Protocol summary
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Study aim
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Evaluatiation of pharmacokinetic(PK) of biosimilar eptacog alfa(AryoSeven)and NovoSeven in phase A(PK)and monitoring inhibiting antibody formation,lack of efficacy,collection of safety data in the following 12 months(Phase B)
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Design
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A phase III multicenter double-blind cross-over study with 24 sample size who based on 1:1 randomization receive either single dose of AryoSeven and NovoSeven 30 mcg per kg separated by 3days washout period.Patients hospitalized at time of medication administration and plasma sampling.Plasma sampling atleast 5ml at 10min before,10,20min,1,3,6,8,12,24,30h post drug administration.Phase B:At end of PK phase all patients receive AryoSeven on demand for every bleeding episode that occurs during 12 months or prophylaxis.The treatment modality(on demand at study center or home,or prophylaxis)decided by Investigator.Sampling for determination of antibody taken every 3 months.
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Settings and conduct
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Multicenter Iran and Turkey.First phase 1 week with infusion of single dose aryoseven and novoseven randomly.Second phase 1year receiving aryoseven for all bleedings.Blinding by an independent third party nurse or pharmacist unblinded who prepares undistinguishable syringes with patient dosing and labelling
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Participants/Inclusion and exclusion criteria
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Inclusion:Aَdult and children more than12 years with confirmed diagnosis of severe Factor VII Deficiency(less than 1%)with more than 2 episodes of bleeding per year requiring treatment with FVII infusions
Exclusion:inhibitor against FVII is positive at time of study entry.Active hepatitis and liver cirrhosis
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Intervention groups
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Intervention group are congenital FVII deficient patients who receive AryoSeven 30 mcg per kg
Control group are congenital FVII deficient patients who receive NovoSeven 30 mcg per kg
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Main outcome variables
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similar pharmacokinetic profile
General information
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Reason for update
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Trial completion date is recorded wrong and needs correction.
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Acronym
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IRCT registration information
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IRCT registration number:
IRCT2016120231193N1
Registration date:
2016-12-25, 1395/10/05
Registration timing:
prospective
Last update:
2022-02-27, 1400/12/08
Update count:
2
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Registration date
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2016-12-25, 1395/10/05
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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 Company
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Expected recruitment start date
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2016-12-21, 1395/10/01
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Expected recruitment end date
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2017-09-23, 1396/07/01
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Actual recruitment start date
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2017-06-24, 1396/04/03
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Actual recruitment end date
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2018-09-01, 1397/06/10
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Trial completion date
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2019-09-14, 1398/06/23
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Scientific title
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A Randomized, Multi-center, Single Dose, Cross over Study Comparing the Pharmacokinetic of Bio-similar EPTACOG Alfa with NOVOSEVEN®, in Patients with Congenital Factor VII Deficiency
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Public title
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The pharmacokinetic study of AryoSeven with Novoseven in Patients with Congenital Factor VII Deficiency
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Purpose
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Treatment
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Inclusion/Exclusion criteria
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Inclusion criteria:
Patients with a confirmed diagnosis of congenital, severe Factor VII deficiency (FVII <1%), with >2 episodes of bleeding/year requiring treatment with FVII infusions, in non-bleeding status.
Male and female 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.
Patients in the Pharmacokinetic (PK) phase will be hospitalized at time of study medication administration and plasma sampling (2 times during the study).
Exclusion criteria:
Any other type of congenital or acquired coagulopathy (except congenital Factor VII deficiency), such as: liver disease (hepatitis), vitamin k deficiency, uremia, malignancy.
Antibodies against Factor VII
Patients entering the PK Phase who have not suspended prophylactic regime with Novoseven or AryoSeven 3 days before starting the trial (receiving first dose of study medication).
Platelet count less than 100.000 platelets/mcL (at screening visit)
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)
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
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 to 99 years old
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Gender
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Both
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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:
24
Actual sample size reached:
24
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Randomization (investigator's opinion)
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Randomized
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Randomization description
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The eligible patients are administered randomly in a 1:1 manner with either AryoSeven or NovoSeven. Allocation of treatment in this study is performed randomly using block randomization. Randomization sequence is prepared using R-CAN software version 4.0.1 in a blocks of 2 or 4 for 24 patients. Randomization list is prepared by an independent statisticians based on a balanced Latin Square design and the code is allocated to a patient by a third party in the study site based on the order of enrollment.
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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 (nurse/pharmacist, unblinded), who will prepared undistinguishable syringes with patient’s dosing and labelling.
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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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NCT03079063
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Registration date
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2017-03-14, 1395/12/24
Ethics committees
1
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Ethics committee
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Approval date
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2016-09-25, 1395/07/04
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Ethics committee reference number
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IR.IUMS.REC.1395.28155
2
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Ethics committee
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Approval date
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2016-12-14, 1395/09/24
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Ethics committee reference number
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IR.SUMS.REC.1395.158
Health conditions studied
1
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Description of health condition studied
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Hereditary deficiency of factor VII
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ICD-10 code
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D68.2
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ICD-10 code description
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Hereditary deficiency of other clotting factors
Primary outcomes
1
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Description
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PK-parameters: the area under the plasma activity-time curve from time 0 to last quantifiable activity (AUClast)
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Timepoint
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10 min before drug administration,10 min, 20 min, 1 h, 3 h, 6 h, 8 h and 12 h and 24 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 blinded to the patient’s treatment.
2
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Description
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PK-parameters: maximum plasma activity Cmax
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Timepoint
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10 min before drug administration,10 min, 20 min, 1 h, 3 h, 6 h, 8 h and 12 h and 24 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 blinded to the patient’s treatment.
Secondary outcomes
1
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Description
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Secondary Pharmacokinetic parameters: AUCinf, Vd, Thalf, Tmax, Clearance, Mean Residence Time, λz.
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Timepoint
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For secondary PK parameters:10 min before drug administration,10 min, 20 min, 1 h, 3 h, 6 h, 8 h and 12 h and 24 h after AryoSeven or NovoSeven injection.
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Method of measurement
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PK Parameters: Measurement of plasma level of factor VII clotting activity (FVII:C) performed by a central lab.
2
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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 dose/second drug administration (visit 3) and then every 3 months for a year.
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Method of measurement
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Immunogenicity by PT-based bethesda assay by local lab and confirmatory test by the modified Nijmegen method of the Bethesda assay by central lab
3
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Description
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Clinical response in treatment of bleeding
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Timepoint
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2h , 6h and 12 h after last dose of Aryoseven injection at every bleeding
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Method of measurement
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4 point scale (Excellent, Good, Moderate, None) by investigator
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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Biosimilar eptacog alfa (AryoSeven) product of AryoGen Pharmed, intravenous, single dose of 30 mcg per kg
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Category
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Treatment - Drugs
2
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Description
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Novo Nordisk eptacog alfa (Novoseven), intravenous, single dose of 30 mcg per kg
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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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Undecided - It is not yet known if there will be 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