Protocol summary
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Study aim
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Bioequivalence according to Pharmacokinetic,Pharmacodynamic parameters.Clinical response in controlling acute bleeding.Immunogenicity,ADRs
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Design
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Patients enrolled are randomized to receive injections of either doses of AryoSeven or NovoSeven,separated by washout period of 3 days.Blood samples for the PKPD phase(atleast 5 ml) is collected 10 min prior dose administration and at 10, 20min,1,3,5,8,12,24 and 30h after administration.For plasma sample stability study and only for maximum 10 patients,9ml blood instead of 5ml will be drawn during Visit 2 and 3 at timepoints1h and 12h.Before second dose blood is taken for immunogenicity test.Patients hospitalized at time of study medication administration and plasma sampling.Patients will be followed for 12 months to receive AryoSeven for bleedings at center or home(by patient at home or caregiver) with dose and duration of treatment decided by Investigator.Plasma sampling for determination of antibody formation against FVII will be taken every 3 months at the center.
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Settings and conduct
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Multicenter(Tehran,Shiraz,Zahedan,Istanbul,Adana,Bursa)Randomized,Double blind,crossover.Blinding is performed by independent third party who prepares and labels undistinguishable syringes according to randomization.
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Participants/Inclusion and exclusion criteria
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Over 12 years with congenital Hemophilia A or B with inhibitors over 5BU with over2 episodes of bleeding oer year requiring treatment with FVII, not in bleeding episode. without inhibitor to FVII and any other type of congenital or acquired coagulopathy
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Intervention groups
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AryoGEn Eptacog alfa(AryoSeven),IV 90 or 270 mcg perkg. NovoNordisk Eptacog alfa(Novoseven), IV 90 or 270 mcg per kg
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Main outcome variables
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PK:Area Under Curveinf(AUCinf)
PD:Thrombin Generation Assay,D-Dimer,F1.2 prothrombin fragments.
General information
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Reason for update
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registering patient recruitment start
patient recruitment end
trial completion date
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Acronym
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UGA 2014-01
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IRCT registration information
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IRCT registration number:
IRCT2017021831193N2
Registration date:
2017-08-05, 1396/05/14
Registration timing:
prospective
Last update:
2022-03-02, 1400/12/11
Update count:
4
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Registration date
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2017-08-05, 1396/05/14
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Registrant information
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Recruitment status
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Recruitment complete
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Funding source
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AryoGen Pharmed
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Expected recruitment start date
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2018-09-17, 1397/06/26
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Expected recruitment end date
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2019-05-31, 1398/03/10
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Actual recruitment start date
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2018-09-17, 1397/06/26
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Actual recruitment end date
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2020-10-31, 1399/08/10
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Trial completion date
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2021-09-23, 1400/07/01
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Scientific title
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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
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Public title
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Pharmacodynamic, Pharmacokinetic Study ofAryoSeven with Novoseven®, in Patient with Hemophilia A or B with Inhibitors
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Purpose
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Treatment
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Inclusion/Exclusion criteria
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Inclusion criteria:
-Confirmed diagnosis of congenital haemophilia 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, non in bleeding episode
-Male subjects
-Adult and children (>12 years)
-Patients to be enrolled must also provide voluntary written informed consent to the protocol to be eligible for the study. For minor patients, parent/legal guardian will provide consent and, when possible, patient assent will also be obtained. For compromised patients, their designated proxy must provide informed consent.
-For the PK/PD phase, patients will be hospitalized at time of study medication administration for plasma sampling (2 times during the study).
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.
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Age
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From 12 years old
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Gender
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Male
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Phase
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3
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Groups that have been masked
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- Participant
- Care provider
- Investigator
- Outcome assessor
- Data and Safety Monitoring Board
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Sample size
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Target sample size:
48
Actual sample size reached:
48
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Randomization (investigator's opinion)
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Randomized
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Randomization description
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1:1 manner stratified by center
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Blinding (investigator's opinion)
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Double blinded
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Blinding description
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Blinding is performed by an independent third party operator
(pharmacist or nurse, unblinded), who will prepare undistinguishable
syringes with patient’s dosing and labelling. As soon as the patient is registered (centrally) and randomization code assigned, the central randomization office will inform the pharmacist or nurse through email of the treatment assigned to the patient; the pharmacist or nurse will prepare the study treatment on the basis of the treatment assigned and body weight of patient (defined as weight on the date of admission). The third party operator (pharmacist or nurse) will label the study treatment syringes with with labels supplied by AryoGen.
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Placebo
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Not used
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Assignment
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Crossover
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Other design features
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Secondary Ids
1
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Registry name
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clinicaltrials.gov
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Secondary trial Id
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NCT03935334
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Registration date
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2019-05-02, 1398/02/12
2
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Registry name
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clinicaltrialsregister.eu
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Secondary trial Id
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2019-002854-22
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Registration date
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2020-01-03, 1398/10/13
Ethics committees
1
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Ethics committee
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Approval date
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2017-06-19, 1396/03/29
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Ethics committee reference number
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IR.SUMS.REC.1396.43
2
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Ethics committee
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Approval date
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2018-03-06, 1396/12/15
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Ethics committee reference number
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IR.IUMS.REC 1396.9-33058
3
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Ethics committee
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Approval date
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2018-12-19, 1397/09/28
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Ethics committee reference number
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IR.ZAUMS.REC.1397.356
Health conditions studied
1
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Description of health condition studied
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Hemophilia A with inhibitor
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ICD-10 code
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D66
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ICD-10 code description
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Deficiency factor VIII (with functional defect)
2
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Description of health condition studied
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Hemophilia B with inhibitor
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ICD-10 code
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D67
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ICD-10 code description
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Hereditary factor IX deficiency (with functional defect)
Primary outcomes
1
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Description
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Pharmacokinetic parameter: the area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf)
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Timepoint
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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
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Method of measurement
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa–recombinant tissue factor assay (Diagnostica Stago, Asniéres sur Seine, France)performed by a central lab.
2
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Description
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Pharmacodynamic parameters:Thrombin Generation Assay (TGA), D-Dimer, F1.2 prothrombin fragments
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Timepoint
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Thrombin Generation Assay:10 min prior to dose administration and at 10 min,20 min,1h,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 on the same samples obtained for TGA
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Method of measurement
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Validated analytical method performed by central lab
Secondary outcomes
1
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Description
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Secondary PK parameters:AUClast, Cmax,tmax, AUCextra;First order rate constant associated with the terminal (log-linear) portion of the curve (λz);Elimination half-life; MRT; CL; Vss
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Timepoint
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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
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Method of measurement
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Pharmacokinetic assessment by measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa–recombinant tissue factor assay (Diagnostica Stago, Asniéres sur Seine, France)., performed by a central lab
2
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Description
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Clinical parameters in controlling acute bleeding after treatment with AryoSeven.
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Timepoint
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2 h, 6 h and 12 h post infusion (last AryoSeven dose).
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Method of measurement
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4 point scale (Excellent, Good, Moderate, None) by the investigator
3
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Description
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Immunogenicity assessment.
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Timepoint
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At screening visit, after the second drug administration (visit 3) and then every 3 months for a year.
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Method of measurement
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PT based Bethesda assay
4
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Description
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Adverse events
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Timepoint
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at any time during the study
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Method of measurement
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Adverse events grading for severity, seriousness, expected or unexpected, relationship to the study drug, action taken, outcome.
Intervention groups
1
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Description
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AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous 90 microgram per kg single dose. Lyophilized powder for solution with provided solvent
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Category
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Treatment - Drugs
2
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Description
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AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous 270 microgram per kg single dose. Lyophilized powder for solution with provided solvent
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Category
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Treatment - Drugs
3
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Description
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Novo Nordisk eptacog alfa (Novoseven 1 mg), intravenous 90 microgram per kg Lyophilized powder for solution with provided solvent
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Category
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Treatment - Drugs
4
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Description
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Novo Nordisk eptacog alfa (Novoseven 1 mg), intravenous 270 microgram per kg Lyophilized powder for solution with provided solvent
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Category
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Treatment - Drugs
1
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Sponsor
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Grant name
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Grant code / Reference number
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Is the source of funding the same sponsor organization/entity?
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Yes
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Title of funding source
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AryoGen Pharmed
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Proportion provided by this source
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100
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Public or private sector
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Private
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Domestic or foreign origin
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Domestic
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Category of foreign source of funding
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empty
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Country of origin
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Type of organization providing the funding
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Industry
Sharing plan
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Deidentified Individual Participant Data Set (IPD)
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Undecided - It is not yet known if there will be a plan to make this available
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Study Protocol
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Undecided - It is not yet known if there will be a plan to make this available
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Statistical Analysis Plan
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Undecided - It is not yet known if there will be a plan to make this available
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Informed Consent Form
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No - There is not a plan to make this available
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Clinical Study Report
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Undecided - It is not yet known if there will be a plan to make this available
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Analytic Code
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Undecided - It is not yet known if there will be a plan to make this available
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Data Dictionary
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Undecided - It is not yet known if there will be a plan to make this available