Study of TU7710 in Warfarin Anti-coagulated Healthy Male Subjects

Study Overview
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Brief Summary
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This is a Phase 1a, double-blind, randomized, placebo- controlled, SAD study to assess safety, tolerability, PK, and PD of TU7710 in warfarin treated healthy male participants.

Detailed Description
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The 40 subjects will be divided into 5 cohorts, and the subjects assigned to each cohort will be randomly assigned with 6 persons receiving TU7710 and 2 persons receiving a placebo for TU7710. Each cohort will proceed in sequence and the next cohort study will be decided by the Safety Monitoring Committee (SMC) . Subjects will be participated in the study after warfarin anti-coagulation to maintain the INR between 2.00 and 3.00 as a preventive measure for potential thrombosis prior to the IP administration.

Official Title
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A First-in-Human (FIH), Randomized, Double-Blind, Placebo-controlled, Phase 1a Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Activity of TU7710 Following Single, Ascending, Intravenous, Dose Administration in Warfarin Anti-coagulated Healthy Male Subjects

Conditions
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Hemophilia A, Hemophilia B, Blood Coagulation Disorders

Intervention / Treatment
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* Drug: TU7710
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥19 and ≤45 BMI of ≥18.0 kg/m2 and ≤30.0 kg/m2 Body weight of ≥55.0 kg and ≤90.0 kg Provide informed consent and willing to comply with study requirements. Exclusion Criteria: History or at risk of developing diseases related to venous thromboembolic events or has family history of such disease History of major bleeding/traumatic event or major surgery within 6 month History of any other clinically relevant coagulation disorder (such as gastrointestinal bleeding, hemorrhoid hemorrhage) Abnormal coagulation related laboratory abnormal test results, including protein C, protein S, PT, aPTT history or current symptoms of gastrointestinal, liver, or renal disease that may affect the pharmacokinetics of the IP History of or are currently with hepatitis B or C (active or carrier state) or human immunodeficiency virus (HIV) or syphilis infection. Currently smoking or have smoked within 1 month before IP or positive cotinine results History of alcohol abuse or positive alcohol breath test Excessive caffeine intake within 7 days before IP INR results not between 2.0 3.0 range after warfarin treatment History of hypersensitivity to medicinal product similar to TU7710 active ingredient or excipient Laboratory abnormal test results, such as QTcF <340msec or >450msec (or family history of long QT syndrome), LDL >190mg/dl , Total cholesterol >300mg/dl, triglycerides > 350mg/dl, ALT >1.5*ULN, AST >1.5*ULN, bilirubin >1.5*ULN Abnormal vital sign SBP >140mmHG, DBP <90mmHg, heart rate <40bpm or >85bpm Any medical history that may increase the risk or affect the evaluation of study objectives by participating in this study at the discretion of the investigator. (e.g., neurology or psychiatric history)

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 5 cohorts with 5 dose levels will sequentially be escalated after safety review. 8 subjects in each cohort who will be randomly assigned to placebo or TU7710 group in 2:6 ratio.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TU7710<br>TU7710 of escalating 5 doses | Drug: TU7710<br>* In each dose level, 6 subjects will be assigned to TU7710. Anticipated escalating dose levels are 100mcg/kg, 200mcg/kg, 400mcg/kg, 800mcg/kg and the last dose will be decided after assessing cohort 1 4 PK, PD, safety, and exploratory efficacy data.<br>|
| Placebo Comparator: Normal Saline (placebo of TU7710)<br>Placebo of TU7710 at corresponding TU7710 dose level | Drug: Normal saline<br>* Placebo of TU7710 at corresponding TU7710 dose level. In each dose level, 2 subjects will be assigned to placebo group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and proportion of participants with adverse events | Number and proportion of participants with adverse events/ adverse reaction /SAE overall and by treatment group | 30 days post-dose | 
| Number of subjects with significant abnormal laboratory values | Mean with standard deviation, median, maximum, minimum results of laboratory values in each treatment group. The laboratory parameters that will be assessed are clinical chemistry, hematology and urinalysis. | 30 days post-dose | 
| ADA and Neutralizing antibody results | Incidence of subjects with ADA and Nab positive results | 30 days post-dose | 
| Number of subjects with significant abnormal Electrocardiography (ECG) findings | Mean with standard deviation, median, maximum, minimum results of ECG results in each treatment group. The ECG parameters that will be assessed are heart rate, PR interval, QRS interval, QT interval, and QTcF interval. | 30 days post-dose | 
| Number of subjects With Significant Abnormal vital sign findings | Mean with standard deviation, median, maximum, minimum results of vital sign values in each treatment group. The vital signs that will be assessed are body temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure. | 30 days post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics assessment_Maximum concentration | Maximum plasma VIIa activity level in each dose level | 4 days post-dose | 
| Pharmacokinetics assessment_AUC last | Area under plasma activity-time curve after TU7710 single administration from time zero to last quantifiable concentration | 4 days post-dose | 
| Pharmacokinetics assessment_AUC inf | Area Under the Plasma activity-time curve after TU7710 single administration From Time Zero Extrapolated to Infinity | 4 days post-dose | 
| Pharmacokinetics assessment_Clearance | Clearance after TU7710 single administration | 4 days post-dose | 
| Pharmacokinetics assessment_Volume of distribution | Volume of distribution after TU7710 single administration | 4 days post-dose | 
| Pharmacokinetics assessment_Dose proportionality | Regression analysis using the power model between the log-converted Cmax, AUClast, and the log-converted dose can be performed, and each parameter adjusted by dose can be calculated and compared between the dose groups | 4 days post-dose | 
| Pharmacokinetics assessment_Tmax | Time from administration to maximum plasma VIIa level in each dose level | 4 days post-dose | 
| Pharmacodynamic assessment_INR change from baseline | INR measurement change from baseline to day 5 in each treatment group and dose level | 5 days post-dose | 
| Pharmacodynamic assessment_PT change from baseline | PT measurement change from baseline to day 5 in each treatment group and dose level | 5 days post-dose | 
| Pharmacodynamic assessment_aPTT change from baseline | aPTT measurement change from baseline to day 5 in each treatment group and dose level | 5 days post-dose | 
| Pharmacokinetics assessment_incremental recovery | Incremental recovery after TU7710 single administration expressed as the ratio of measured peak level against dose per bodyweight | 4 days post-dose |