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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General information
2018-09-14, 1397/06/23
2019-09-14, 1398/06/23
20182019-09-14 00:00:00
Patient recruitment is overو adding the date of study end.
Protocol has had amendments. Updating the protocol as per the the last amendments.
Explanation of Randomization
Explanation of Blinding
Changing the sample size
Mentioning the date of first and last patient actually enrolled.
Trial completion date is recorded wrong and needs correction.
Patient recruitmentTrial completion date is overو adding the date of study end. Protocol has had amendments. Updating the protocol as per the the last amendments. Explanation of Randomization Explanation of Blinding Changing the sample size Mentioning the date of firstrecorded wrong and last patient actually enrolledneeds correction.
بیمارگیری مطالعه خاتمه یافته است، درج تاریخ خاتمه مطالعه.
پروتوکل اصلاحیات داشته است. بروزرسانی پروتوکل بر اساس اصلاحیه آخر.
توصیف روش تصادفی سازی
توصیف نحوه کورسازی
تغییر حجم نمونه
درج تاریخ شروع و پایان بیمار گیری تحقق یافته
تاریخ اتمام مطالعه به شاتباه درج شده است نیاز به اصلاح دارد
بیمارگیریتاریخ اتمام مطالعه خاتمه یافته است،به شاتباه درج تاریخ خاتمه مطالعه. پروتوکل اصلاحیات داشتهشده است. بروزرسانی پروتوکل بر اساس اصلاحیه آخر. توصیف روش تصادفی سازی توصیف نحوه کورسازی تغییر حجم نمونه درج تاریخ شروع و پایان بیمار گیری تحقق یافته نیاز به اصلاح دارد
Recruitment centers
#1
Name of recruitment center - English: Iran Comprehensive Hemophilia Care Center
Name of recruitment center - Persian: مرکز درمان جامع هموفیلی ایران
Full name of responsible person - English: Dr. Mohammadreza Baghaipour
Full name of responsible person - Persian: دکتر محمد رضا بقایی پور
Street address - English: Tehran, No. 3,Cross Zartosht and Felestin St
Street address - Persian: تهران تقاطع زرتشت و فلسطین
City - English: Tehran
City - Persian: تهران
Province: Tehran
Country: Iran (Islamic Republic of)
Postal code: 1415863675
Phone: +98 21 8891 0001
Fax:
Email: mrbaghaipour@yahoo.com
Web page address:
Name of recruitment center - English: Iran Comprehensive Hemophilia Care Center
Name of recruitment center - Persian: مرکز درمان جامع هموفیلی ایران
Full name of responsible person - English: Dr. Mohammadreza Baghaipour
Full name of responsible person - Persian: دکتر محمد رضا بقایی پور
Street address - English: No. 3,Cross Zartosht and Felestin St, Tehran, Iran
Street address - Persian: تهران تقاطع زرتشت و فلسطین
City - English: Tehran
City - Persian: تهران
Province: Tehran
Country: Iran (Islamic Republic of)
Postal code: 1415863675
Phone: +98 21 8891 0001
Fax:
Email: mrbaghaipour@yahoo.com
Web page address:
Name of recruitment center - English: Iran Comprehensive Hemophilia Care Center Name of recruitment center - Persian: مرکز درمان جامع هموفیلی ایران Full name of responsible person - English: Dr. Mohammadreza Baghaipour Full name of responsible person - Persian: دکتر محمد رضا بقایی پور Street address - English: Tehran, No. 3,Cross Zartosht and Felestin St, Tehran, Iran Street address - Persian: تهران تقاطع زرتشت و فلسطین City - English: Tehran City - Persian: تهران Province: Tehran Country: Iran (Islamic Republic of) Postal code: 1415863675 Phone: +98 21 8891 0001 Fax: Email: mrbaghaipour@yahoo.com Web page address:
#2
Name of recruitment center - English: Added at 2017-01-07: Hematology research center
Name of recruitment center - Persian: بروزرسانی 1395/10/18: مرکز تحقیقات هماتولوژی
Full name of responsible person - English: Added at 2017-01-07: Dr. Mohammad Reza Bordbar
Full name of responsible person - Persian: بروزرسانی 1395/10/18: دکتر محمدرضا بردبار
Street address - English: Added at 2017-01-07: Khalili street-Mohammad Rasoul allah research building-6th floor-Hematology research center
Street address - Persian: خیابان خلیل، ساختمان تحقیقات محمد رسول الله، طبقه ششم، مرکز تحقیقات هماتولوژی
City - English: Added at 2017-01-07: Shiraz
City - Persian: بروزرسانی 1395/10/18: شیراز
Province: Fars
Country: Iran (Islamic Republic of)
Postal code: ۷۱۴۵۶۸۳۷۶۹
Phone: +98 71 3228 9308
Fax:
Email: bordbarm@sums.ac.ir
Web page address:
Name of recruitment center - English: Added at 2017-01-07: Hematology research center
Name of recruitment center - Persian: بروزرسانی 1395/10/18: مرکز تحقیقات هماتولوژی
Full name of responsible person - English: Added at 2017-01-07: Dr. Mohammad Reza Bordbar
Full name of responsible person - Persian: بروزرسانی 1395/10/18: دکتر محمدرضا بردبار
Street address - English: Added at 2017-01-07: Hematology research center, 6th floor, Mohammad Rasoul allah research building,Khalili street, Shiraz, Iran
Street address - Persian: خیابان خلیل، ساختمان تحقیقات محمد رسول الله، طبقه ششم، مرکز تحقیقات هماتولوژی
City - English: Added at 2017-01-07: Shiraz
City - Persian: بروزرسانی 1395/10/18: شیراز
Province: Fars
Country: Iran (Islamic Republic of)
Postal code: ۷۱۴۵۶۸۳۷۶۹
Phone: +98 71 3228 9308
Fax:
Email: bordbarm@sums.ac.ir
Web page address:
Name of recruitment center - English: Added at 2017-01-07: Hematology research center Name of recruitment center - Persian: بروزرسانی 1395/10/18: مرکز تحقیقات هماتولوژی Full name of responsible person - English: Added at 2017-01-07: Dr. Mohammad Reza Bordbar Full name of responsible person - Persian: بروزرسانی 1395/10/18: دکتر محمدرضا بردبار Street address - English: Added at 2017-01-07: Khalili street-Hematology research center, 6th floor, Mohammad Rasoul allah research building-6th floor-Hematology research centerbuilding,Khalili street, Shiraz, Iran Street address - Persian: خیابان خلیل، ساختمان تحقیقات محمد رسول الله، طبقه ششم، مرکز تحقیقات هماتولوژی City - English: Added at 2017-01-07: Shiraz City - Persian: بروزرسانی 1395/10/18: شیراز Province: Fars Country: Iran (Islamic Republic of) Postal code: ۷۱۴۵۶۸۳۷۶۹ Phone: +98 71 3228 9308 Fax: Email: bordbarm@sums.ac.ir Web page address:
Protocol summary
Study aim
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)
Design
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.
Settings and conduct
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
Participants/Inclusion and exclusion criteria
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
Intervention groups
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
Main outcome variables
similar pharmacokinetic profile
General information
Reason for update
Trial completion date is recorded wrong and needs correction.
Acronym
IRCT registration information
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
Registration date
2016-12-25, 1395/10/05
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 Company
Expected recruitment start date
2016-12-21, 1395/10/01
Expected recruitment end date
2017-09-23, 1396/07/01
Actual recruitment start date
2017-06-24, 1396/04/03
Actual recruitment end date
2018-09-01, 1397/06/10
Trial completion date
2019-09-14, 1398/06/23
Scientific title
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
Public title
The pharmacokinetic study of AryoSeven with Novoseven in Patients with Congenital Factor VII Deficiency
Purpose
Treatment
Inclusion/Exclusion criteria
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.
Age
From 12 years old to 99 years old
Gender
Both
Phase
3
Groups that have been masked
Participant
Care provider
Investigator
Outcome assessor
Data and Safety Monitoring Board
Sample size
Target sample size:
24
Actual sample size reached:
24
Randomization (investigator's opinion)
Randomized
Randomization description
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.
Blinding (investigator's opinion)
Double blinded
Blinding description
Blinding is performed by an independent third party operator (nurse/pharmacist, unblinded), who will prepared undistinguishable syringes with patient’s dosing and labelling.
Placebo
Not used
Assignment
Crossover
Other design features
Secondary Ids
1
Registry name
clinicaltrials.gov
Secondary trial Id
NCT03079063
Registration date
2017-03-14, 1395/12/24
Ethics committees
1
Ethics committee
Name of ethics committee
Iran University of Medical science
Street address
Iran University of Medical Sciences ,Shahid Hemmat Highway
City
Tehran
Province
Tehran
Postal code
1449614535
Approval date
2016-09-25, 1395/07/04
Ethics committee reference number
IR.IUMS.REC.1395.28155
2
Ethics committee
Name of ethics committee
Added at 2017-01-07: Shiraz University of Medical Sciences
Street address
Added at 2017-01-07: Shiraz University of Medical Sciences
City
Added at 2017-01-07: Shiraz
Province
Fars
Postal code
Added at 2017-01-07:
Approval date
2016-12-14, 1395/09/24
Ethics committee reference number
IR.SUMS.REC.1395.158
Health conditions studied
1
Description of health condition studied
Hereditary deficiency of factor VII
ICD-10 code
D68.2
ICD-10 code description
Hereditary deficiency of other clotting factors
Primary outcomes
1
Description
PK-parameters: the area under the plasma activity-time curve from time 0 to last quantifiable activity (AUClast)
Timepoint
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.
Method of measurement
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
Description
PK-parameters: maximum plasma activity Cmax
Timepoint
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.
Method of measurement
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
Description
Secondary Pharmacokinetic parameters: AUCinf, Vd, Thalf, Tmax, Clearance, Mean Residence Time, λz.
Timepoint
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.
Method of measurement
PK Parameters: Measurement of plasma level of factor VII clotting activity (FVII:C) performed by a central lab.
2
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
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
Description
Clinical response in treatment of bleeding
Timepoint
2h , 6h and 12 h after last dose of Aryoseven injection at every bleeding
Method of measurement
4 point scale (Excellent, Good, Moderate, None) by investigator
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.
Intervention groups
1
Description
Biosimilar eptacog alfa (AryoSeven) product of AryoGen Pharmed, intravenous, single dose of 30 mcg per kg
Category
Treatment - Drugs
2
Description
Novo Nordisk eptacog alfa (Novoseven), intravenous, single dose of 30 mcg per kg
Category
Treatment - Drugs
Recruitment centers
1
Recruitment center
Name of recruitment center
Iran Comprehensive Hemophilia Care Center
Full name of responsible person
Dr. Mohammadreza Baghaipour
Street address
No. 3,Cross Zartosht and Felestin St, Tehran, Iran
City
Tehran
Province
Tehran
Postal code
1415863675
Phone
+98 21 8891 0001
Email
mrbaghaipour@yahoo.com
2
Recruitment center
Name of recruitment center
Added at 2017-01-07: Hematology research center
Full name of responsible person
Added at 2017-01-07: Dr. Mohammad Reza Bordbar
Street address
Added at 2017-01-07: Hematology research center, 6th floor, Mohammad Rasoul allah research building,Khalili street, Shiraz, Iran
City
Added at 2017-01-07: Shiraz
Province
Fars
Postal code
۷۱۴۵۶۸۳۷۶۹
Phone
+98 71 3228 9308
Email
bordbarm@sums.ac.ir
Sponsors / Funding sources
1
Sponsor
Name of organization / entity
AryoGen Pharmed
Full name of responsible person
Amrhossein Saadatirad
Street address
No 140, Corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
City
Garmdareh
Province
Alborz
Postal code
3164819712
Phone
+98 26 3610 6480
Email
saadatirada@aryogen.com
Grant name
Grant code / Reference number
Is the source of funding the same sponsor organization/entity?
Yes
Title of funding source
AryoGen Pharmed
Proportion provided by this source
100
Public or private sector
Private
Domestic or foreign origin
Domestic
Category of foreign source of funding
empty
Country of origin
Type of organization providing the funding
Industry
Person responsible for general inquiries
Contact
Name of organization / entity
AryoGen Pharmed
Full name of responsible person
Amirhossein Saadatirad
Position
Project Manager of rFVIIa registration in Europe
Latest degree
Ph.D.
Other areas of specialty/work
Medical Pharmacy
Street address
No 140, corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road