration (Cmax) of multiple oral doses of PTI 808 + PTI 801 co-administered with or without PTI 428 | 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 | Day 1 through 28 | |
| Secondary | 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 | 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 | Day 1 through 28 | |
| Secondary | Part 4 CF: FEV1 | Change in forced expiratory volume in one second (FEV1) over time | Baseline through Day 42 | |
| Secondary | Part 4 CF Sweat Chloride | Change in sweat chloride concentrations over time | Baseline through Day 42 |