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

Green Cross Corporation

Status and phase: Unknown; Phase 3

Conditions: Hemophilia A

Treatments: Biological: GreenGene™ F; Biological: GreenGene™ F and an approved recombinant Factor VIII product

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01619046

GreenGeneF_P3

Details and patient eligibility

About

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).

Enrollment: 124 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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124 participants in 4 patient groups

PK substudy

Active Comparator group

Description:

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).

Treatment:

Biological: GreenGene™ F and an approved recombinant Factor VIII product

Prophylaxis safety and efficacy substudy

Experimental group

Description:

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.

Treatment:

Biological: GreenGene™ F

Biological: GreenGene™ F

Biological: GreenGene™ F

On-demand safety and efficacy substudy

Experimental group

Description:

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.

Treatment:

Biological: GreenGene™ F

Biological: GreenGene™ F

Biological: GreenGene™ F

Surgical substudy

Experimental group

Description:

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

Treatment:

Biological: GreenGene™ F

Biological: GreenGene™ F

Biological: GreenGene™ F