Safety, Efficacy and Pharmacokinetics of GreenGene™ F to Previously Treated Patients With Severe Hemophilia A

Study Description

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Brief Summary:

The purpose of this study is to assess the safety, efficacy and pharmacokinetics of GreenGene™ F in subjects with severe hemophilia A previously treated (> 150 exposure days) with a Factor VIII concentrate and without presence or history of inhibitors to FVIII (Factor VIII).

Condition or disease	Intervention/treatment	Phase
Hemophilia A	Biological: GreenGene™ F and an approved recombinant Factor VIII product; Biological: GreenGene™ F	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	124 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Determination of Safety, Efficacy and Pharmacokinetics of GreenGene™ F in Previously Treated Patients 12 Years of Age or Older Diagnosed With Severe Hemophilia A
Study Start Date :	March 2013
Estimated Primary Completion Date :	July 2015
Estimated Study Completion Date :	September 2015

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: PK substudy; A cohort of 13-18 subjects will be included in the pharmacokinetic (PK) evaluation of GreenGene™ F and an approved recombinant Factor VIII product (Refacto AF); a minimum of 13 of these subjects will be re-evaluated at study end (50 exposure day).	Biological: GreenGene™ F and an approved recombinant Factor VIII product; one 50 IU/kg, intra-venous infusion over 5 minutes, Infusion rate < 10 mL/min; Other Names: GreenGeneF; GreenGene F
Experimental: Prophylaxis safety and efficacy substudy; Hemostatic efficacy of GreenGene™ F will be assessed by its effectiveness in controlling spontaneous or traumatic bleeding episodes and by the rate of breakthrough bleeding during prophylaxis over ≥ 50 exposure days.	Biological: GreenGene™ F; intra-venous infusion, 30 ± 5 IU/kg infusions 3 times per week with dose escalation to 45 ± 5 IU/kg if appropriate, for 50 exposure days; Other Names: GreenGeneF; GreenGene F
Experimental: On-demand safety and efficacy substudy; Hemostatic efficacy of GreenGene™ F will be assessed by its effectiveness in controlling spontaneous or traumatic bleeding episodes and by the rate of breakthrough bleeding in a minimum of 10 on demand treated subjects during 50 exposure days.	Biological: GreenGene™ F; intra-venous infusion, On-demand safety and efficacy substudy: minor bleed = 10-20 IU/kg moderate bleed = 15-30 IU/kg major bleed = 30-50 IU/kg; Other Names: GreenGeneF; GreenGene F
Experimental: Surgical substudy; Peri-operative hemostatic control of GreenGene™ F in surgery or invasive procedures will be assessed in at least 10 surgeries, some of them major, in at least five subjects	Biological: GreenGene™ F; intra venous infusion, Surgical substudy: Minor surgery including tooth extraction = Post in fusion FVIII level of 60-100% of normal. A single bolus infusion (30-50 IU/kg) beginning within one hour of the operation. Optional additional dosing every 12 to 24 hours as needed to control bleeding. Major surgery = Pre- and post infusion FVIII level 80-120% of normal. Preoperative bolus infusion: 40-60 IU/kg. Verified 100% activity prior to surgery. Maintenance bolus infusion (40-60 IU/kg) repeat infusions every 8 to 24 hours, depending on the desired level.; Other Names: GreenGeneF; GreenGene F

Outcome Measures

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Primary Outcome Measures :

1. Number of subject with development of inhibitors [ Time Frame: evert 3 months, up to 18 months ]
   Development of neutralizing antibodies (inhibitors) will be followed during the regular visits, average of 3 months.

Secondary Outcome Measures :

1. Describe the PK profile of GreenGene™ F [ Time Frame: Pre-dose, 0~48hours post-dose ]
   AUC, AUMC, Half-life, Incremental recovery, Mean residence time (MRT), Clearance, Volume of distribution - steady state, Cmax, Tmax

Eligibility Criteria

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Ages Eligible for Study:	12 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Male or female subjects age ≥ 12 years at the time of informed consent
2. Body weight ≥ 35 kg
3. Diagnosed with severe hemophilia A. All subjects must have severe hemophilia A with baseline FVIII <1% activity; <0.01 IU/mL
4. Have ≥ 150 previous exposure days to FVIII concentrates, as documented in the subject's medical records
5. Subjects included in the on-demand treatment cohort must have a verifiable record of at least three bleeding episodes per month on average in the last 6 months prior to enrollment
6. Negative assays for FVIII inhibitor at inclusion (<0.6BU Nijmegen assay)
7. Negative assays for FVIII inhibitor in subject files (<0.6BU Nijmegen assay) No history of positive inhibitor is allowed
8. Normal liver and kidney function.
9. Platelet count ≥ 100,000 μL
10. Normal prothrombin time or International Normalized Ratio (INR) < 1.5
11. Subjects receiving therapy for human immunodeficiency virus (HIV) or hepatitis must be on a stable treatment regimen
12. Subjects must be able to withhold FVIII infusions for approximately 72 h prior to each FVIII activity and inhibitor assay (96 h if participating in the PK sub study)
13. Absolute CD4 lymphocyte cell count ≥ 200 μL
14. Signed the written informed consent form or informed consent was obtained from the subject's legal guardian
15. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [ß hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug
16. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e. bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least one month before dosing)
17. Willing and able to comply with all aspects of the protocol

Exclusion Criteria:

1. Presence at Screening of FVIII inhibitor ≥ 0.6 BU as tested with the Nijmegen modification of the Bethesda assay in either central or local laboratory
2. History of FVIII inhibitor of ≥ 0.6 BU as measured using the Nijmegen modification of the Bethesda assay
3. History of FVIII inhibitor ≥ 1.0 BU if the subject has been tested routinely using the original Bethesda assay, or history of periods with low recovery and no response to Factor VIII treatment
4. Demonstrated an inability to respond to conventional doses of FVIII therapy
5. History of incremental recovery of Factor VIII <1.35% per IU/kg infused
6. Hematological disorders or blood coagulation diseases (e.g., idiopathic thrombocytopenic purpura, von Willebrand disease, etc.) other than hemophilia A
7. Laboratory or clinical evidence of portal vein hypertension including,(but not limited to, an INR > 1.4, the presence of splenomegaly and/or spider angiomata on physical examination and/or a history of esophageal hemorrhage or documented esophageal varices
8. Uncontrolled hypertension (diastolic blood pressure >100 mm Hg)
9. Hemoglobin < 10 g.dL
10. HIV disease symptoms regardless of presence of HIV antibodies
11. Routine administration (or planned routine administration during the course of the study), of immunosuppressive or immunomodulating drugs other than antiretroviral therapy (e.g., steroids, beta-interferon)
12. Severe renal dysfunction (creatinine > 2x upper limit of normal [ULN], total bilirubin > 2x the ULN)
13. Liver disease (alanine aminotransferase [ALT], aspartate aminotransferase [ AST] > 3x the ULN)
14. History of diabetes or other metabolic disease
15. History of hypersensitivity or serious adverse reaction to recombinant or plasma-derived FVIII concentrate
16. History of pretreatment prior to the administration of FVIII products (e.g., of antihistamines)
17. Regular use of antifibrinolytics or medications affecting platelet function
18. Hypersensitivity to hamster-or mouse derived proteins
19. Blood transfusions within 30 days of enrollment into the study
20. Current participation in another investigational drug or device study, or participated in a clinical study involving an investigational drug or device within 30 days of enrollment into the study
21. Unable or unwilling to cooperate with study procedures

Contacts and Locations

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Contacts

Contact: Kevin Wait	540-649-5490	kwait@atlanticresearchgroup.com

  Show 34 Study Locations

Sponsors and Collaborators

Green Cross Corporation

Atlantic Research Group

Investigators

Principal Investigator:	Paul LeoFrancis Giangrande, MD	Oxford Haemophilic Centre and Thrombosis Unit, Churchill Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Green Cross Corporation
ClinicalTrials.gov Identifier:	NCT01619046 History of Changes
Other Study ID Numbers:	GreenGeneF_P3
First Posted:	June 14, 2012
Last Update Posted:	July 3, 2014
Last Verified:	July 2014

Keywords provided by Green Cross Corporation:

GreenGene™F, Previously Treated Patients

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders	Hemorrhagic Disorders; Genetic Diseases, Inborn; Factor VIII; Coagulants