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This study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of multiple subcutaneous doses of KN057 in subjects with hemophilia A or B, with or without inhibitors to Factor VIII (FVIII) or Factor IX (FIX). 24 adult participants 18 to 70 years of age with moderately severe to severe hemophilia A or hemophilia B (defined as FVIII or FIX activity ≤2%, respectively) with or without inhibitors (including 18 HA/HB patients without inhibitors and 6 HA/HB patients with inhibitors) are expected to be enrolled in this study during which they will receive prophylaxis treatment (defined as treatment by SC injection once weekly of KN057).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| KN057 (Cohort 1:HA/HB) | Experimental | Injection, once a week |
|
| KN057 (Cohort 2:HA/HB) | Experimental | Injection, once a week |
|
| KN057 (Cohort 3:HA/HB) | Experimental | Injection, once a week |
|
| KN057 (Cohort 4:HAW/HBW) | Experimental | Injection, once a week |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| KN057 doseⅠ | Biological | KN057 subcutaneous (SC) injection |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Frequency and severity of treatment emergent adverse events(TEAEs) | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) is any untoward medical occurrence at any dose that resulted in death; life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and non-serious AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. | Day 1 up to Day 85 |
| Withdrawals due to TEAEs | An AE is any untoward medical occurrence in a clinical investigation participant administered a product and the event does not need to have a causal relationship with the treatment. TEAEs are AEs occurred following the start of treatment or AEs increasing in severity during treatment. | Day 1 up to Day 85 |
| Number of Participants With Abnormal Laboratory Findings-Hematology | White blood cells, red blood cells; the count of lymphocyte, neutrophils, monocytes, eosinophils, basophils; the percentage of lymphocyte, neutrophils, monocytes, eosinophils, basophils; hemoglobin, red blood cell pressure, platelet count | Day 1 up to Day 85 |
| Number of Participants With Abnormal Laboratory Findings-Urinalysis | blood, urobilirubin, urobiliogen, ketone body, protein, nitrite, red blood cell (qualitative and/or quantitative), white blood cell (qualitative and/or quantitative), pH, urinary glucose. | Day 1 up to Day 85 |
| Number of Participants With Abnormal Laboratory Findings-Blood biochemistry |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of KN057 | Day 1 up to Day 8 | |
| Time to Reach Maximum Plasma Concentration (Tmax) of KN057 | Day 1 up to Day 8 | |
| Area Under the Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of KN057 |
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Inclusion Criteria:
Male, 18-70 years old (including threshold), weight≥40kg;
Moderately severe to severe hemophilia A or B (Factor VIII or Factor IX activity ≤2%)
Participants who are enrolled into the Non-Inhibitor Cohort must meet the following criteria:
①negtive results of of inhibitors to Factor VIII (FVIII) or Factor IX (FIX) in screening period.
②with ≥6 acute bleeding episodes (spontaneous or traumatic, not including episodes of bleeding during surgery) that required treatment within 6 months before screening and willing to continue to receive on-demand treatment during the study.
③using coagulation factor replacement therapy for more than 50 exposure days before screening.
Participants who are enrolled into the Inhibitor Cohort must meet the following criteria:
①positive results of inhibitors to Factor VIII (FVIII) or Factor IX (FIX) in screening period.
②with ≥6 acute bleeding episodes (spontaneous or traumatic, not including episodes of bleeding during surgery) that required treatment within 6 months before screening and willing to continue to receive on-demand treatment during the study.
Be willing to undergo a washout period of the original treatment regimen before the administration of KN057: at least 48 hours for recombinant activated coagulation factor Ⅶ (rFⅦa); at least 72 hours for FⅧ and prothrombin complex (PCC); at least 96 hours for FⅨ; For other drugs or investigational products with a long half-life, such as Emicizumab, at least five half-lives should have passed prior to dosing.
Be willing to comply with the relevant management regulations of the clinical trial unit, and follow study procedures.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Renchi Yang, Doctor | Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences | Principal Investigator |
| Shujie Wang, Doctor | Peking Union Medical College Hospital | Principal Investigator |
| Hu Zhou, Doctor | Henan Cancer Hospital(The Affiliated Cancer Hospital Of ZhengZhou University) | Principal Investigator |
| Ziqiang Yu, Doctor | The First Affiliated Hospital of Soochow University | Principal Investigator |
| Changcheng Zheng, Doctor | The First Affiliated Hospital of USTC (Anhui Provincial Hospital) | Principal Investigator |
| Jing Sun, Doctor | Nanfang Hospital, Southern Medical University | Principal Investigator |
| Xielan Zhao, Doctor | Xiangya Hospital of Central South University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences | Tianjin | Tianjin Municipality | 300020 | China | ||
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| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| KN057 dose Ⅱ |
| Biological |
KN057 SC injection |
|
| KN057 dose Ⅲ | Biological | KN057 SC injection |
|
Total bilirubin and indirect bilirubin, direct bilirubin, alanine aminotransferase, aspertate aminotransferase, GGTP (gamma glutamyl transpeptidase), alkaline phosphatase, total protein, albumin, globulin, albumin-globulin ratio, urea, creatinine, uric acid, glucose, total cholesterol, triglyceride, low density lipoprotein cholesterol (ldl-c), high-density lipoprotein cholesterol (hdl-c), lactate dehydrogenase, creatine kinase, chlorine, calcium, sodium, potassium, C reactive protein
| Day 1 up to Day 85 |
| Number of Participants With Abnormal Laboratory Findings-Coagulation tests | Prothrombin time (PT), International Standardized ratio (INR), Activated partial thrombin time (APTT), thrombin time (TT), fibrinogen (FBG/FIB), D-dimer (D-DI), fibrinogen degradation product (FDP), antithrombin - ⅲ (AT- ⅲ) | Day 1 up to Day 85 |
| Number of Participants With Clinically Significant Changes in Vital Signs Data | Vital signs:blood pressure (systolic blood pressure, diastolic blood pressure), respiration, temperature, pulse; | Day 1 up to Day 85 |
| Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) | ECG: HR; RR; PR; QRS; QT; QTc | Day 1 up to Day 85 |
| Number of Participants With Clinically Significant Changes in Physical Examination Findings | Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Clinical significance was judged by the investigator. | Day 1 up to Day 85 |
| Number of Participants With Injection Site Reactions | Injection site reactions may include, but are not limited to: erythema, sclerosis, ecchymosis, pain, and itching. | Day 1 up to Day 85 |
| Day 1 up to Day 8 |
| Cmax,ss: Maximum observed KN057 concentration at steady-state | Day 36 up to Day 43 |
| Time to Reach Maximum Plasma Concentration at steady-state (Tmax,ss) of KN057 | Day 36 up to Day 43 |
| Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of KN057 | Day 36 up to Day 43 |
| Apparent Clearance (CL/F) of KN057 | Day 36 up to Day 43 |
| Lowest Concentration Observed During the Dosing Interval (Cmin) of KN057 | Day 36 up to Day 43 |
| Pharmacodynamics index: Changes of TFPI from baseline; | Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits early phases of the procoagulant response. TFPI: Total TFPI, Free TFPI | Day 1 up to Day 169 |
| Pharmacodynamics index: Changes of Prothrombin fragment 1+2 (PF1+2) from baseline; | Prothrombin fragment 1+2 (F1+2) is the amino terminus fragment of the prothrombin molecule. | Day 1 up to Day 169 |
| Pharmacodynamics index: Thrombin Generation (TGA); | Lag Time; Peak Thrombin; Endogenous Thrombin Potential; | Day 1 up to Day 169 |
| Number of Participants Who Tested Positive for Anti-KN057 Antibody (ADA) | Human plasma ADA samples were analyzed for the detection of anti KN057 antibodies. | Day 1 up to Day 169 |
| Number of Participants Who Tested Positive for Neutralizing Antibody (NAb) | Human plasma NAb samples were analyzed for the presence or absence of NAb to KN057. | Day 1 up to Day 169 |
| Annualized Bleeding Rate | ABR = number of bleeds requiring treatments/ (days on treatment period / 365.25) | Day 1 up to Day 169 |
| stitute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences |
| Tianjin |
| Tianjin Municipality |
| 300020 |
| China |
| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |