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The primary purpose of this study is to evaluate the safety and tolerability of H021 tablets following oral administration of single and multiple ascending doses in healthy participants.
This is a single center, Phase 1, randomized, double-blind, placebo controlled, sequential single ascending dose/multiple ascending dose (SAD/MAD) study, with a food-effect arm. The study will be divided into two parts:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| SAD Cohort 1: H021 6.25 milligrams (mg) | Experimental | Participants will receive H021, 6.25 mg oral tablet, as single-dose on Day 1 under fasting or fed conditions. |
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| SAD Cohort 2: H021 12.5 mg | Experimental | Participants will receive H021, 12.5 mg oral tablet, as single-dose on Day 1 under fasting conditions. |
|
| SAD Cohort 3: H021 25 mg | Experimental | Participants will receive H021, 25 mg oral tablet, as single-dose on Day 1 under fasting conditions. |
|
| SAD Cohort 4: H021 50 mg | Experimental | Participants will receive H021, 50 mg oral tablet, as single-dose on Day 1 under fasting conditions. |
|
| SAD Cohort 5: H021 100 mg | Experimental | Participants will receive H021, 100 mg oral tablet, as single-dose on Day 1 under fasting conditions. |
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| MAD Cohort 6: H021 12.5 mg |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| H021 | Drug | H021 oral tablet. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants with Adverse Events (AEs) | An AE is defined as any untoward medical occurrence in a participant or clinical trial participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. Any clinically significant changes in vital signs, electrocardiogram (ECG) measurement, physical examination and clinical laboratory parameters will be recorded as AE. | Up to final follow-up (SAD Part: up to 8 days: MAD Part: up to 14 days) |
| Measure | Description | Time Frame |
|---|---|---|
| SAD Part: Area under the concentration-time curve from time zero until the last observed concentration (AUC0-t) of H021 | AUC0-t is an area under the concentration-time curve from time zero (pre-dose) to time of last observed concentration. | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| MAD Part: Change From Baseline in Micro-RNA-124 (miR-124) Expression in Peripheral Blood Mononuclear Cells (PBMCs) | Change from baseline in miR-124 expression in PBMCs will be assessed. | Day 1 at predose, and at 12 hours, on Day 5 at predose, and on Day 7 at predose, and at 12 hours post-last dose |
| MAD Part: Change From Baseline in Interleukin (IL)-6, Tumor Necrosis Factor Alpha (TNF-α), IL-17A, and Interferon Gamma (IFN-γ) in Blood Serum |
Inclusion Criteria:
Male or female, non-smoker (no use of tobacco or nicotine products within 3 months prior to screening), greater than and equal to (>=) 18 and less than and equal to (<=) 55 years of age, with body mass index (BMI) greater than (>)18.5 and less than (<) 32.0 kilograms per square meter (kg/m^2).
Healthy as defined by:
Female participants of non-childbearing potential must be:
Participants must be willing not to donate sperm for 90 days or ova (egg) for 6 months after the last dose.
Sexually active females of childbearing potential and non-sterile males must be willing to use an acceptable contraceptive method throughout the study.
Able to understand the study procedures and provide signed informed consent to participate in the study.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dr. Ofer Gonen | Contact | 0385939801 | o.gonen@nucleusnetwork.com.au |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nucleus Network Ply Ltd. | Recruiting | Melbourne | Victoria | 3004 | Australia |
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| ID | Term |
|---|---|
| D003093 | Colitis, Ulcerative |
| ID | Term |
|---|---|
| D003092 | Colitis |
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
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Participants will receive H021, 12.5 mg oral tablet once daily from Day 1 to Day 7 under fasting conditions. |
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| MAD Cohort 7: H021 25 mg | Experimental | Participants will receive H021, 25 mg oral tablet once daily from Day 1 to Day 7 under fasting conditions. |
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| MAD Cohort 8: H021 50 mg | Experimental | Participants will receive H021, 50 mg oral tablet once daily from Day 1 to Day 7 under fasting conditions. |
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| SAD-H021 Placebo | Placebo Comparator | Participants will receive H021, placebo oral tablet, as single-dose on Day 1 under fasting or fed conditions. |
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| MAD-H021 Placebo | Placebo Comparator | Participants will receive H021, placebo oral tablet once daily from Day 1 to Day 7 under fasting conditions. |
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| H021 Placebo | Drug | H021 placebo oral tablet. |
|
| SAD Part: Area under the concentration-time curve from time zero to infinity (AUC0-infinity) of H021 |
AUC0-infinity is an area under the concentration-time curve from time zero to infinity (extrapolated). |
| pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Maximal observed concentration (Cmax) of H021 | Cmax is a measure of the maximum amount of drug in the plasma after the dose was given. | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Time to Reach Cmax (Tmax) of H021 | Tmax is a measure of the time to reach the maximum concentration in the plasma after the dose was given. | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Lag Time (Tlag) of H021 | Tlag is time of observation prior to the first observation with a measurable (non-zero) concentration (for food effect cohort only). | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Residual area of H021 | Residual area is calculated as percentage of AUC0-inf due to extrapolation from the time of the last observed concentration to infinity, calculated as [1 - (AUC0-t/AUC0-inf)] x 100. | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24), and 48 hours post-dose |
| SAD Part: Terminal elimination half-life (T1/2 el) of H021 | T1/2 el is defined as the duration until observation of half of the maximum concentration of drug dose. | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Terminal elimination rate constant (Kel) of H021 | Kel is defined as first-order rate constant associated with the terminal (log-linear) portion of the curve. | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Apparent clearance (CL/F) of H021 | CL/F is apparent total clearance of the drug from plasma after oral administration | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Apparent volume of distribution (Vz/F) of H021 | Vz/F is apparent volume of distribution during terminal phase after non-intravenous administration | pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours post-dose |
| SAD Part: Cumulative Urinary Excretion From Time Zero to Time t (Ae0-t) of H021 | Ae0-t is defined as cumulative urinary excretion from time zero to time t, calculated as the sum of the amounts excreted over each collection interval. | pre-dose (spot; within 2 hours) and 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
| SAD Part: Maximal Rate of Urinary Excretion (Rmax) of H021 | Rmax is defined as maximal rate of urinary excretion, calculated by dividing the amount of drug excreted in each collection interval by the time over which it was collected. | pre-dose (spot; within 2 hours) and 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
| SAD Part: Time of Maximal Urinary Excretion (TRmax) of H021 | TRmax is defined as time of maximal urinary excretion, calculated as the midpoint of the collection interval during which Rmax occurred. | pre-dose (spot; within 2 hours) and 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
| SAD Part: Renal Clearance (CLR) of H021 | CLR is renal clearance, calculated as Ae0-t /AUC0-t. | pre-dose (spot; within 2 hours) and 0-4, 4-8, 8-12, 12-24, and 24-48 hours post-dose |
| MAD Part: Area under the concentration-time curve from time zero to time 24 hours (AUC0-24) of H021 | AUC0-24 is an area under the concentration-time curve from time zero to 24 hours post-dose. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Cmax of H021 | Cmax is a measure of the maximum amount of drug in the plasma after the dose was given. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Tmax of H021 | Tmax is a measure of the time to reach the maximum concentration in the plasma after the dose was given. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Area under the concentration-time curve for one dosing interval (τ) at steady- state (AUC0-τ) of H021 | AUC0-τ is an area under the concentration-time curve for one dosing interval (τ) at steady- state. In this study τ = 24 hours (equivalent to AUC0-24) will be reported. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Cmax ss of H021 | Cmax ss is a measure of the maximum amount of drug in the plasma at steady-state after the dose was given. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Tmax ss of H021 | Tmax ss is a measure of the time to reach the maximum concentration in the plasma at steady state after the dose was given. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Minimal observed concentration at steady-state (Cmin ss) of H021 | Cmin ss is minimal observed concentration at steady-state. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: AUC0-t of H021 | AUC0-t is an area under the concentration-time curve from time zero (pre-dose) to time of last observed concentration. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: AUC0-inf of H021 | AUC0-infinity is an area under the concentration-time curve from time zero to infinity (extrapolated). | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Residual area of H021 | Residual area is calculated as percentage of AUC0-inf due to extrapolation from the time of the last observed concentration to infinity, calculated as [1 - (AUC0-t/AUC0-inf)] x 100. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: T½ el of H021 | T1/2 el is defined as the duration until observation of half of the maximum concentration of drug dose. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Kel of H021 | Kel is defined as first-order rate constant associated with the terminal (log-linear) portion of the curve. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Apparent clearance at steady-state (Clss/F) of H021 | Clss/F is apparent clearance at steady-state. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Apparent volume of distribution at steady-state (Vz ss/F) of H021 | Vz ss/F is apparent volume of distribution at steady-state. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Accumulation ratio (RAUC) | RAUC is accumulation ratio for AUC. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
| MAD Part: Accumulation Ratio (RCmax) | RCmax is accumulation ratio for Cmax. | Day 1 at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-first dose; predose on Days 4, 5, 6; Day 7 at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48 hours post-last dose |
Change from baseline in IL-6, TNF-α, IL-17A, and IFN-γ in blood serum will be assessed. |
| Day 1 at predose, and at 12 hours, on Day 5 at predose, and on Day 7 at predose, and at 12 hours post-last dose |
| D015212 |
| Inflammatory Bowel Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |