A Phase I of SS109 in Hemophilia A or and B With Inhibitors

Study Overview
=================
Brief Summary
-----------------
This phase I study aims to evaluate the safety, PK/PD and immunogenicity of SS109 in hemophilia A or and B with inhibitors. Twenty -seven patients are enrolled in study, and divided into five dose cohorts, from 30μg/kg to 360μg/kg. Dose 1 cohort enrolls three patients, each other dose cohorts enroll six patients. All patients included in the study will continue to be followed up until 28 days after SS109 administration.

Detailed Description
-----------------
This study is an open label, dose escalation, multicenter clinical trial. The study sets up a science review committee to assess the dose escalation. Serial blood samples for PK/PD analysis will be taken up to 72 hours after SS109 injection. Patients safety will be routinely monitored throughout the study.

Official Title
-----------------
To Evaluate the Safety, PK/PD and Immunogenicity of SS109 in Hemophilia Patients With Blood Coagulation Factor Ⅷ or Ⅸ Inhibitors After Single Administration, Open Label, Dose Escalation, and Multicenter Phase I Clinical Trial

Conditions
-----------------
Hemophilia A With Inhibitor, Hemophilia B With Inhibitor, Factor VII Deficiency

Intervention / Treatment
-----------------
* Biological: SS109


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age was 18 to 65 years old，when signing the informed consent form, male; Clinical diagnosis of hemophilia A or B (previous or screening period FⅧ activity level≤ 1% or FⅨ activity level≤ 2%), and there is one of the following conditions: FⅧ or FⅨ inhibitor level ≥ 5Bu/mL during screening period; During the screening period, the level of FⅧ and FⅨ inhibitors was less than 5 Bu/mL and more than 0.6 Bu/mL, but had a high response to factor Ⅷ or IX injection (such as, the patient had a positive history of FⅧ/FⅨ inhibitors, and then the inhibitor level is ≥ 5Bu/mL, after the second infusion of FⅧ/FⅨ); No active bleeding symptoms before the first injection; Patients can comply with the requirements of the protocol and be willing to complete the study as planned and provide biological samples for test; Be able to understand the procedures and methods of this clinical trial. The patient voluntarily participates and signs by himself or by the impartial witness Exclusion Criteria: Patients with known history of hypersensitivity to the investigational drug preparation and any of its components; There was hypersensitivity or anaphylaxis after FⅦ or IgG2 injection treatment in the past; Patients with FⅦ inhibitor positive or with FⅦ inhibitor positive history in screening period; Severe anemia (hemoglobin < 60g/L); Platelet count < 100 × 109/L； Patients with abnormal liver and kidney functions: alanine aminotransferase (ALT) or aspartate aminotransferase (AST)≥ 2.5 times the upper limit of normal value (ULN), or total bilirubin ≥ 1.5 times ULN; or blood creatinine (Cr) ≥ 1.5 times; One or more tests are positive, such as HBsAg, HCV antibody, anti-human immunity for HIV antibody and anti-treponema pallidum specific antibody (TPHA); Except for hemophilia A or B, the coagulation indexes of any other bleeding disease or other diseases are obviously different(such as platelet disease, vitamin K deficiency, etc.); History or symptoms of any previous arterial or venous thromboembolism event (such as atherosclerosis, myocardial infarction, ischemic stroke, transient ischemic attack, deep vein thrombosis or pulmonary hypertension, pulmonary embolism), or patients with history of disseminated intravascular coagulation (DIC); Suffered from serious heart disease, such as unstable angina, congestive heart failure (New York Heart Association, ≥ Grade III), severe arrhythmia (QTc interval>450ms, corrected by Fridericia formula), hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg) not controlled by treatment; Receive any product containing FⅦ or FⅦa (plasma derived or recombinate) within 48 hours before the first injection; Receive any product containing FⅧ (plasma derived or recombinate) within 72 hours before the first injection; or receive any product containing FIX (plasma derived or recombinate) within 96 hours before administration; Patients have used any anticoagulant, anti-fibrinol solvent, chemical, biological products or traditional Chinese medicine that affect platelet function within one week before the first injection or need to use any anticoagulant, anti-fibrinol solvent during PK/PD period, including non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin; Patients have received immunomodulator (such as gamma globulin α- Interferon and prednisone>10mg/d [and>7 days] or similar drugs, except antiretroviral drugs); Patients who received whole blood or plasma treatment within 2 weeks before the first injection; Patients who have received vaccines within 4 weeks or planned to be vaccinated during the trial before the first injection; Major surgery (such as orthopedic surgery and abdominal surgery) was performed within 1 month before the first injection, or planned to undergo surgery during the study; Patients who have been selected into other clinical trials within 1 month before the first injection; Patients with a history of drug abuse or alcohol abuse (alcohol abuse standard: male with a long-term alcohol consumption history of more than 5 years, equivalent to alcohol ≥ 40g/d, ≥ 20g/d for women, or a history of heavy drinking within 2 weeks, with the equivalent alcohol volume > 80g/d. Patients suffering from mental illness or obvious mental disorder, or incapacity and lack of cognition caused by other reasons A birth plan or sperm donation plan from the study to 3 months after the study, or patients are unwilling to take contraceptive measures (such as condoms, diaphragms, intrauterine devices, etc.); A disease with clinical significance or other reasons that the researcher thinks patients are not suitable for participating in this clinical trial (if patients cannot benefit from clinical trials); The investigator considers patients with poor compliance, and patients will be impossible to evaluate the efficacy or accomplish the course of treatment and follow-up.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose cohorts<br>Dose cohorts were designed to evaluate the safety, immunogenicity and PK/PD. | Biological: SS109<br>* 27 patients are enrolled in cohorts ,and will continue to be followed up until 28 days after SS109 administration for evaluating safety, PK/PD and immunogenicity.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of adverse event/serious adverse event/specical interest adverse event(AE/SAE/AESI) | AE/SAE/AESI is any untoward clinical signs, symptoms or outcomes | Up to 28 days after SS109 injected | 
| Number of patients with positive FVII inhibitor, anti- drug antibody (ADA) | Number of patients with positive FVII inhibitor, anti drug antibody (ADA) | Up to 28 days after SS109 injected | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| t½ | Half-life | Up to 72 hours after SS109 injected | 
| Cmax | Maximum concentration | Up to 72 hours after SS109 injected | 
| Tmax | Time to reach maximum concentration | Up to 72 hours after SS109 injected | 
| AUC0-last | Area under the curve from 0 to last | Up to 72 hours after SS109 injected | 
| AUC0-72 | Area under the curve from 0 to 72 hour | Up to 72 hours after SS109 injected | 
| AUC0-∞ | Area under the curve from 0 to ∞ | Up to 72 hours after SS109 injected | 
| CL | Clearance | Up to 72 hours after SS109 injected | 
| Vd | Volume of distribution | Up to 72 hours after SS109 injected | 
| MRT | Mean residence time | Up to 72 hours after SS109 injected | 
| IR | Incremental recovery rate | Up to 72 hours after SS109 injected |