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A Phase 1, Evaluate the Safety, Tolerability, and Pharmacokinetics of INS018_055 in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT05154240
Recruitment Status : Recruiting
First Posted : December 13, 2021
Last Update Posted : March 24, 2022
Sponsor:
Information provided by (Responsible Party):
InSilico Medicine Hong Kong Limited

Brief 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]).

Condition or disease Intervention/treatment Phase
Idiopathic Pulmonary Fibrosis Drug: INS018_055 Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
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
Official Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Oral Single and Multiple Ascending Doses, Parallel Group Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INS018_055 in Healthy Subjects
Actual Study Start Date : February 21, 2022
Estimated Primary Completion Date : February 28, 2023
Estimated Study Completion Date : February 28, 2023


Arm Intervention/treatment
Active Comparator: INS018_055
oral doses of INS018_055_single dose; oral doses of INS018_055_multiple ascending dose over 10days.
Drug: INS018_055
INS018_055 is a small molecule compound. INS018_055 has good solubility in water and was chemically and physically stable at different temperatures.

Placebo Comparator: Placebo
No active ingredient. Frequency similar to the 2 arms above.
Drug: Placebo
Placebo




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events based on subjective and objective examination [ Time Frame: 12 months ]

    Subjective examination refers to the participant response to standard question to elicit any medically related changes in their well-being.

    Descriptive examination refers to laboratory values as reviewed by the investigator, physical examination findings and ECG Changes, or other documents that are relevant to participant safety.

    AEs will be classified as:

    Mild: These events require minimal or no treatment and do not interfere with the subject's daily activities. Moderate: These events result in a low level of inconvenience or require minor therapeutic measures. Moderate events may cause some interference with normal functioning. Severe: These events interrupt a subject's usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually incapacitating.



Secondary Outcome Measures :
  1. Maximum Plasma Concentration [Cmax] [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  2. Area under the plasma concentration versus time curve (AUC) from time 0 to the last quantifiable concentration (AUC0-t) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  3. AUC from time 0 extrapolated to infinity (AUC0-inf) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  4. AUC from time 0 to the time of the dosing interval (To; AUC0-To) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  5. Accumulation ratio (AR), calculated as AUC0-To (Day 10)/AUC0-To (Day 1) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  6. AR calculated as Cmax (Day 10)/Cmax (Day 1) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  7. Time to reach Cmax (Tmax) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  8. Pre-dose concentrations on Days 1 through 10 (C trough) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  9. Average concentration on Day 1 and Day 10 (Cav) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  10. Terminal elimination rate constant (Kel) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  11. Terminal elimination half-life (t1/2) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  12. Apparent total body clearance (CL/F) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  13. Peak to trough ratio calculated as Cmax/Ctrough [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  14. Apparent volume of distribution (Vd/F) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  15. Metabolite-to parent ratio based on AUC calculated as AUCmetabolite/AUCparent [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  16. Metabolite-to parent ratio based on Cmax calculated as Cmax, metabolite/Cmax, parent [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  17. Renal clearance (CLr) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.

  18. Total amount of drug excreted unchanged in urine from 0 to 24 hours after dosing (XU0-24) [ Time Frame: 12 months ]
    • To determine the PK of INS018_055 following single and multiple oral escalating doses in healthy subjects.
    • To assess the effect of food on the PK of INS018_055 following an oral dose.


Other Outcome Measures:
  1. Characterisation of CD4+ and CD8+ subpopulation of T cells after single dose and of the same after multiple oral escalating doses of INS018_055 [ Time Frame: 12 months ]
    To determine the effect of single doses of INS018_055 on the circulating CD4+ and CD8+ subpopulation of T cells and the effect of multiple oral escalating doses of INS018_055 on circulating CD4+ and CD8+ subpopulation of T cells as these could be used as biomarkers for the selection of the therapeutic dose range.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. The subject is a male or female 18 to 55 years of age, inclusive.
  2. The subject has a body mass index 18 to 32 kg/m2, inclusive, and a total body weight ≥50 kg, inclusive, at screening.
  3. The subject is considered by the investigator to be in good general health as determined by medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG results, and physical examination findings at screening.
  4. Female subjects of childbearing potential must be non-pregnant and non-lactating and must use one of the methods of contraception listed below for the duration of the treatment until at least 28 days after the last dose of the study drug, or be surgically sterile (ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or postmenopausal (defined as amenorrhea 12 consecutive months and documented plasma follicle stimulating hormone level >40 IU/mL). Female subjects must have a negative pregnancy test at screening and before the first dose of study drug.

    Highly effective methods of contraception are those that result in a failure rate of less than 1% per year when used consistently. Examples are provided below:

    1. Implant contraceptive (eg, Jadelle®)
    2. Intrauterine device containing either copper or levonorgestrel (eg, Mirena®)
    3. Male sterilization with absence of sperm in the post-vasectomy ejaculate

      OR an effective method that result in a failure rate of less than 5% to 10% per year. Examples are provided below:

    4. Injectable contraceptive (eg, Depo Provera)
    5. Oral contraceptive pill (combined hormonal contraceptive pill or progestogen-only 'mini-pill')
    6. Vaginal contraceptive ring (eg, NuvaRing®)

    Female subjects must also agree not to donate eggs, from dosing until at least 28 days after the last dose of study drug.

    A male subject and his female partner who is of childbearing potential must agree to use one of the methods of contraception listed above for the duration of the treatment until at least 28 days after the last dose of the study drug. A male subject must also agree not to donate sperm, for the duration of the treatment until at least 28 days after the last dose of the study drug.

  5. The subject agrees to comply with all protocol requirements.
  6. The subject is able to provide written informed consent.

Exclusion Criteria:

  1. The subject has current evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
  2. The subject has any condition possibly affecting drug absorption (eg, gastrectomy).
  3. The subject has a history of cancer with the exception of adequately treated basal cell or squamous cell carcinoma of the skin.
  4. The subject has supine blood pressure (BP) >140 mm Hg (systolic) or >90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is >140 mm Hg (systolic) or >90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the subject's eligibility at screening.
  5. The subject has 12-lead ECG demonstrating corrected QT interval by Fridericia (QTcF) >450 msec, or a QRS interval >120 msec at screening. If QTcF exceeds 450 msec, or QRS interval exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF (or QRS interval) values should be used to determine the subject's eligibility.
  6. The subject has ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat, if deemed necessary:

    1. Serum creatinine level above the upper limit of normal (ULN) or an estimated glomerular filtration rate value <80 mL/min/1.73 m2 calculated with the Chronic Kidney Disease Epidemiology Collaboration formula and the absence of protein in urine, at screening.
    2. Aspartate aminotransferase or alanine aminotransferase values more than >1.5 × ULN.
    3. Fasting glucose >110 mg/dL (6.1 mmol/L).
    4. Total bilirubin >1.5 × ULN.
    5. Hematological values outside the normal reference range for local laboratory results.
    6. Positive fecal occult blood test at screening or at check-in (Day -1).
  7. The subject has any medical history of disease that has the potential to cause a rise in total bilirubin over the ULN. Subjects with borderline clinical laboratory values outside the reference range may be included in the study if the investigator deems that the values are not clinically significant.

    Note: Subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is <ULN.

  8. The subject has a history of any lymphoproliferative disorder (such as Epstein Barr Virus related lymphoproliferative disorder, as reported in some subjects on immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease.
  9. The subject has a history of relevant drug and/or food allergies (ie, allergy to any study drug or excipients, or any significant food allergy that could preclude a standard diet in the clinical unit).
  10. The subject has a clinically significant infection currently or within 6 months of first dose of study drug (eg, those requiring hospitalization or parenteral antimicrobial therapy or opportunistic infections within the last 6 months), or a history of chronic or recurrent infectious disease.
  11. The subject has other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
  12. The subject has or has had symptomatic herpes zoster or herpes simplex within 12 weeks, more than one episode of local herpes zoster, or a history (single episode) of disseminated zoster.
  13. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening.
  14. The subject is a female who is pregnant or lactating.
  15. The subject is a fertile male who is unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product.
  16. The subject is unwilling or unable to comply with the lifestyle restrictions described in this protocol.
  17. The subject is a smoker or has used nicotine or nicotine-containing products (eg, snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers) within 6 months before the first dose of study drug.
  18. The subject has a positive test result for drugs of abuse, or cotinine (indicating active current smoking) at screening or before the first dose of study drug.
  19. The subject has used any prescription or over the counter medications (except paracetamol [up to 2 g per day]), including herbal supplements, within 14 days before the first dose of study drug. Nutritional supplements are allowed if unlikely to interfere with the study results and agreed by medical monitor and investigator.
  20. The subject has consumed grapefruit or grapefruit juice, Seville orange or Seville orange containing products (eg, marmalade), or alcohol-, caffeine-, or xanthine containing products within 48 hours before the first dose of study drug.
  21. The subject will have vaccination with live virus, attenuated live virus, or any live viral components within 2 weeks prior to the first dose of study drug or is to receive these vaccines at any time during treatment or within 8 weeks following completion of study treatment.
  22. The subject has a positive test result for severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). The subject has received the Coronavirus disease 2019 (COVID-19) vaccine within 2 weeks prior to the first dose of study drug or plans to receive a COVID-19 vaccine within 12 weeks after study drug dosing or has positive test for SARS CoV 2 during screening or presence of COVID 19 symptoms within 4 weeks prior to Day -1.
  23. The subject has undergone significant trauma or major surgery within 4 weeks of screening.
  24. The subject has bleeding risk: genetic predisposition to bleeding, a hemorrhagic event in the 12 months before the start of screening, or abnormal laboratory coagulation parameters.
  25. The subject has a first-degree relative with a hereditary immunodeficiency.
  26. The subject has investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are sponsor employees including their family members are directly involved in the conduct of the study.
  27. The subject has a history of alcohol abuse or drug addiction within the last year or excessive alcohol consumption (regular alcohol intake >21 units per week for male subjects and >14 units of alcohol per week for female subjects) (1 unit is equal to approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) or use of alcohol 48 hours before the first dose of study drug.
  28. The subject is involved in strenuous activity or contact sports within 24 hours before dosing and during the study.
  29. The subject has donated blood or blood products >450 mL within 30 days before the first dose of study drug.
  30. The subject has received study drug in another investigational study within 30 days of dosing.
  31. The subject received cytochrome P450 (CYP)/ multidrug and toxin extrusion (MATE) classes of medications within 4 weeks of first dose of INS018_055 or was likely to receive CYP/MATE classes of medications during the study.
  32. In the opinion of the investigator, the subject is not suitable for entry into the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05154240


Contacts
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Contact: Andrey Kukharenko, PhD +852 8192 5741 andrey.kukharenko@insilicomedicine.com

Locations
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New Zealand
NZCR Ltd Recruiting
Christchurch, New Zealand, 8011
Contact: Christopher J Wynne, Doctor    +6433729477    chris.wynne@nzcr.co.nz   
Sponsors and Collaborators
InSilico Medicine Hong Kong Limited
Investigators
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Principal Investigator: Christopher J Wynne, MBChB New Zealand Clinical Research
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Responsible Party: InSilico Medicine Hong Kong Limited
ClinicalTrials.gov Identifier: NCT05154240    
Other Study ID Numbers: INS018-055-001
First Posted: December 13, 2021    Key Record Dates
Last Update Posted: March 24, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by InSilico Medicine Hong Kong Limited:
IPF
Additional relevant MeSH terms:
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Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Lung Diseases
Respiratory Tract Diseases