Hemophilia A With Inhibitor Clinical Trial
Official title:
A Pharmacokinetic and Clotting Activity Study of FVIII-PEGLip Administered Intravenously to Severe Haemophilia A Patients With and Without Inhibitors to FVIII
The purpose of this study is to demonstrate that PEGylated liposomes (PEGLip) can shield FVIII from the immune system and inhibitors, and therefore provide a prophylactic FVIII replacement therapy for patients with inhibitors to FVIII.
Status | Recruiting |
Enrollment | 20 |
Est. completion date | May 31, 2022 |
Est. primary completion date | February 28, 2022 |
Accepts healthy volunteers | No |
Gender | Male |
Age group | 18 Years to 60 Years |
Eligibility | Inclusion Criteria: - Male adult patients aged 18 to 60 years; - Severe Haemophilia A (FVIII plasma level <1IU/dL) with documented history of bleeds (for at least 6 months prior to enrolment); - For patients without inhibitors: inhibitor titre < 0,6 Bethesda units and no medi-cal history of inhibitors; - For patients with inhibitors: inhibitor titre =0,6 Bethesda units or documented medical history of inhibitors titre =0,6 Bethesda units; - Adequate hematologic function, defined as platelet count = 100,000/µL and hemoglobin = 8 g/dL (= 4.97 mmol/L) at the time of screening; - Adequate hepatic function, defined as total bilirubin = 1.5 × the upper limit of normal (ULN) (excluding Gilbert's syndrome) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 ×ULN at the time of screening; no clinical signs or known laboratory/radiographic evidence consistent with cirrho-sis; - Adequate renal function, defined as serum creatinine = 2.5 × ULN and creati-nine clearance by Cockcroft-Gault formula = 30 mL/min; - Patient's written informed consent, confirming his willingness to comply with the requirements of this protocol. Exclusion Criteria: - Low platelet counts (<100000 / µl); - Congenital or acquired bleeding defects (including acquired hemophilia) other than Hemophilia A; - Abnormal renal function (serum creatinine concentrations greater than 1.3 mg/dL); - Active hepatic disease (persistent aspartate aminotransferase [AST] or alanine aminotransferase [ALT] increases to greater than five times the upper limit of normal); - A history of severe adverse reactions to blood products and/or plasma derived FVIII concentrates or liposomes, or PEG, or Nuwiq; - A history of allergic reactions to bypassing agents; - Any concomitant immunological disease (e.g. autoimmune chronic active hepati-tis, autoimmune thrombocytopenic purpura or Immune Thrombocytopenic Pur-pura (ITP), lupus, Multiple Sclerosis (MS)); - Patients receiving immunosuppressive treatment (excluding glucocorticoids); - Patients receiving therapy with interferon; - Patients receiving any immune tolerance induction (ITI) therapy at the moment of the screening; - Any individual with known dyslipidemia disease or actively taking cholesterol lowering drugs for the treatment of hypercholesterolemia or hyperlipidemia (e.g., statins, cholesterol absorption inhibitors, bile acid sequestrates, nicotinic acid or fibrates); - Intake of NSAIDs (except COX-2 inhibitors), acetylsalicylic acid (Aspirin) or any other antiplatelet agents, opioids.; - Patients who have participated in another Clinical Trial (including medical device studies) within the past 60 days; - Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the patient's safe participation in and completion of the study or interpretation of the study results, according to the Investigator. - For patients without inhibitors - a history of demonstrating long half-lives for FVIII. |
Country | Name | City | State |
---|---|---|---|
Russian Federation | Kemerovo District Clinical Hospital | Kemerovo | |
Russian Federation | Kirov Scientific Research Institute of Hematology and Blood Transfusion | Kirov | |
Russian Federation | National Medical Research Centre of Hematology | Moscow | |
Russian Federation | Novosibirsk State Medical University, Novosibirsk City Haematology Center | Novosibirsk | |
Russian Federation | Samara State Medical University | Samara |
Lead Sponsor | Collaborator |
---|---|
Ascension Healthcare Development Limited |
Russian Federation,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Adverse events | Adverse events / Serious Adverse Events developed in the course of the study | Approximately 12 weeks | |
Primary | Clotting activity based on ROTEM [single dose] | Clotting profile of single IV injection of FVIII-PEGLip based on key ROTEM parameters (CT+CFT) determined at 0 hours (pre-injection) and at 20 min, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after injection in severe Haemophilia A patients with inhibitors and in patients without inhibitors | 7 days | |
Primary | Clotting activity based on FVIII:C concentration [single dose] | Clotting profile of single IV injection of FVIII-PEGLip based on FVIII:C plasma assay measured at 0 hours (pre-injection) and at 20 min, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after injection in severe Haemophilia A patients with inhibitors and in patients without inhibitors | 7 days | |
Primary | Clotting activity based on ROTEM [multiple dose] | Dynamics of blood clotting activity as quantified by key ROTEM parameters (CT+CFT) measured before and 20 minutes after each injection of FVIII-PEGLip at weeks 2, 4 and 6 of 6-week multiple dosing of FVIII-PEGLip in severe Haemophilia A patients with inhibitors and patients without inhibitors. | 6 weeks | |
Primary | Bleed frequency | Frequency of spontaneous bleeding episodes and average length (days) of bleeding-free periods | 6 weeks | |
Primary | Area under the concentration-time curve (AUC) of FVIII:C (FVIII-PEGLip) [single dose] | AUC0-8 of FVIII:C after single IV FVIII-PEGLip injection in severe Haemophilia A patients with inhibitors and in patients without inhibitors | 7 days | |
Primary | Area under the concentration-time curve (AUC) of FVIII:C (FVIII-WFI) [single dose] | AUC0-8 of FVIII:C after single IV FVIII-WFI injection in severe Haemophilia A patients without inhibitors | 4 days | |
Primary | Maximum plasma concentration (Cmax) of FVIII:C (FVIII-PEGLip) [single dose] | Cmax of FVIII:C after single IV FVIII-PEGLip injection in severe Haemophilia A patients with inhibitors and in patients without inhibitors | 7 days | |
Primary | Maximum plasma concentration (Cmax) of FVIII:C (FVIII-WFI) [single dose] | Cmax of FVIII:C after single IV FVIII-WFI injection in severe Haemophilia A patients without inhibitors | 4 days | |
Primary | Time to reaching maximum plasma concentration (Tmax) of FVIII:C (FVIII-PEGLip) [single dose] | Tmax of FVIII:C after single IV FVIII-PEGLip injection in severe Haemophilia A patients with inhibitors and in patients without inhibitors | 7 days | |
Primary | Time to reaching maximum plasma concentration (Tmax) of FVIII:C (FVIII-WFI) [single dose] | Tmax of FVIII:C after single IV FVIII-WFI injection in severe Haemophilia A patients with inhibitors and in patients without inhibitors | 4 days | |
Primary | Half-life (t1/2) of FVIII:C (FVIII-PEGLip) [single dose] | T1/2 of FVIII:C after single IV FVIII-PEGLip injection in severe Haemophilia A patients with inhibitors and in patients without inhibitors | 7 days | |
Primary | Half-life (t1/2) of FVIII:C (FVIII-WFI) | T1/2 of FVIII:C after single IV FVIII-WFI injection in severe Haemophilia A patients without inhibitors | 4 days | |
Secondary | Inhibitor titres | Individual changes of inhibitor titres from baseline measurement to 168 hours after single IV injection of FVIII-PEGLip and at weeks 2, 4, and 6 of 6-week FVIII-PEGLip multiple dosing period | Approximately 12 weeks | |
Secondary | Area under the concentration-time curve (AUC) of PEGLip [single dose] | AUC0-8 of PEGLip determined at 0 hours (pre-injection) and at 20 min, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after single IV injection of FVIII-PEGLip | 7 days | |
Secondary | Maximum plasma concentration (Cmax) of PEGLip [single dose] | Cmax of PEGLip determined at 0 hours (pre-injection) and at 20 min, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after single IV injection of FVIII-PEGLip | 7 days | |
Secondary | Time to reaching maximum plasma concentration (Tmax) of PEGLip [single dose] | Tmax of PEGLip determined at 0 hours (pre-injection) and at 20 min, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after single IV injection of FVIII-PEGLip | 7 days | |
Secondary | Half-life (t1/2) of PEGLip [single dose] | t1/2 of PEGLip determined at 0 hours (pre-injection) and at 20 min, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after single IV injection of FVIII-PEGLip | 7 days | |
Secondary | PEGLip concentration [multiple dose] | PEGLip concentration measured before and 20 minutes after each injection of FVIII-PEGLip at weeks 2, 4 and 6 of 6-week multiple dosing of FVIII-PEGLip | 6 weeks |
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