A Randomized, Multicenter, Double blind, Single doses Study Comparing the Pharmacodynamic, Pharmacokinetic and Safety of Biosimilar EPTACOG Alfa with Novoseven®, in Patient with Hemophilia A or B with Inhibitors
Multicenter, randomized, single doses, double blind, 2 ways cross-over clinical trial comparing two different doses (90μg/kg and 270μg/kg) of the biosimilar Eptacog alfa (activated) (Aryoseven) and NovoSeven® on PK and PD parameters in adult and paediatric patients (>12 years) with hemophilia A/B with inhibitors titer >5 Bethesda Units [BU] , and with >2 episodes of bleeding requiring treatment with FVII infusions within the previous 12 months at trial start, not in bleeding status. Screened patients will be enrolled if the results of Factor VII antibodies assessed by the central lab will be negative. Patients enrolled, not bleeding, randomized to receive two injections of either (A) AryoSeven 90 μg/kg or (B) NovoSeven 90 μg/kg, or (C) AryoSeven 270 μg/kg or (D) NovoSeven 270 μg/kg, separated by a washout period of 2 weeks. At the end of this phase (one month after), all patients will be tested for immunogenicity against factor VII, and if negative, followed for 12 months with the aim of monitoring of inhibiting antibody formation, clinical efficacy and collection of safety data. These patients will be followed to receive AryoSeven for one or more days until resolution of bleeding, with dose and duration of treatment decided by Investigator. In all patients, plasma sampling for determination of antibody formation against Factor VII will be taken every 3 months with instruction to reach the study center every time they have a bleeding. Patients will be hospitalized at time of study medication administration and plasma sampling.
General information
Acronym
IRCT registration information
IRCT registration number:IRCT2017021831193N2
Registration date:2017-08-05, 1396/05/14
Registration timing:prospective
Last update:
Update count:4
Registration date
2017-08-05, 1396/05/14
Registrant information
Name
Amirhossein Saadatirad
Name of organization / entity
AryoGen Pharmed
Country
Iran (Islamic Republic of)
Phone
+98 26 3610 6480
Email address
saadatirada@aryogen.com
Recruitment status
Recruitment complete
Funding source
AryoGen Pharmed
Expected recruitment start date
2017-08-23, 1396/06/01
Expected recruitment end date
2018-01-21, 1396/11/01
Actual recruitment start date
empty
Actual recruitment end date
empty
Trial completion date
empty
Scientific title
A Randomized, Multicenter, Double blind, Single doses Study Comparing the Pharmacodynamic, Pharmacokinetic and Safety of Biosimilar EPTACOG Alfa with Novoseven®, in Patient with Hemophilia A or B with Inhibitors
Public title
A Randomized, Multicenter, Double blind, Single doses Study Comparing the Pharmacodynamic, Pharmacokinetic and Safety of Biosimilar EPTACOG Alfa with Novoseven®, in Patient with Hemophilia A or B with Inhibitors
Purpose
Health service research
Inclusion/Exclusion criteria
Inclusion criteria: Confirmed diagnosis of congenital Hemophilia A or B with inhibitors to FVIII or FIX titer >5 Bethesda Units [BU] with > 2 episodes of bleeding/year requiring treatment with FVII infusions, not in bleeding episode.
Exclusion criteria: Any other type of congenital or acquired coagulopathy, such as: liver disease (hepatitis), vitamin k deficiency, uremia, malignancy. Antibodies against Factor VII. Ongoing bleeding prophylaxis regimens with Novoseven or planned to occur during the trial. Patients who have received routine (prophylactic) treatment with rFVIIa in the period between screening visit (visit 1) and visit 2 of this study (first dose administration). Platelet count less than 100.000 platelets/mcL (at screening visit). Any clinical sign or known history of arterial thrombotic event or deep venous- thrombosis or pulmonary embolism. HIV positive with current CD4+ count of less than 200/μL. Liver cirrhosis. Factor VIII/IX immune tolerance induction regimen planned to occur during the trial. Known hypersensitivity to the study medication. Parallel participation in another experimental drug trial. Parallel participation in another marketed drug trial that may affect the primary end point of the study.
Age
From 12 years old to 99 years old
Gender
Male
Phase
3
Groups that have been masked
No information
Sample size
Target sample size:
48
Randomization (investigator's opinion)
Randomized
Randomization description
Blinding (investigator's opinion)
Double blinded
Blinding description
Placebo
Not used
Assignment
Crossover
Other design features
Secondary Ids
empty
Ethics committees
1
Ethics committee
Name of ethics committee
Shiraz University of Medical Sciences
Street address
Shiraz University of Medical Sciences
City
Shiraz
Postal code
Approval date
2017-06-19, 1396/03/29
Ethics committee reference number
IR.SUMS.REC.1396.43
Health conditions studied
1
Description of health condition studied
Hemophilia A with inhibitor
ICD-10 code
D66
ICD-10 code description
Deficiency factor VIII (with functional defect)
2
Description of health condition studied
Hemophilia B with inhibitor
ICD-10 code
D67
ICD-10 code description
Hereditary factor IX deficiency (with functional defect)
Primary outcomes
1
Description
PK: the area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf)
Timepoint
10 min- prior to dose administration and at 10 min, 20 min, 1 h, 3 h, 5 h, 8 h, 12 h, 24 h and 30 h after AryoSeven or NovoSeven injection
Method of measurement
Measurement of plasma level of factor VII clotting activity (FVII:C) performed by a central lab.
TGA: 10 min- prior to dose administration and at 10 min, 20 min, 1 h, 3 h, 5 h, 8 h, 12 h, 24 h and 30 h after AryoSeven or NovoSeven injection. D-dimer and F1.2 prothrombin fragments- 10 min- prior to dose administration and at 20 min, 1 h, 5 h, and 12 h and 24 h after.
Method of measurement
Validated analytical method performed by central lab
Secondary outcomes
1
Description
Secondary PK parameters
Timepoint
10 min- prior to dose administration and at 10 min, 20 min, 1 h, 3 h, 5 h, 8 h and 12 h, 24 h and 30 h after AryoSeven or NovoSeven injection
Method of measurement
Measurement of plasma level of factor VII clotting activity (FVII:C) performed by a central lab.
2
Description
Clinical parameters in controlling acute bleeding
Timepoint
2 h, 6 h and 12 h post infusion
Method of measurement
4 point scale (Excellent, Good, Moderate, None)
3
Description
Immunogenicity assessment.
Timepoint
At screening visit, after the second dose/second drug administration (visit 3) and then every 3 months for a year.
Method of measurement
PT based Bethesda assay
4
Description
Adverse events
Timepoint
at any time during the study
Method of measurement
Adverse events grading for severity, seriousness, expected or unexpected, relationship to the study drug, action taken, outcome.