History
# Registration date Revision Id
4 2022-02-26, 1400/12/07 218378
3 2021-01-31, 1399/11/12 202631
2 2016-12-25, 1395/10/05 24586
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  • Protocol summary

    Multicentre, randomized, single dose, double blinded, two-way cross-over study, evaluating the pharmacokinetic of biosimilar eptacog alfa (AryoSeven) and NovoSeven (Novo Nordisk) in adult and children (>12 years) patients with a confirmed diagnosis of severe Factor VII Deficiency (FVII <1%), with > 2 episodes of bleeding/year requiring treatment with FVII infusions. Screened patients will be enrolled if the results of anti-Factor VII antibodies assessed by the study center lab will be negative. Patients enrolled, not bleeding, will be randomized to receive both a single dose of AryoSeven 30 µg/kg and one single dose of NovoSeven 30 µg/kg, or vice versa, with doses separated by a washout period of 2 weeks. At the end of this phase, all patients will be followed for 12 months for monitoring of inhibiting antibody formation, lack of efficacy and collection of safety data to test. An additional group of patients, not entering the PK study, will be followed for Immunogenicity study only. These patients will be treated with AryoSeven 30 µg/kg for one of more days until resolution of bleeding, based on the Investigator’s decision, for every bleeding episode that should occur during 12 months. Plasma sampling for determination of antibody formation will be taken every 3 months. Patients in prophylaxis with AryoSeven (Iran) will stop prophylactic treatment 1 week before starting the trial (receiving first dose of study medication), Patients will be hospitalized at time of study medication administration and plasma sampling.
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    مطالعه‎ی چندمرکزی، تصادفی شده، تک دوز، دوسوکور و متقاطع دوسویه، به ارزیابیِ فارماکوکینتیکِ اپتاکوگ آلفای بیوسیمیلار (آریوسِون) و نوروسِون در بیماران بزرگسالان و کودکانِ بیشتر از 12 سالی می‎پردازد که نقص حاد فاکتور هفت در آنها تشخیص قطعی داده شده است (FVII<1%) و بیش از 2 اپیزود خونریزی در سال دارند و نیازمند درمان با استفاده از انفوزیونهای FVII می‌باشند. بیماران غربال شده زمانی ثبت نام میشوند که نتایج آنتی بادی‎های آنتی فاکتور هفت که توسط آزمایشگاه مرکز مطالعه ارزیابی می‎شوند، منفی باشد. بیمارانی که ثبت نام می‎کنند اما خونریزی ندارند، بصورت راندوم، هم تک دوزِ آریوسون 30µg/kg و هم یک تک دوز از نووسون 30 µg/kg را دریافت می‎کنند (با برعکس)، با دوزهایی که با یک دوره‎ی بدون درمانِ دو هفته ایی از هم تفکیک می‎شوند. در انتهای این فاز تمام بیماران برای 12 ماه از لحاظ تشکیل آنتی بادی علیه فاکتور هفت، عدم کارایی دارو و جمع آوری اطلاعات ایمنی دارو بررسی می شوند. یک گروه 26 نفره اضافی از بیماران که وارد فاز PK نشده اند برای مطالعه ایمونوژنیسیتی فقط به مدت 12 ماه بررسی می شوند.این بیماران در هر بار خونریزی در این مدت 12 ماهه بر اساس تشخیص پزشک با آریوسون به میزان 30 µg/kg تا زمان بهبود کامل خونریزی درمان میشوند. هر 3 ماه یک بار از این بیماران برای بررسی تشکیل آنتی بادی علیه فاکتور هفت خون گرفته می شود. بیمارانی که تحت پیشگیری و حفاظت با آریوسون (ایران) قرار دارند، درمان پیشگیرانه را یک هفته قبل از شروع آزمون، متوقف میکنند.
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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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    ارزیابیِ فارماکوکینتیکِ اپتاکوگ آلفا بیوسیمیلار(آریوسِون)و نووسِون در فاز اول(فارماکوکینتیک)و با بررسی تشکیل آنتی‎بادیِ مهارکننده،فقدان کارایی و گردآوریِ اطلاعات در مورد ایمنی دارو در 12 ماه آتی (فاز دوم)
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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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    مطالعه فاز سه چندمرکزی دوسو کور متقاطع با حجم 24 بیمار که بصورت تصادفی 1:1 هم تک دوزِ آریوسون و هم تک دوز نووسون 30 میکروگرم در کیلوگرم را دریافت می‎کنند، که با یک دورهه بدون درمانِ سه روزه از هم تفکیک می‎شوند.بیماران طی زمان دریافت دارو و نمونه گیری خون، بستری می‎شوند.نمونه گیری خون حداقل 5 میلیتر 10 دقیقه قبل، 10، 20دقیقه،24،12،8،6،3،1 و 30 ساعت بعد از تزریق دارو انجام میشود.فاز دوم:در انتهای فاز مطالعه فارماکوکینتیک،تمام بیماران به ازای هر اپیزود خونریزی که ممکن است طی 12 ماه رخ دهد بر اساس تقاضا درمان یا پیشگیری با آریوسون دریافت میکنند.روش درمان با آریوسون(بر اساس تقاضا در مرکز مطالعه یا در خانه یا پیشگیری)توسط پژوهشگر تعیین می شود.نمونه گیری از خون برای تعیین شکل‎گیریِ آنتی بادی هر سه ماه گرفته خواهد شد.
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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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    چند مرکزی ایران و ترکیه.فاز اول یک هفته تزریق تک دوز آریوسون و نووسون به صورت تصادفی گرفتن نمونه خون در ده زمان مختلف.فاز دوم یک سال دریافت آریوسون برای تمامی خونریزیها.کورسازی توسط شخص سوم مستقل پرستار یا داروساز غیر کور که سرنگ های غیر قابل تشخیص را لیبل زده و با دوز بیمار آماده میکند
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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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    شرایط ورود: بزرگسالان و کودکانِ بالای 12 سال با تشخیص قطعی نقص حاد فاکتور هفت(کمتر1درصد) با بیش از 2 اپیزود خونریزی در سال نیازمند درمان با استفاده از انفوزیونهای فاکتور هفت شرایط خروج: در زمان ورود به مطالعه مهارکننده علیه فاکتور هفت آنها مثبت باشد.دارای هپاتیت فعال و سیروز کبدی باشند
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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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    گروه مداخله شامل بیماران کمبود مادرزادری فاکتور هفت است که آریوسون 30 میکروگرم در کیلوگرم دریافت می کنند. گروه کنترل شامل بیماران کمبود مادرزادری فاکتور هفت است که نووسون 30 میکروگرم در کیلوگرم دریافت می کنند.
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    similar pharmacokinetic profile
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    پروفایل مشابه فارماکوکینتیک
  • General information

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    Health service research
    Treatment
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    2017-06-24, 1396/04/03
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    2018-09-01, 1397/06/10
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    2018-09-14, 1397/06/23
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    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.
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    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
    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
    The pharmacokinetic study of AryoSeven with Novoseven in Patients with Congenital Factor VII Deficiency
    یک مطالعه تصادفی، چند مرکزی، تک دوز و متقاطع که فارماکوکینتیک داروی بیوسیمیلار اپتاکوگ آلفا را با نووسون در بیماران با کمبود مادرزادی فاکتور هفت مقایسه میکند
    مطالعه فارماکوکینتیک آریوسون با نووسون در بیماران با کمبود مادرزادی فاکتور هفت
    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).
    بیمارانی که نقص حاد و مادرزادیِ فاکتور هفت در آنها تشخیص قطعی داده شده است (فاکتور هفت کمتر از 1 درصد)، و بیش از دو اپیزود خونریزی در سال دارند و نیازمند درمان با انفوزیونِ فاکتور هفت میباشند (لازم نمی باشد که در اپیزود خونریزی باشند).
    افراد مذکر و مونث
    بزرگسالان و کودکان (بیش از 12 سال)
    بیماران باید رضایت داوطلبانه نوشته شده برای پروتکل را ارائه دهند تا واجد شرایط مطالعه باشند. برای بیماران کم سن، والدین یا سرپرست قانونی رضایت خود را ارائه می دهد و در صورت امکان، موافقت بیمار نیز به دست می آید. برای بیماران فاقد توانایی ذهنی، فرد تعیین شده باید رضایت آگاهانه ارائه دهد.
    بیماران در فاز فارماکوکینتیک در زمان مطالعه دارو و نمونه گیری پلاسما (2 بار در طول مطالعه) بستری خواهند شد.
    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.
    هر گونه اختلال انعقادی اکتسابی یا مادرزادی (به استثنای نقص مادرزادیِ فاکتور هفت)، نظیر بیماری کبد (هپاتیت)، کمبود ویتامین کا، اورمی، تومور بدخیم.
    آنتی ‎بادی‎ ها علیه فاکتور هفت
    بیماران که رژیم پیشگیرانه با نووسون یا آریوسون دارند و سه روز قبل از شروع مطالعه فاز فارماکوکینتیک (دریافت اولین دوز دارو مطالعه) رژیم پیشگیرانه را تعلیق نکرده اند.
    تعداد پلاکتها، کمتر از 100.000 در هر میکرولیتر (در ویزیت غربالگری)
    بیماران دریافت کننده درمان روتین (پیشگیرانه) با فاکتور هفت در دوره بین ویزیت غربالگری (ویزیت 1) و ویزیت 2 مطالعه (تجویز دوز اول)
    هرگونه نشانه‎‌ی کلینیکی یا سابقه‎ ی شناخته شده از اختلال ترمبوتیک شریان یا ترومبوز عمیق وریدی و یا آمبولیِ ریوی
    HIV مثبت با تعداد CD4+ فعلیِ کمتر از 200 در میکرولیتر
    سیروز کبدی
    حساسیت بسیار زیاد به داروی مورد مطالعه
    مشارکت همزمان بیمار در یک آزمایش دارویِ آزمایشیِ دیگر
    مشارکت همزمان بیمار در آزمایش یک داروی وارد بازار شده‎ ی دیگر که بر نقطه اولیه و پایانیِ مطالعه ممکن است تاثیر بگذارد.
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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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    برای بیماران واجد شرایط، به صورت تصادفی و به نسبت 1:1 داروی آریوسون یا نووسون تجویز می‌شود.تخصیص افراد به گروه‌های درمانی در این مطالعه به صورت تصادفی سازی بلوکی صورت می‌پذیرد.سری تصادفی توسط نرم‌افزار R-CAN نسخه 4.0.1 به صورت بلوکی با بلوک‌های دو یا چهارتایی برای 24 بیمار مشخص خواهد شد.تصادفی سازی با استفاده از یک لیست تصادفی سازی توسط یه فرد آمارگر مستقل بر اساس یک طراحی لاتین تناسبی با طراحی مربعی آماده شده است و کد در مرکز بیمارگیری توسط یک فرد مستقل از محقق به ترتیب ورود افراد اختصاص داده میشود.
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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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    کورسازی توسط یک فرد سوم مستقل (پرستار یا داروساز غیر کور) که سرنگ های غیر قابل تشخیص را لیبل زده و با دوز بیمار آماده می کند، صورت می گیرد.
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  • Secondary Ids

    #1
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    clinicaltrials.gov
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    NCT03079063
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    2017-03-14, 1395/12/24
  • Ethics committees

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    Added at 2017-01-07: IR.SUMS.REC.1395.158
    IR.SUMS.REC.1395.158
  • Primary outcomes

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    PK-parameters: the area under the plasma activity-time curve from time 0 to last quantifiable activity (AUClast) and maximum plasma activity Cmax
    PK-parameters: the area under the plasma activity-time curve from time 0 to last quantifiable activity (AUClast)
    پارامترهای فارماکوکینتیک: سطح زیر منحنی فعالیت پلاسمایی در برابر زمان از زمان صفر تا اخرین زمان فعالیت قابل اندازه گیری (AUClast) و حداکثر فعالیت پلاسمایی (Cmax)
    پارامترهای فارماکوکینتیک: سطح زیر منحنی فعالیت پلاسمایی در برابر زمان از زمان صفر تا اخرین زمان فعالیت قابل اندازه گیری (AUClast)
    10 min, 20 min, 1 h, 3 h, 6 h, 8 h and 12 h and 24 h after AryoSeven or NovoSeven injection.
    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.
    10 و 20 دقیقه و 1، 3، 6، 8، 12، 24 و 30 ساعت پس از تزریق آریوسون و یا نووسون
    10 دقیقه قبل از تزریق دارو، 10 و 20 دقیقه و 1، 3، 6، 8، 12، 24 و 30 ساعت پس از تزریق آریوسون و یا نووسون
    Measurement of plasma level of factor VII clotting activity (FVII:C) performed by a central lab.
    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.
    اندازه گیری سطح خونی فاکتور هفت (FVII:C) توسط آزمایشگاه مرکزی
    ارزیابی فارماکوکینتیک با اندازه گیریِ سطح پلاسمایی فعالیت انعقادی فاکتور هفت (FVII:C)، با استفاده از آزمون تجاری Staclot® VIIa–recombinant tissue factor (Diagnostica Stago, Asniéres sur Seine, France)، که توسط آزمایشگاه مرکزی که به درمان بیمار کور شده است انجام میگیرد.
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    PK-parameters: maximum plasma activity Cmax
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    پارامترهای فارماکوکینتیک: حداکثر فعالیت پلاسمایی (Cmax)
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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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    10 دقیقه قبل از تزریق دارو، 10 و 20 دقیقه و 1، 3، 6، 8، 12، 24 و 30 ساعت پس از تزریق آریوسون و یا نووسون
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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.
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    ارزیابی فارماکوکینتیک با اندازه گیریِ سطح پلاسمایی فعالیت انعقادی فاکتور هفت (FVII:C)، با استفاده از آزمون تجاری Staclot® VIIa–recombinant tissue factor (Diagnostica Stago, Asniéres sur Seine, France)، که توسط آزمایشگاه مرکزی که به درمان بیمار کور شده است انجام میگیرد.
  • Secondary outcomes

    #1
    Secondary Pharmacokinetic parameters.
    Secondary Pharmacokinetic parameters: AUCinf, Vd, Thalf, Tmax, Clearance, Mean Residence Time, λz.
    پارامترهای ثانویه فارماکوکینتیک
    پارامترهای ثانویه فارماکوکینتیک:سطح زیر منحنی فعالیت پلاسمایی در برابر زمان از زمان صفر تا بی نهایت. حجم توزیع، نیمه عمر، ماکسیمم زمان برای رسیدن به ماکسیمم غلظت، کلیرانس، زمان استقرار، λz.
    10 min, 20 min, 1 h, 3 h, 6 h, 8 h and 12 h and 24 h after AryoSeven or NovoSeven injection.
    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.
    10 و 20 دقیقه و 1، 3، 6، 8، 12، 24 و 30 ساعت پس از تزریق آریوسون و یا نووسون
    برای پارامترهای فارماکوکینتیک: 10 دقیقه قبل از تزریق دارو 10 و 20 دقیقه و 1، 3، 6، 8، 12، 24 و 30 ساعت پس از تزریق آریوسون و یا نووسون.
    Measurement of plasma level of factor VII clotting activity (FVII:C) performed by a central lab.
    PK Parameters: Measurement of plasma level of factor VII clotting activity (FVII:C) performed by a central lab.
    اندازه گیری سطح خونی فعالیت فاکتور هفت (FVII:C) توسط آزمایشگاه مرکزی
    پارامترهای فارماکوکینتیک: اندازه گیری سطح خونی فعالیت فاکتور هفت (FVII:C) توسط آزمایشگاه مرکزی
    #2
    The modified Nijmegen method of the Bethesda assay.
    Immunogenicity by PT-based bethesda assay by local lab and confirmatory test by the modified Nijmegen method of the Bethesda assay by central lab
    آزمون Bethesda، روش اصلاح شده Nijmegen
    ایمونوژنیسیتی توسط PT-based bethesda assay در آزمایشگاه محل مطالعه و تست تاییدیه با استفاده از The modified Nijmegen method of the Bethesda assay در آزمایشگاه مرکزی
    #3
    Every bleeding
    2h , 6h and 12 h after last dose of Aryoseven injection at every bleeding
    در هر بار خونریزی
    در هر بار خونریزی 2 ساعت، 6 ساعت و 12 ساعت بعد از تزریق آخرین دوز آریوسون
    4 point scale (Excellent, Good, Moderate, None)
    4 point scale (Excellent, Good, Moderate, None) by investigator
    عالی، خوب، متوسط، بدون پاسخ
    عالی، خوب، متوسط، بدون پاسخ توسط محقق
  • Intervention groups

    #1
    AryoGen eptacog alfa (AryoSeven), intravenous, single dose of 30 µg/kg
    Biosimilar eptacog alfa (AryoSeven) product of AryoGen Pharmed, intravenous, single dose of 30 mcg per kg
    اپتاکوگ آلفا آریوژن (آریوسون) ، داخل وریدی، تک دوز 30 microgram/kg
    اپتاکوگ آلفا بیوسیمیلار (آریوسون) شرکت آریوژن فارمد، داخل وریدی، تک دوز 30 میکروگرم در کیلوگرم
    #2
    Novo Nordisk eptacog alfa (Novoseven), intravenous, single dose of 30 µg/kg
    Novo Nordisk eptacog alfa (Novoseven), intravenous, single dose of 30 mcg per kg
    اپتاکوگ آلفا شرکت نونوردیسک (نووسون) ، داخل وریدی، تک دوز 30 microgram/kg
    اپتاکوگ آلفا شرکت نونوردیسک (نووسون) ، داخل وریدی، تک دوز 30 میکروگرم در کیلوگرم
  • 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, N Felestin St
    Street address - Persian: تهران تقاطع زرتشت و فلسطین
    City - English: Tehran
    City - Persian: تهران
    Province:
    Country: Iran (Islamic Republic of)
    Postal code:
    Phone:
    Fax:
    Email:
    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
    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: Rasool Akram Hospital
    Name of recruitment center - Persian: بیمارستان رسول اکرم
    Full name of responsible person - English: Dr. Mohammad Faranoush
    Full name of responsible person - Persian: دکتر محمد فرانوش
    Street address - English: Sattar Khan St, Niayesh ave
    Street address - Persian: خیابان ستارخان، خیابان نیایش
    City - English: Tehran
    City - Persian: تهران
    Province:
    Country: Iran (Islamic Republic of)
    Postal code:
    Phone:
    Fax:
    Email:
    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-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:
    #3
    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:
    Country: Iran (Islamic Republic of)
    Postal code:
    Phone:
    Fax:
    Email:
    Web page address:
  • Sponsors / Funding sources

    #1
    contact.organization_id:
    Name of organization / entity - English: AryoGen Pharmed
    Name of organization / entity - Persian: آریوژن فارمد
    Full name of responsible person - English: Amrhossein Saadatirad
    Full name of responsible person - Persian: امیرحسین سعادتی راد
    Street address - English: No 140, Corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
    Street address - Persian: کیلومتر 24 جاده مخصوص تهران کرج نبش خیابان تاج بخش پلاک 140
    City - English: Tehran
    City - Persian: تهران
    Province:
    Country: Iran (Islamic Republic of)
    Postal code:
    Phone:
    Fax:
    Email:
    Web page address:
    contact.organization_id:
    Name of organization / entity - English: AryoGen Pharmed
    Name of organization / entity - Persian: آریوژن فارمد
    Full name of responsible person - English: Amrhossein Saadatirad
    Full name of responsible person - Persian: امیرحسین سعادتی راد
    Street address - English: No 140, Corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
    Street address - Persian: کیلومتر 24 جاده مخصوص تهران کرج نبش خیابان تاج بخش پلاک 140
    City - English: Garmdareh
    City - Persian: گرمدره
    Province: Alborz
    Country: Iran (Islamic Republic of)
    Postal code: 3164819712
    Phone: +98 26 3610 6480
    Fax:
    Email: saadatirada@aryogen.com
    Web page address:
    empty
    Private
    empty
    Domestic
    empty
    Industry
  • Person responsible for general inquiries

    contact.organization_id:
    Name of organization / entity - English: AryoGen Pharmed
    Name of organization / entity - Persian: آریوژن فارمد
    Full name of responsible person - English: Amirhossein Saadatirad
    Full name of responsible person - Persian: امیرحسین سعادتی راد
    Position - English: PhD
    Position - Persian: PhD
    Latest degree:
    Area of specialty/work: 0
    Area of specialty/work title - English:
    Area of specialty/work title - Persian:
    Street address - English: No 140, corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
    Street address - Persian: کیلومتر 24 جاده مخصوص تهران کرج نبش خیابان تاج بخش پلاک 140
    City - English: Tehran
    City - Persian: تهران
    Province:
    Province - English:
    Province - Persian:
    contact.provinces_available: 1
    Country: Iran (Islamic Republic of)
    Postal code: 3164819711
    Phone: +98 21 3610 6480
    Mobile:
    Fax:
    Email: saadatirada@aryogen.com
    Web page address:
    contact.organization_id:
    Name of organization / entity - English: AryoGen Pharmed
    Name of organization / entity - Persian: آریوژن فارمد
    Full name of responsible person - English: Amirhossein Saadatirad
    Full name of responsible person - Persian: امیرحسین سعادتی راد
    Position - English: Project Manager of rFVIIa registration in Europe
    Position - Persian: مدیر پروژه ثبت فاکتور هفت در اروپا
    Latest degree: phd
    Area of specialty/work: 41
    Area of specialty/work title - English:
    Area of specialty/work title - Persian:
    Street address - English: No 140, corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
    Street address - Persian: کیلومتر 24 جاده مخصوص تهران کرج نبش خیابان تاج بخش پلاک 140
    City - English: Garmdareh
    City - Persian: گرمدره
    Province: Alborz
    Province - English:
    Province - Persian:
    contact.provinces_available: 1
    Country: Iran (Islamic Republic of)
    Postal code: 3164819712
    Phone: +98 26 3610 6480
    Mobile: +98 912 322 6076
    Fax:
    Email: saadatirada@aryogen.com
    Web page address:
  • Person responsible for scientific inquiries

    contact.organization_id:
    Name of organization / entity - English: Baqiyatallah Hospital
    Name of organization / entity - Persian: بیمارستان بقیه الله
    Full name of responsible person - English: Dr. Hasan Abolghasemi
    Full name of responsible person - Persian: دکتر حسن ابوالقاسمی
    Position - English: Full professor
    Position - Persian: استاد تمام
    Latest degree:
    Area of specialty/work: 0
    Area of specialty/work title - English:
    Area of specialty/work title - Persian:
    Street address - English: Mollasadra str, south Sheykh Bahaii str, Tehran
    Street address - Persian: خیابان ملاصدرا، خیابان شیخ بهایی جنوبی، درمانگاه بیمارستان بقیه الله «عج»
    City - English: Tehran
    City - Persian: تهران
    Province:
    Province - English:
    Province - Persian:
    contact.provinces_available: 1
    Country: Iran (Islamic Republic of)
    Postal code:
    Phone: +98 218882742
    Mobile:
    Fax:
    Email: Abolghasem@bmsu.ac.ir
    Web page address:
    contact.organization_id:
    Name of organization / entity - English: Baqiyatallah Hospital
    Name of organization / entity - Persian: بیمارستان بقیه الله
    Full name of responsible person - English: Dr. Hasan Abolghasemi
    Full name of responsible person - Persian: دکتر حسن ابوالقاسمی
    Position - English: Full professor
    Position - Persian: استاد تمام
    Latest degree: sub_specialist
    Area of specialty/work: 74
    Area of specialty/work title - English:
    Area of specialty/work title - Persian:
    Street address - English: Baqiatallah hospital clinic, Mollasadra st, south Sheykh Bahaii st, Tehran, Iran
    Street address - Persian: خیابان ملاصدرا، خیابان شیخ بهایی جنوبی، درمانگاه بیمارستان بقیه الله «عج»
    City - English: Tehran
    City - Persian: تهران
    Province: Tehran
    Province - English:
    Province - Persian:
    contact.provinces_available: 1
    Country: Iran (Islamic Republic of)
    Postal code: 1435915371
    Phone: 0098218882742
    Mobile: +98 912 137 4362
    Fax:
    Email: Abolghasem@bmsu.ac.ir
    Web page address:
  • Person responsible for updating data

    contact.organization_id:
    Name of organization / entity - English: AryoGen Pharmed
    Name of organization / entity - Persian: آریوژن فارمد
    Full name of responsible person - English: Amirhossein Saadatirad
    Full name of responsible person - Persian: امیرحسین سعادتی راد
    Position - English: PhD
    Position - Persian: PhD
    Latest degree:
    Area of specialty/work: 0
    Area of specialty/work title - English:
    Area of specialty/work title - Persian:
    Street address - English: No 140, corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
    Street address - Persian: کیلومتر 24 جاده مخصوص تهران کرج نبش خیابان تاج بخش پلاک 140
    City - English: Tehran
    City - Persian: تهران
    Province:
    Province - English:
    Province - Persian:
    contact.provinces_available: 1
    Country: Iran (Islamic Republic of)
    Postal code:
    Phone: +98 21 3610 6480
    Mobile:
    Fax:
    Email:
    Web page address:
    contact.organization_id:
    Name of organization / entity - English: AryoGen Pharmed
    Name of organization / entity - Persian: آریوژن فارمد
    Full name of responsible person - English: Amirhossein Saadatirad
    Full name of responsible person - Persian: امیرحسین سعادتی راد
    Position - English: Project Manager of rFVIIa registration in Europe
    Position - Persian: مدیر پروژه ثبت فاکتور هفت در اروپا
    Latest degree: phd
    Area of specialty/work: 41
    Area of specialty/work title - English:
    Area of specialty/work title - Persian:
    Street address - English: No 140, corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
    Street address - Persian: کیلومتر 24 جاده مخصوص تهران کرج نبش خیابان تاج بخش پلاک 140
    City - English: Garmdareh
    City - Persian: گرمدره
    Province: Alborz
    Province - English:
    Province - Persian:
    contact.provinces_available: 1
    Country: Iran (Islamic Republic of)
    Postal code: 3164819712
    Phone: +98 26 3610 6480
    Mobile: +98 912 322 6076
    Fax:
    Email: saadatirada@aryogen.com
    Web page address:
  • Sharing plan

    undecided
    undecided
    undecided
    undecided
    undecided
    undecided
    undecided
    empty
    not yet decided
    empty
    هنوز تصمیم گیری نشده است

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
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.
Acronym
IRCT registration information
IRCT registration number: IRCT2016120231193N1
Registration date: 2016-12-25, 1395/10/05
Registration timing: prospective

Last update: 2021-10-24, 1400/08/02
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
2018-09-14, 1397/06/23
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
Tehran, No. 3,Cross Zartosht and Felestin St
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: Khalili street-Mohammad Rasoul allah research building-6th floor-Hematology research center
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
City
Garmdareh
Province
Alborz
Postal code
3164819712
Phone
+98 26 3610 6480
Fax
Email
saadatirada@aryogen.com
Web page address

Person responsible for scientific inquiries

Contact
Name of organization / entity
Baqiyatallah Hospital
Full name of responsible person
Dr. Hasan Abolghasemi
Position
Full professor
Latest degree
Subspecialist
Other areas of specialty/work
Pediatrics
Street address
Baqiatallah hospital clinic, Mollasadra st, south Sheykh Bahaii st, Tehran, Iran
City
Tehran
Province
Tehran
Postal code
1435915371
Phone
0098218882742
Fax
Email
Abolghasem@bmsu.ac.ir
Web page address

Person responsible for updating data

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
City
Garmdareh
Province
Alborz
Postal code
3164819712
Phone
+98 26 3610 6480
Fax
Email
saadatirada@aryogen.com
Web page address

Sharing plan

Deidentified Individual Participant Data Set (IPD)
Undecided - It is not yet known if there will be a plan to make this available
Study Protocol
Undecided - It is not yet known if there will be a plan to make this available
Statistical Analysis Plan
Undecided - It is not yet known if there will be a plan to make this available
Informed Consent Form
Undecided - It is not yet known if there will be a plan to make this available
Clinical Study Report
Undecided - It is not yet known if there will be a plan to make this available
Analytic Code
Undecided - It is not yet known if there will be a plan to make this available
Data Dictionary
Undecided - It is not yet known if there will be a plan to make this available
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