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Study to Assess the Efficacy, Safety and Pharmacokinetic of Octafibrin in Paediatric Subjects With Fibrinogen Deficiency

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ClinicalTrials.gov Identifier: NCT02408484
Recruitment Status : Recruiting
First Posted : April 3, 2015
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Octapharma

Brief Summary:

This study will assess the efficacy of Octafibrin, a fibrinogen concentrate in in the on-demand treatment of spontaneous or traumatic bleeding episodes in paediatric patients less than 12 years of age.The planned study duration is up to 5 years. The study will be considered completed when a minimum of 6 subjects (i.e., at least 3 subjects aged between 0 and <6 years and 3 subjects aged between 6 and <12 years) have at least one documented bleeding episode and when in total a minimum of 2 surgical procedures have been performed.

All patients will undergo a pharmacokinetic (PK) study after screening. This will have a duration of 14 days, after which a patient can be treated for a bleeding episode or planned surgical procedure when they occur.


Condition or disease Intervention/treatment Phase
Congenital Fibrinogen Deficiency Biological: Octafibrin Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective, Open-label, Uncontrolled, Phase III Study to Assess the Efficacy, Safety and Pharmacokinetic of Octafibrin for On-demand Treatment of Acute Bleeding and to Prevent Bleeding During and After Surgery in Paediatric Subjects With Congenital Fibrinogen Deficiency
Study Start Date : December 2015
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020


Arm Intervention/treatment
Experimental: Octafibrin
Plasma-derived fibrinogen concentrate
Biological: Octafibrin
Plasma-derived Fibrinogen concentrate
Other Name: Fibrinogen concentrate




Primary Outcome Measures :
  1. Overall clinical assessment of the haemostatic efficacy of Octafibrin in treating the first documented bleeding episode of each patient [ Time Frame: First Octafibrin infusion for the treatment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever comes last ]
    The investigator's overall clinical assessment of haemostatic efficacy for bleeding will be based on a 4-point haemostatic efficacy scale. The final efficacy assessment of each patient will be adjudicated by the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). The number of subjects per outcome category will be assessed in the final analysis.


Secondary Outcome Measures :
  1. Single-dose pharmacokinetics of Octafibrin: Area under the concentration-time curve (AUC) [ Time Frame: Before first infusion to 14 days post-infusion ]
    AUC will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  2. Single-dose pharmacokinetics of Octafibrin: Response - Incremental in vivo recovery (IVR) [ Time Frame: Before first infusion to 14 days post-infusion ]
    IVR will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  3. Single-dose pharmacokinetics of Octafibrin: Classical incremental in vivo recovery (IVR) [ Time Frame: Before first infusion to 14 days post-infusion ]
    Classical IVR will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  4. Single-dose pharmacokinetics of Octafibrin: Terminal elimination half-life (t1/2) [ Time Frame: Before first infusion to 14 days post-infusion ]
    t1/2 will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  5. Single-dose pharmacokinetics of Octafibrin: Maximum plasma concentration (Cmax) [ Time Frame: Before first infusion to 14 days post-infusion ]
    Cmax will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  6. Single-dose pharmacokinetics of Octafibrin: Time to reach maximum plasma concentration (Tmax) [ Time Frame: Before first infusion to 14 days post-infusion ]
    Tmax will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  7. Single-dose pharmacokinetics of Octafibrin: Mean residence time (MRT) [ Time Frame: Before first infusion to 14 days post-infusion ]
    MRT will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  8. Single-dose pharmacokinetics of Octafibrin: Volume of distribution (Vss) [ Time Frame: Before first infusion to 14 days post-infusion ]
    Vss will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  9. Single-dose pharmacokinetics of Octafibrin: Clearance (Cl) [ Time Frame: Before first infusion to 14 days post-infusion ]
    Cl will be assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.

  10. Maximum clot firmness (MCF) before and following first infusion of each documented bleeding episode [ Time Frame: Before first infusion and 1 hour after end of first infusion of each documented bleeding episode ]
    MCF will be determined using thromboelastometry (ROTEM) and will be used as a surrogate marker for haemostatic efficacy. ROTEM is a method for the continuous measurement of clot formation and clot firmness. It utilises a mechanical detection system which is based on the ability of the blood or plasma clot to form a mechanical coupling over a distance of 1 mm.

  11. Fibrinogen plasma level [ Time Frame: Before and 1 hour after the end of each infusion as well as at the time of the overall clinical assessment of haemostatic efficacy (i.e., 24 hours after the last infusion or end of the observation period of each documented bleeding episode) ]
    Fibrinogen plasma level will be assessed using the Clauss fibrinogen assay.

  12. Response after the first infusion of each bleeding episode as indicated by incremental in vivo recovery [ Time Frame: Pre-infusion and 3 hours post-infusion ]
    Incremental IVR calculated as the maximum increase in plasma fibrinogen (Clauss data) between the pre-infusion and the 3-hour post-infusion measurement, divided by the exact dose of Octafibrin.

  13. Efficacy of Octafibrin in all bleeding episodes [ Time Frame: First Octafibrin infusion for the treatment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever comes last ]
    The investigator's overall clinical assessment of haemostatic efficacy for bleeding will be based on a 4-point haemostatic efficacy scale. The final efficacy assessment of each patient will be adjudicated by the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). The number of subjects per outcome category will be assessed in the final analysis.

  14. Efficacy of Octafibrin in surgical prophylaxis [ Time Frame: First dose of Octafibrin prior to elective surgery, to at least 3 post-operative days for minor and 7 post-operative days for major surgeries or until the day of the last post-operative infusion, whichever comes last ]
    Efficacy of Octafibrin will be assessed at the end of surgery by the surgeon and post-operatively by the haematologist using two four-point scales. An overall efficacy assessment taking both the intra- and post-operative assessment into account will be adjudicated by the IDMEAC. The final endpoint determination will be based on the adjudicated assessments using an agreed algorithm.

  15. Safety assessment: Thromboembolic event (TEE) questionnaire [ Time Frame: Start of the first Octafibrin infusion to the end of PK, end of 30-day observation and follow-up period for on-demand treatment, or the end of the surgical observation period ]
    TEE questionnaire completed at all study visits for the treatment of bleeding episodes and for surgeries.

  16. Safety assessment: Adverse events [ Time Frame: Start of the first Octafibrin infusion to the end of PK, end of 30-day observation and follow-up period for on-demand treatment, or the end of the surgical observation period ]
    Adverse events, including thromboembolic complications and early signs of allergic or hypersensitivity reactions.

  17. Safety assessment: Immunogenicity testing for anti-fibrinogen antibodies [ Time Frame: Start of the first Octafibrin infusion to the end of each 30-day observation and follow-up period for on-demand treatment ]
    Immunogenicity testing for the presence of anti-fibrinogen antibodies before the first infusion of Octafibrin and on Day 30 after the treatment of each bleeding episode.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 11 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged <12 years (at the start of treatment).
  • Documented diagnosis of congenital fibrinogen deficiency, expected to require on-demand treatment for bleeding or surgical prophylaxis:

    • Fibrinogen deficiency manifested as afibrinogenaemia or severe hypofibrino-genaemia.
    • Historical plasma fibrinogen activity of <50 mg/dL or levels below the limit of detection of the local assay method.
  • Expected to have an acute bleeding episode (spontaneous or after trauma) or planning to undergo elective surgery.
  • Informed consent signed by the subject's legal guardian.

Exclusion Criteria:

  1. Life expectancy <6 months.
  2. Bleeding disorder other than congenital fibrinogen deficiency, including dysfi-brinogenaemia.
  3. Prophylactic treatment with a fibrinogen concentrate.
  4. Treatment with:

    • Any fibrinogen concentrate or other fibrinogen-containing blood product within 2 weeks prior to start of treatment for the PK phase, a bleeding episode, or surgery.
    • Any coagulation-active drug (i.e., non-steroidal anti-inflammatory drugs, war-farin, coumarin derivatives, platelet aggregation inhibitors) within 1 week prior to start of the PK phase or treatment for the bleeding episode or surgery, or as a planned or expected medication during the time period from Day 1 until 24 hours (i.e., 1 day) after the last Octafibrin infusion.
  5. Presence or history of:

    • Hypersensitivity to study medication.
    • Deep vein thrombosis or pulmonary embolism within 1 year prior to start of treatment for the bleeding episode or surgery.
    • Arterial thrombosis within 1 year prior to start of treatment for the bleeding episode or surgery
    • Hypersensitivity to human plasma proteins.
    • Oesophageal varicose bleeding.
    • End-stage liver disease (i.e., Child-Pugh score B or C).
  6. Known positive HIV infection with a viral load >200 particles/μL or >400,000 copies/mL.
  7. Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery.
  8. Diagnosis or suspicion of a neutralizing anti-fibrinogen inhibitor currently or any time in the past.
  9. Acute or chronic medical condition which may, in the opinion of investigator, affect the conduct of the study, including subjects receiving immune-modulating drugs (other than anti-retroviral chemotherapy), such as alpha-interferon, predni-sone (equivalent to >10 mg/day), or similar drugs, at study start.
  10. Treatment with IMP in another interventional clinical study currently or during the past 4 weeks.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02408484


Contacts
Contact: Cristina Solomon, MD +41554512189 cristina.solomon@octapharma.com

Locations
India
St. John's Medical College Hospital Recruiting
Bangalore, India, 560034
S.S Institute of Medical Science and Research Center Recruiting
Davangere, India, 577005
Sahyadri Specialty Hospital Withdrawn
Pune, India
Iran, Islamic Republic of
Nemazee Hospital Shiraz University of Medical Sciences Completed
Shiraz, Iran, Islamic Republic of
Lebanon
Hotel De Dieu de France Recruiting
Beirut, Lebanon
Sponsors and Collaborators
Octapharma
Investigators
Study Director: Cristina Solomon, MD Octapharma

Responsible Party: Octapharma
ClinicalTrials.gov Identifier: NCT02408484     History of Changes
Other Study ID Numbers: FORMA-04
First Posted: April 3, 2015    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Afibrinogenemia
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn