Hemophilia A With Inhibitor, Hemophilia B With Inhibitor
Conditions
Brief summary
The purpose of this study is to show that KN057 can prevent bleeds in patients with haemophilia A or B with inhibitors and is safe to use. Successfully screened participants will be randomly assigned to KN057 Prophylaxis (Arm 1) versus No Prophylaxis (Arm 2) at a ratio of 2:1. Participants in KN057 Prophylaxis will receive KN057 prophylaxis for 52 weeks upon enrollment. Participants in No Prophylaxis will first receive on-demand treatment for 26 weeks, then switch to KN057 prophylaxis for 26 weeks.The trial period is 59 weeks, including a 3-week screening period, a 26-week main trial, a 26-week extension period, and a 4-week follow-up period after the last administration.
Interventions
DRUGKN057
KN057 will be administered subcutaneously once a week.
Sponsors
Suzhou Alphamab Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male, 12 to 70 years old at the time of signing informed consent (including the cut-off value), body weight ≥25 kg and BMI \<28 kg/m\^2 at screening; 2. The FVIII or FIX inhibitor test is positive at a high titer (≥5 BU/ml) during the screening period; or the FVIII or FIX inhibitor is detected at a low titer (0.6 BU/ml or the upper limit of normal value \< inhibitor titer \< 5 BU/ml) during the screening period and treatment with bypass agents (rFVIIa or PCC) has been started; 3. ≥6 treated bleeding episodes within 26 weeks before screening; 4. Have not used TFPI antibody drugs before; 5. Be able and agree to elute prior drugs for the treatment of hemophilia.
Exclusion criteria
1. Have serious or poorly controlled chronic diseases or obvious systemic diseases; 2. Have a history of thromboembolic disease, or currently have symptoms or signs related to thromboembolic disease or being treated with thrombolytic/antithrombotic therapy; 3. Have high-risk factors for thrombosis: such as a history of coronary atherosclerotic disease, ischemic disease of important organs, vascular occlusive disease, autoimmune diseases with a high risk of thrombosis, or indwelling central venous catheter; 4. The presence of other inherited or acquired bleeding disorders other than hemophilia A and hemophilia B; 5. Being on standard prophylaxis and maintaining it for more than 12 weeks (standard prophylaxis is defined as at least 80% compliance with a predetermined prophylaxis regimen); 6. Ongoing or planned Immune Tolerance Induction treatment; 7. When bleeding occurred in the past, rFVIIa was ineffective and PCC treatment must be used; 8. Known or suspected hypersensitivity to any constituent of the trial product or related products; 9. Have undergone major surgery (as determined by the investigator) within 3 months before screening, or have elective surgery planned during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized bleeding rate (ABR) calculated based on treated spontaneous and traumatic bleeding episodes in Arm 1 and Arm 2. | From Day 1 (the beginning of the main trial) to Day 183 (the end of the main trial), approximately 26 weeks in total | Treated bleeding refers to the use of bypass agents and/or coagulation factors for hemostatic treatment of the bleeding. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with clinically significant changes from baseline in vital signs. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | — |
| KN057 plasma trough concentration. | From start of KN057 treatment (Day 1 for KN057 prophylaxis group, Day 183 for no prophylaxis group) to 4 weeks after the last dose of KN057, approximately 56 weeks for KN057 prophylaxis group and 30 weeks for no prophylaxis group in total | pharmacokinetics |
| ABR calculated based on bleeding episodes, treated spontaneous bleeding episodes, treated joint bleeding episodes, and treated target joint bleeding respectively in Arm 1 and Arm 2. | From Day 1 (the beginning of the main trial) to Day 183 (the end of the main trial), approximately 26 weeks in total | Bleeding episodes includes spontaneous and/or traumatic bleeding episodes, excluding surgery/procedure-related bleeding episodes. Treated bleeding refers to the use of bypass agents and/or coagulation factors for hemostatic treatment of the bleeding. Target joint are those with spontaneous bleeding ≥3 times in the 6 months prior to screening. |
| ABR calculated based on bleeding episodes and treated bleeding episodes respectively in Arm 2. | From Day 183 (the beginning of the extension period) to Day 365 (the end of the extension period), approximately 26 weeks in total | Bleeding episodes includes spontaneous and/or traumatic bleeding episodes, excluding surgery/procedure-related bleeding episodes. Treated bleeding refers to the use of bypass agents and/or coagulation factors for hemostatic treatment of the bleeding. |
| ABR calculated based on bleeding episodes, treated bleeding episodes, treated spontaneous bleeding episodes, treated joint bleeding episodes, and treated target joint bleeding respectively in Arm 1. | From Day 1 (the beginning of the main trial) to Day 365 (the end of the extension period), approximately 52 weeks in total | Bleeding episodes includes spontaneous and/or traumatic bleeding episodes, excluding surgery/procedure-related bleeding episodes. Treated bleeding refers to the use of bypass agents and/or coagulation factors for hemostatic treatment of the bleeding. Target joint are those with spontaneous bleeding ≥3 times in the 6 months prior to screening. |
| Change from baseline in Hemophilia Joint Health Score (HJHS) scores in Arm 1 and Arm 2. | From Day 1 (the beginning of the main trial) to Day 183 (the end of the main trial), approximately 26 weeks in total | Hemophilia Joint Health Scores (HJHS) is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. It comprised an evaluation of the elbows, knee and ankle joints: swelling (0 to 3), duration of swelling (0 and 1), muscle atrophy (0 to 2), crepitus on motion (0 to 2), flexion loss (0 to 3), extension loss (0 to 3), joint pain (0 to 2) and strength (0 to 4), in each item 0 = none and higher score = severe damage and global gait (walking, stairs, running, hopping on 1 leg) scored on scale ranged from 0 to 4, where 0 = all skills in normal limit and 4 = no skills within normal limits). Total HJHS score = sum of joint totals (0 to 120) + general gait (1 to 4) and ranged from 0 (no joint damage) to 124 (severe joint damage), where higher score indicated severe joint damage. |
| Change in HJHS scores from baseline in Arm 1 and from the 26th week in Arm 2. | From Day 1 (the beginning of the main trial) to Day 365 (the end of the extension period), approximately 52 weeks in total | Hemophilia Joint Health Scores (HJHS) is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. It comprised an evaluation of the elbows, knee and ankle joints: swelling (0 to 3), duration of swelling (0 and 1), muscle atrophy (0 to 2), crepitus on motion (0 to 2), flexion loss (0 to 3), extension loss (0 to 3), joint pain (0 to 2) and strength (0 to 4), in each item 0 = none and higher score = severe damage and global gait (walking, stairs, running, hopping on 1 leg) scored on scale ranged from 0 to 4, where 0 = all skills in normal limit and 4 = no skills within normal limits). Total HJHS score = sum of joint totals (0 to 120) + general gait (1 to 4) and ranged from 0 (no joint damage) to 124 (severe joint damage), where higher score indicated severe joint damage. |
| Change from baseline in EuroQol 5 Dimensions 5 Level (EQ-5D-5L) in Arm 1 and Arm 2. | From Day 1 (the beginning of the main trial) to Day 183 (the end of the main trial), approximately 26 weeks in total | The EQ-5D-5L questionnaire is made up for 2 components, health state description and evaluation. In description part, health status is measured in terms of 5 dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression; every dimension contains 5 levels (5L): no difficulty, a little difficulty, moderate difficulty, severe difficulty, very severe difficulty/inability to perform. In evaluation part, the respondents evaluate their overall health status using the visual analogue scale (EQ-VAS) ranging from 0 (worst imaginable health) to 100 (best imaginable health). |
| Change in EQ-5D-5L from baseline in Arm 1 and from the 26th week in Arm 2. | From Day 1 (the beginning of the main trial) to Day 365 (the end of the extension period), approximately 52 weeks in total | The EQ-5D-5L questionnaire is made up for 2 components, health state description and evaluation. In description part, health status is measured in terms of 5 dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression; every dimension contains 5 levels (5L): no difficulty, a little difficulty, moderate difficulty, severe difficulty, very severe difficulty/inability to perform. In evaluation part, the respondents evaluate their overall health status using the visual analogue scale (EQ-VAS) ranging from 0 (worst imaginable health) to 100 (best imaginable health). |
| Number of participants with clinically significant changes from baseline in electrocardiograms. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | — |
| Incidence of thromboembolic events, TMA and DIC. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | TMA refers to 'thrombotic microangiopathy'. DIC refers to 'disseminated intravascular coagulation'. |
| Incidence of hypersensitivity type reactions. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | — |
| Incidence of injection site reactions. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | — |
| Incidence of clinically significant laboratory value abnormalities. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | — |
| Number of participants with clinically significant changes from baseline in physical exam. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | — |
| Levels of Free TFPI. | From start of KN057 treatment (Day 1 for KN057 prophylaxis group, Day 183 for no prophylaxis group) to Day 365, approximately 52 weeks for KN057 prophylaxis group and 26 weeks for no prophylaxis group in total | pharmacodynamics |
| Levels of prothrombin fragment 1+2 (PF1+2). | From start of KN057 treatment (Day 1 for KN057 prophylaxis group, Day 183 for no prophylaxis group) to Day 365, approximately 52 weeks for KN057 prophylaxis group and 26 weeks for no prophylaxis group in total | pharmacodynamics |
| Incidence of anti-KN057 antibody (ADA) and neutralizing antibody (Nab). | From start of KN057 treatment (Day 1 for KN057 prophylaxis group, Day 183 for no prophylaxis group) to 4 weeks after the last dose of KN057, approximately 56 weeks for KN057 prophylaxis group and 30 weeks for no prophylaxis group in total | immunogenicity |
| Incidence of TEAE, TEAE related to the experimental drug and SAE. | From the signing of informed consent to 4 weeks after the last dose of KN057 (the end of the trial), approximately 59 weeks in total | TEAE refers to 'treatment emergent adverse event'. SAE refers to 'serious adverse event'. |
Countries
China
Outcome results
None listed