A Pharmacokinetic and Clotting Activity Study of FVIII-PEGLip

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04592692
• Other study ID #: CL-SelectAte-II-01
• Status: Recruiting
• Phase: Phase 2
• Start date: December 23, 2019
• Est. completion date: May 31, 2022

Study information

• Verified date: October 2021
• Source: Ascension Healthcare Development Limited
• Contact: Sam Yurdakul
• Phone: +44(0)2072915400
• Email: sam.yurdakul[@]ascension.co.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

This is an open-label multicenter trial for patients with severe haemophilia A with inhibitors to FVIII and without inhibitors as control. The trial consists of 4 periods: Screening, Stage A, Stage B and Safety Follow-up. After signing informed consent, patients are assessed for eligibility during a Screening period lasting up to 21 days. All eligible patients enter Stage A - Regimen estimation. The non-inhibitor patients receive a single IV injection at a dose of 35 IU/kg FVIII reconstituted with Water For Injection. Following a 4-day wash-out period, these patients as well as patients with inhibitors receive a single IV injection of FVIII-PEGLip at a dose of 35 IU/kg FVIII + PEGLip 22 mg/kg to determine the duration of haemostatic cover and therefore required injection frequency to prevent bleeds. Stage B - multiple dosing: all patients receive injections of FVIII-PEGLip for 6 weeks at a frequency determined in Stage A for each individual patient. Safety follow-up: 15 and 30 days after the last injection of FVIII-PEGLip, patients are contacted for any adverse events or bleeding episodes.

Recruitment information / eligibility

• 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.

Related Conditions & MeSH terms

• Hemophilia A
• Hemophilia A With Inhibitor

Intervention

Drug:
• PEGylated Liposome (PEGLip)
Intravenous co-administration of PEGLip with Simoctocog alfa

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ascension Healthcare Development Limited

Country where clinical trial is conducted

Russian Federation, 

Outcome

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