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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TU7710 | Experimental | TU7710 of escalating 5 doses |
|
| Normal Saline (placebo of TU7710) | Placebo Comparator | Placebo of TU7710 at corresponding TU7710 dose level |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TU7710 | Drug | 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Seoul National University Hospital | Seoul | South Korea |
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| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| D002836 | Hemophilia B |
| D001778 | Blood Coagulation Disorders |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D020147 | Coagulation Protein Disorders |
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| ID | Term |
|---|---|
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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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.
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| Normal saline | Drug | Placebo of TU7710 at corresponding TU7710 dose level. In each dose level, 2 subjects will be assigned to placebo group. |
|
| 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 |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D040181 | Genetic Diseases, X-Linked |