临床试验/NCT03251092

NCT03251092已完成1 期

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

Proteostasis Therapeutics, Inc.48 个研究点分布在 9 个国家目标入组 179 人开始时间: 2017年7月17日最近更新: 2020年4月22日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方: Proteostasis Therapeutics, Inc.
入组人数: 179
试验地点: 48
主要终点: Part 1 SAD and MAD: ECGs

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

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.

详细描述

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 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.

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Sequential
主要目的: Treatment
盲法: Triple (Participant, Care Provider, Investigator)

入排标准

年龄范围: 18 Years 至 99 Years（Adult, Older Adult）
性别: All
接受健康志愿者: 是

入选标准

•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
•Part 1 & Part 2

排除标准

•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
•Use of prohibited medications within 14 days prior to dosing of study drug
•Part 3 CF Inclusion Criteria:
•Confirmed diagnosis of CF with the F508del/F508del genotype
•Forced expiratory volume in 1 second (FEV1) 40-90% predicted, inclusive
•Non-smoker and non-tobacco user for a minimum of 30 days prior to screening
•Part 3 CF Exclusion Criteria:
•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
•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)
•History of organ transplantation
•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
•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
•History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
•Pregnant or nursing women
•Currently taking or has taken a CFTR modulator within 30 days prior to initial dose of study drugs
•Part 4 CF Inclusion Criteria:
•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
•Forced expiratory volume in 1 second (FEV1) 40-90% predicted, inclusive
•Non-smoker and non-tobacco user for a minimum of 30 days prior to screening
•Part 4 CF Exclusion Criteria:
•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
•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)
•History of organ transplantation
•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
•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
•History or current evidence of alcohol or drug abuse or dependence within 12 months of screening as determined by the investigator
•Pregnant or nursing women
•Currently taking or has taken a CFTR modulator within 14 days prior to the screening visit

研究组 & 干预措施

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.

干预措施: Placebo (Drug)

SAD PTI-808 Active

Active Comparator

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

干预措施: PTI-808 (Drug)

SAD PTI-808 Placebo

Placebo Comparator

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

干预措施: Placebo (Drug)

MAD PTI-808 Active

Active Comparator

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

干预措施: PTI-808 (Drug)

MAD PTI-808 Placebo

Placebo Comparator

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

干预措施: Placebo (Drug)

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.

干预措施: PTI-808 (Drug)

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.

干预措施: PTI-808 (Drug)

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.

干预措施: PTI-428 (Drug)

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.

干预措施: PTI-801 (Drug)

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.

干预措施: Placebo (Drug)

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.

干预措施: Placebo (Drug)

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.

干预措施: PTI-428 (Drug)

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.

干预措施: PTI-801 (Drug)

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.

干预措施: PTI-808 (Drug)

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.

干预措施: Placebo (Drug)

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.

干预措施: PTI-801 (Drug)

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.

干预措施: PTI-808 (Drug)

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

Active Comparator

干预措施: PTI-428 (Drug)

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

Active Comparator

干预措施: PTI-801 (Drug)

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.

干预措施: Placebo (Drug)

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.

干预措施: PTI-808 (Drug)

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.

干预措施: PTI-428 (Drug)

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.

干预措施: PTI-801 (Drug)

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.

干预措施: PTI-808 (Drug)

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.

干预措施: PTI-801 (Drug)

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.

干预措施: Placebo (Drug)

结局指标

主要结局

Part 1 SAD and MAD: ECGs

时间窗: 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: Adverse Events

时间窗: 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

时间窗: 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

时间窗: 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 : AUC

时间窗: 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

时间窗: 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

时间窗: Through 72 hours post dose

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

Part 1 MAD: t1/2

时间窗: Through 72 hours post dose

t1/2 of multiple oral dose

Part 1 MAD: Tmax

时间窗: Through 72 hours post dose

Tmax of multiple oral doses

Part 1 MAD: Cmax

时间窗: Through 72 hours post last dose

Cmax of multiple oral doses

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

时间窗: 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

时间窗: Through 72 hours post dose

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

Part 1 SAD and FE : Tmax

时间窗: Through 72 hours post dose

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

Part 1 SAD and FE: Cmax

时间窗: Through 72 hours post dose

Maximum plasma concentration (Cmax) of single oral dose

Part 1 MAD: AUC0-24

时间窗: Through 24 hours post last dose

AUC0-24 of multiple oral dose

Part 1 MAD: AUC0-last

时间窗: Through 72 hours post last dose

AUC0-last of multiple oral doses

Part 1 MAD: Urine

时间窗: 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

时间窗: Through 24 hours post dose

Renal clearance (CLR) of multiple oral doses

Part 2: Physical Exams

时间窗: 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

时间窗: 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

时间窗: 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

时间窗: Baseline up to 14 days

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

Part 3 CF: Physical Exams

时间窗: 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

时间窗: 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

时间窗: 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

时间窗: Baseline up to 28 days

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

Part 4 CF: Physical Exams

时间窗: 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

时间窗: 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

时间窗: Baseline up to 42 days

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

Part 4 CF: Vital Signs

时间窗: Baseline up to 42 days

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

次要结局

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)
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)
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)
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)
Part 3 CF: FEV1(Baseline through Day 28)
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)
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)
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)
Part 4 CF: FEV1(Baseline through Day 42)
Part 4 CF Sweat Chloride(Baseline through Day 42)

研究者

发起方

Proteostasis Therapeutics, Inc.

申办方类型

Industry

责任方

Sponsor

研究点 (48)

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