A Phase 1, Evaluate the Safety, Tolerability, and Pharmacokinetics of INS018_055 in Healthy Subjects
Condition: Idiopathic Pulmonary Fibrosis
MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis
Study type: Interventional
Phase: Phase 1

Summary: 
      The sponsor is planning to conduct a Phase 1, randomized, double-blind, placebo-controlled,
      oral single and multiple ascending-doses, parallel group study to evaluate the safety,
      tolerability and PK of INS018_055 in healthy subjects. The study will be conducted in 1
      clinical site in the New Zealand, consisting of 2 parts: Part A (single ascending dose [SAD])
      and Part B (multiple ascending dose [MAD]).
    

Detailed description: 
      This is a Phase 1, randomized, 2-part (Part A and B), double-blind, placebo controlled single
      and multiple ascending doses study designed to assess the safety, tolerability, and PK of
      INS018_055 when administered as oral doses to healthy subjects. Additionally, this study will
      investigate the impact of food on the PK of INS018_055.

      Part A (Single Ascending Dose [SAD]):

      Eight healthy subjects will be assigned to each of up to 5 sequential dose cohorts and will
      be randomly assigned within each dose cohort to receive INS018_055 or a matched placebo in a
      ratio of 3:1 (6 active, 2 placebo) on Day 1 for a total of up to approximately 40 subjects.
      Subjects in Part A will be admitted to the study site on Day -1 and dosed on Day 1 after
      fasting (nothing to eat or drink, except water) for at least 10 hours. Water is not allowed 1
      hour prior to and 1 hour after dosing. Water can be consumed ad libitum at other times.
      Subjects will remain fasted on Day 1 for 4 hours after dosing. Subjects will be discharged
      from the study site on Day 4, after the scheduled procedures and review of the Day 4 safety
      data by the investigator (or designee). Subjects will come back for an end of study (EOS)
      visit on Day 8 (± 1 day).

      A sentinel cohort of 2 subjects will be used to mitigate the risk of unexpected adverse
      events (AEs) not predicted by preclinical pharmacology and toxicology studies for each dosing
      cohort, starting with Cohort 1 (the initial dose cohort). The sentinel subjects will be dosed
      in a blinded fashion (1 active, 1 placebo) and monitored for at least 1 day before the
      remaining 6 subjects in that cohort are dosed. Initiation of dosing of the remaining 6
      subjects will depend on an initial safety review by the investigator indicating that
      administration of the study treatment was safe and well tolerated in the sentinel subjects.

      Dose escalation will occur only after the real time PK, safety, and tolerability data
      (including reported AEs, physical examinations, vital signs, electrocardiograms (ECGs), and
      clinical laboratory results up to 48 hours after dosing) of the preceding dose cohort for at
      least 6 subjects are assessed and the study treatment is deemed safe and well tolerated by
      the safety review committee (SRC). As new safety and/or PK data become available, the
      anticipated dose escalation scheme may change following a review of the data by the SRC.
      Preliminary PK data from subjects in this study will help guide dose escalation to higher
      doses. Dose escalation in Cohorts 4 and 5 will only occur after the PK data from at least the
      first 2 cohorts have been assessed and deemed sufficient to model exposures for Cohorts 4 and
      5.

      Food Effect Assessment (Cohort 4 in Part A only): Subjects in Cohort 4 of Part A will
      participate in a food effect arm. The actual dose level for food effect cohort is subject to
      change and will be confirmed by the SRC after review of data from at least the first 2
      cohorts of the SAD. Following the standard SAD dosing on Day 1 and at least 3 days of follow
      up/washout (or 5 times the estimated half-life of INS018_055 based on the observed data,
      whichever is longer) (Period 1), enrolled subjects will enter Period 2 and be re administered
      the same dose of INS018_055 or matching placebo (the same treatment that they received on Day
      1 of Period 1) after completing a standard high-fat meal. Subjects will fast (nothing to eat
      and drink, except water) for at least 10 hours overnight and receive a standard high-fat
      breakfast 30 minutes prior to dosing. The high-fat breakfast will be consumed within
      approximately 30 minutes. Subjects will remain at the study site on Day 4 of Period 2 until
      the scheduled procedures and review of the Day 4 safety data by the investigator (or
      designee) are completed. The washout period of at least 3 days (or 5 times the estimated half
      life of INS018_055 based on the observed data, whichever is longer) may be extended based on
      available PK data from previous cohorts. The Day -1 procedures will not be repeated for
      Period 2.

      Physical examinations, vital sign measurements, 12-lead ECGs, and clinical laboratory
      evaluations will be performed at selected time points throughout the study. Subjects will
      also be closely monitored for AEs throughout the study. Blood samples for PK will be
      collected up to 72 hours after study treatment administration on Day 1 for all cohorts. For
      biomarkers (CD4+ and CD8+ T-cells), blood samples will be collected at check-in (Day -1), Day
      2, and Day 4 after administration of INS018_055. Fecal occult blood tests will be done with
      all stools passed at screening, check-in (Day -1), and during the 72 hour observation period.
      Subjects will be discharged on Day 4.

      Part B (Multiple Ascending Dose [MAD]):

      Eight healthy subjects will be assigned to each of up to 5 sequential once daily (QD) or
      twice daily (BID) dose cohorts and will be randomly assigned within each dose cohort to
      receive INS018_055 or a matched placebo for 10 days in a ratio of 3:1 (6 active, 2 placebo),
      for a total of up to approximately 40 subjects.

      Subjects in Part B will begin dosing, after safety and tolerability data (including reported
      AEs, physical examination, clinical laboratory results, 12-lead ECGs, and vital signs) from
      at least the first 3 cohorts (Cohorts 1 to 3) in Part A are assessed and the study treatment
      is deemed safe and well tolerated by the SRC. Additionally, sufficient PK data from at least
      the first 3 cohorts of Part A must be obtained to model exposures in Part B. The dosing
      schedule, either QD or BID, will be decided by the SRC after review of the PK, safety, and
      tolerability data from the first 3 cohorts of Part A.

      The initial MAD cohorts will begin dosing with the remaining SAD cohorts. The top dose
      explored in Part B will not exceed the maximum dose explored in Part A. Subsequent dose
      escalations in Part B will not occur until the safety (including AEs, physical examination,
      clinical laboratory results, vital signs, and 12-lead ECGs) and tolerability data up to and
      including Day 14 of the preceding MAD dose cohort for at least 6 subjects are assessed and
      the study treatment is deemed safe by the SRC.

      As new safety or PK data become available, the dose escalation scheme may change. Subjects
      may not receive a subsequent higher dose and may instead be administered a lower dose or may
      repeat the same daily dose with a different administration schema, eg, BID instead of QD
      dosing, to achieve lower maximum observed plasma concentration (Cmax) values, particularly if
      the safety findings are believed to be linked to the Cmax values.

      The highest dose in the MAD (either QD or BID) will be dosed in a staggered way if accrued PK
      data from previous cohorts predict potential exposures above the no observed adverse effect
      level, with 2 subjects starting dosing at least 7 days before the remaining 6 subjects;
      initiation of dosing of the remaining 6 subjects will depend on an initial safety review by
      the investigator indicating that administration of the study treatment was safe and well
      tolerated in the sentinel subjects.

      Each subject in Part B will be admitted to the study site on Day -1 and will begin daily
      dosing on Day 1. Study treatment is to be administered daily at approximately the same time
      in the morning. For BID dosing, the second dose of study treatment will be administered
      approximately 12 hours after the morning dose of study treatment.

      Prior to the morning dosing on Days 1 and 10 for Cohorts 6 to 10, subjects will fast (nothing
      to eat and drink, except water) for at least 10 hours overnight and remain fasted for 4 hours
      after study treatment administration. Water is not allowed 1 hour prior to and 1 hour after
      dosing. Water can be consumed ad libitum at other times. Water is not restricted for the
      evening doses when study treatment is being dosed BID. On Days 1 and 10, lunch will be
      provided approximately 4 hours after the morning dose, dinner will be provided approximately
      10 hours after the morning dose, and a snack will be provided approximately 13 hours after
      the morning dose.

      On Days 2 to 9 for Cohorts 6 to 10, breakfast will be provided approximately 60 minutes after
      study treatment administration. Standardized meals will be provided to the subjects
      throughout the study. Lunch will be provided approximately 4 hours after the morning dose,
      dinner will be provided approximately 10 hours after the morning dose, and a snack will be
      provided approximately 13 hours after the morning dose.

      Physical examinations, vital sign measurements, 12-lead ECGs, and clinical laboratory
      evaluations (including liver function test results) will be performed at selected time points
      throughout the dosing interval. Subjects will be closely monitored for AEs throughout the
      study. Blood samples for PK analyses will be collected up to 72 hours after study treatment
      administration on Day 10. Urine samples for PK analysis will be collected before dosing (Day
      1 as a single void collected within 0 to 24 hours) and over the following intervals after
      dosing: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours on Day 1 and 0 to 4, 4 to 8, 8 to 12, 12
      to 24, and 24 to 48 hours on Day 10 for both QD and BID cohorts. For biomarkers (CD4+ and
      CD8+ T-cells), blood samples will be collected at selected time points for QD and BID dosing
      cohorts. Fecal occult blood tests will be done with all stool samples at screening, check-in
      (Day 1), and throughout Part B on site observation periods, ie, up to Day 14.

      Subjects will be discharged from the study site on Day 14, after the scheduled procedures and
      review of the safety data by the investigator (or designee). Subjects will return to the
      study site on Day 28 (± 3 days) for an EOS visit.
    

Intervention name(s): INS018_055; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): INS018_055 is a small molecule compound. INS018_055 has good solubility in water and was chemically and physically stable at different temperatures.; Placebo
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: This is a Phase 1, randomized, 2-part (Part A and B), first-in-human, double-blind, placebo controlled single and multiple ascending dose study designed to assess the safety, tolerability, and PK of INS018_055 when administered as oral doses to healthy subjects. Additionally, this study will investigate the impact of food on the PK of INS018_055.
Part A (Single Ascending Dose [SAD]):
Food Effect Assessment (Cohort 4 in Part A only):
Part B (Multiple Ascending Dose [MAD]):
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: IPF