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Study Comparing the Pharmacokinetic of Biosimilar Eptacog Alfa With Novoseven®, in Patients With Congenital Factor VII Deficiency

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ClinicalTrials.gov Identifier: NCT03079063
Recruitment Status : Recruiting
First Posted : March 14, 2017
Last Update Posted : February 6, 2019
Sponsor:
Information provided by (Responsible Party):
AryoGen Pharmed Co.

Tracking Information
First Submitted Date  ICMJE March 4, 2017
First Posted Date  ICMJE March 14, 2017
Last Update Posted Date February 6, 2019
Actual Study Start Date  ICMJE March 1, 2017
Estimated Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 8, 2017)
  • Area under the plasma activity-time curve from time 0 to last quantifiable activity (AUClast) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)],
  • Maximum plasma concentration of the factor VII activity (Cmax). [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)],
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03079063 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 8, 2017)
  • Area under the plasma concentration-time curve from time 0 to infinity (AUCinf) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • Time of Cmax (tmax) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • Fraction of the total AUCinf that was derived by extrapolation beyond tlast (AUCextra) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • First order rate constant associated with the terminal (log-linear) portion of the curve (λz) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • Elimination half-life (t½) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • Mean residence time (MRT) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • Clearance (CL) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • Volume of distribution (Vss) [ Time Frame: Ten min before injection and 10 min, 20 min, 1h, 3h, 6h, 8h, 12h, 24h and 30h after injection, for both drug administered in the PK phase ]
    Measurement of plasma level of factor VII clotting activity (FVII:C) [one-stage clotting method using recombinant tissue factor preparation (STA-Deficient and STA-Neoplastin R; Diagnostica Stago, France)]
  • Clinical response in controlling acute bleeding. [ Time Frame: 2, 6 and 12 hours post infusion (last dose of Eptacog alfa Biosimilar) ]
    Rated by the treating physician using a 4 point scale (Excellent, Good, Moderate, None).
  • Immunogenicity [ Time Frame: On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year. ]
    The modified Nijmegen method of the Bethesda assay
  • Adverse Events [ Time Frame: Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up. ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study Comparing the Pharmacokinetic of Biosimilar Eptacog Alfa With Novoseven®, in Patients With Congenital Factor VII Deficiency
Official Title  ICMJE Randomized, Multicenter, Single-dose, Cross-over, Double-blind Study Comparing the Pharmacokinetic of Biosimilar Eptacog Alfa With Novoseven®, in Patients With Congenital Factor VII Deficiency
Brief Summary

The purpose of this multicentre, randomized, double blinded, single dose, two-way cross-over study, is to compare the pharmacokinetics (PK) of biosimilar eptacog alfa (activated) with Novoseven in 24 patients, adult and children (>12 years), not bleeding, with inherited coagulation factor VII (FVII) deficiency (FVII <1%). Patients will be randomized to receive either a single dose of eptacog alfa biosimilar 30 μg/kg and one single dose of NovoSeven 30 μg/kg, or vice versa, with doses separated by a washout period. All patients will be followed 12 months and will receive biosimilar eptacog alfa, on demand, for every bleeding episode that should occur - or - for prophylaxis, with the aim of monitoring of inhibiting antibody formation, lack of efficacy and collection of safety data.

Additional 26 patients with the same inclusions and exclusions criteria will be included in this study (for a total 50 patients). These patients will not enter the PK phase of the study but they will be followed to receive biosimilar eptacog alfa, on demand, for every bleeding episode that should occur during 12 months - or - for prophylaxis, with the aim of monitoring of inhibiting antibody formation, lack of efficacy and collection of safety data. The modality of treatment with biosimilar eptacog alfa (on demand or prophylaxis) will be decided by the Investigator.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Randomized, single dose, double blinded, two-way cross-over study.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
Blinding is performed by an independent third party operator (nurse/pharmacist, unblinded), who will prepare undistinguishable syringes with patient's dosing and labeling. Central lab operators will be blinded.
Primary Purpose: Treatment
Condition  ICMJE Factor VII Deficiency
Intervention  ICMJE
  • Biological: Eptacog alfa, biosimilar and reference medicinal product Novoseven
    Either a single dose of eptacog alfa biosimilar 30 μg/kg and one single dose of NovoSeven 30 μg/kg, or vice versa, with doses separated by a washout period. Then, in an open follow up phase of 12 months, for every bleeding episode eptacog alfa biosimilar 30 μg/kg, on demand, for one of more days until resolution of bleeding, based on the Investigator's decision - or - prophylaxis with eptacog alfa biosimilar, with dose, frequency, and duration of treatment based on the Investigator's decision. The modality of treatment (on demand or prophylaxis) will be decided by the Investigator.
  • Biological: Eptacog alfa biosimilar
    Additional patients will receive eptacog alfa biosimilar, on demand, for treatment of every bleeding episode in a 12 months period, at dose 30 μg/kg for one of more days until resolution of bleeding, based on the Investigator's decision - or - prophylaxis with eptacog alfa biosimilar, with dose, frequency, and duration of treatment based on the Investigator's decision. The modality of treatment (on demand or prophylaxis) will be decided by the Investigator.
Study Arms  ICMJE
  • Experimental: Eptacog alfa biosimilar for PK
    Randomized, double-blind, single dose cross-over for PK, with 12 months follow up with eptacog alfa biosimilar provided for treatment of bleeding on demand - or - prophylaxis.
    Intervention: Biological: Eptacog alfa, biosimilar and reference medicinal product Novoseven
  • Experimental: Eptacog alfa biosimilar, additional immunogenicity cohort
    Additional patients receiving eptacog alfa biosimilar for treatment of bleeding on demand - or - prophylaxis, over a 12 months period
    Intervention: Biological: Eptacog alfa biosimilar
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 8, 2017)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
  • Patients for the Additional group for immunogenicity should be enrolled when in a bleeding episode requiring treatment with FVII.
  • Male and female subjects
  • Adult and children (>12 years)
  • Written informed consent. 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.

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 Study Group who have not suspended prophylactic regimen with Novoseven or AryoSeven (biosimilar eptacog alfa) 3 days before starting the trial (receiving first dose of study medication).
  • Patients entering the Additional Group for Immunogenicity study, only, who have been exposed to AryoSeven before starting study [patients who have received Novoseven (on demand or in prophylaxis) before starting study are allowed]
  • Platelet count less than 100.000 platelets/μl (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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Gender Based Eligibility: Yes
Gender Eligibility Description: Male and female
Ages  ICMJE 12 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Amirhossein Saadatirad, PhD +98(26)36106480-84 saadatirada@aryogen.com
Listed Location Countries  ICMJE Iran, Islamic Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03079063
Other Study ID Numbers  ICMJE UGA2014-02
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party AryoGen Pharmed Co.
Study Sponsor  ICMJE AryoGen Pharmed Co.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Massimo Iacobelli, MD
PRS Account AryoGen Pharmed Co.
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP