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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 : February 22, 2019
Sponsor:
Information provided by (Responsible Party):
Octapharma

Tracking Information
First Submitted Date  ICMJE March 25, 2015
First Posted Date  ICMJE April 3, 2015
Last Update Posted Date February 22, 2019
Study Start Date  ICMJE December 2015
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 17, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 2, 2015)
Assess efficacy of Octafibrin for on-demand treatment of acute bleeding episodes (spontaneous or traumatic) [ Time Frame: 5 years ]
The efficacy will be assessed by the investigator using a 4-point ordinary efficacy scale (excellent, good, moderate, none)
Change History Complete list of historical versions of study NCT02408484 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 17, 2017)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 2, 2015)
  • terminal half-life of Octafibrin [ Time Frame: 5 years ]
    Determine pharmacokinetics of Octafibrin: Determine the terminal half-life of Octafibrin in paediatric subjects
  • area under the curve of Octafibrin [ Time Frame: 5 years ]
    Determine pharmacokinetics of Octafibrin: Determine the area under the curve of Octafibrin in paediatric subjects
  • Investigate the association between clinical hemostatic efficacy and MCF (maximum clot firmness) via thromboelastometry (ROTEM) [ Time Frame: 5 years ]
    To investigate an association between the overall clinical assessment of haemostatic efficacy and the surrogate endpoint 'clot strength' or 'clot firmness' (referred to as 'maximum clot firmness' [MCF] in this protocol) via thromboelastometry (ROTEM). Therefore, MCF as surrogate efficacy parameter will be determined before and after the first infusion of IMP for treatment of a bleeding episode.
  • Determine peak target plasma fibrinogen levels in minor and major bleedings [ Time Frame: 5 years ]
    To achieve a peak target plasma fibrinogen level of 100 mg/dL in minor bleeds and 150 mg/dL for major bleeds 1 hour post-infusion.
  • Determine response to Octafibrin based on incremental in vivo recovery [ Time Frame: 5 years ]
    To determine the response to Octafibrin based on incremental in vivo recovery (IVR) by measuring the Fibrinogen plasma level pre- and 1 hour and 3 hours post infusion.
  • Assess efficacy of Octafibrin in preventing bleeding during and after surgery [ Time Frame: 5 years ]
    The efficacy of Octafibrin in preventing bleeding during and after surgery will be assess using a 4-point hemostatic efficacy scale (excellent, good, moderate, none).
  • Number of subjects with (serious) adverse events [ Time Frame: 5 years ]
    Assess the safety of Octafibrin in subject with fibrinogen deficiency. To assess the safety of Octafibrin in subjects with congenital fibrinogen deficiency. Number of subjects with (serious) adverse events, including immunogenicity, thromboembolic complications, and early signs of allergic or hypersensitivity reactions.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Assess the Efficacy, Safety and Pharmacokinetic of Octafibrin in Paediatric Subjects With Fibrinogen Deficiency
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Congenital Fibrinogen Deficiency
Intervention  ICMJE Biological: Octafibrin
Plasma-derived Fibrinogen concentrate
Other Name: Fibrinogen concentrate
Study Arms  ICMJE Experimental: Octafibrin
Plasma-derived fibrinogen concentrate
Intervention: Biological: Octafibrin
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: April 2, 2015)
6
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 11 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Cristina Solomon, MD +41554512189 cristina.solomon@octapharma.com
Listed Location Countries  ICMJE India,   Iran, Islamic Republic of,   Lebanon
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02408484
Other Study ID Numbers  ICMJE FORMA-04
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Octapharma
Study Sponsor  ICMJE Octapharma
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Cristina Solomon, MD Octapharma
PRS Account Octapharma
Verification Date February 2019

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