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

Hemophilia A Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01619046
• Other study ID #: GreenGeneF_P3
• Status: Recruiting
• Phase: Phase 3
• First received: May 31, 2012
• Last updated: July 2, 2014
• Start date: March 2013
• Est. completion date: September 2015

Study information

• Verified date: July 2014
• Source: Green Cross Corporation
• Contact: Kevin Wait
• Phone: 540-649-5490
• Email: kwait[@]atlanticresearchgroup.com
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 124
• Est. completion date: September 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hemophilia A

Intervention

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
• 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
• 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
• 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.

Locations

Country	Name	City	State
Canada	University of Alberta	Edmonton	Alberta
Canada	McMaster Children's Hospital	Hamilton	Ontario
New Zealand	Research Associates, Ltd.	Christchurch
Poland	wojewodzki szpital Specjalistyczny, klinika hematologii uniwersytetu medycznego w lodzi	Lodzi
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Russian Federation	Barnaul Altai State Scientfic Center	Barnaul
Russian Federation	Kirov Research Institute of Hematology and Blood Transfusion	Kirov
Russian Federation	Ismailov City Children's Clinical Hospital of Board of Health of Moscow City	Moscow
Russian Federation	State Budget Educational Institution of Higher professional Education "Samara State Medical University" of the Ministry of Health and Social Process of the Russian Federation	Samara
Russian Federation	Ufa Republican Clinical Hospital	Ufa
Ukraine	Dnepropetrovsk City Clinical Hospital	Dnepropetrovsk
Ukraine	Institute of Urgent and Reconstructive surgery named after V.K. Gusak of National Academy of Medical Sciences of Ukraine	Donetsk
Ukraine	Kharkov Regional Clinical Oncology Center	Kharkov
Ukraine	Kyiv City Clinical Hospital No 91	Kyiv
Ukraine	Institute of Blood Pathology and Transfusion Medicine of National Academy of Medical Sciences of Ukraine Department of Surgery and Clinical Transfusiology	Lviv
Ukraine	Zaporizhzhya Region Clinical Child Hospital	Zaporzhye
United Kingdom	North Hampshire Haemophilia Centre	Basingstoke	North Hampshire
United Kingdom	Hull Haemophillia Centre, Hull Royal Infirmary	Humberside	Hull
United Kingdom	University of Liverpool	Liverpool
United Kingdom	Royal Free Hospital, Haemophilia Centre & Thrombosis Unit	London
United Kingdom	Central Manchester University Hospitals	Manchester	Lancashire
United Kingdom	Churchill Hospital, Oxford	Oxford
United Kingdom	Royal Cornwall Hospital, Department of Haematology	Truro	Cornwall
United Kingdom	St. Thomas' Hospital	Westminster	London
United States	St. Luke's Boise Medical Center	Boise	Idaho
United States	Rush University Medical Center	Chicago	Illinois
United States	Michigan State University Center for Bleeding Disorders & Clotting Disorders	East Lansing	Michigan
United States	Children's Mercy Hospital - Kansas City Regional Hemophilia Center	Kansas City	Missouri
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Los Angeles Orthopaedic Hospital - Hemophilia Treatment Center	Los Angeles	California
United States	University of Miami - Comprehensive Hemophilia Center	Miami	Florida
United States	Long Island Jewish Medical Center - Hemophilia Treatment Center	New Hyde Park	New York
United States	Oregon Health and Science University	Portland	Oregon
United States	Harbor - UCLA Pediatrics	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
Green Cross Corporation	Atlantic Research Group

Countries where clinical trial is conducted

United States,  Canada,  New Zealand,  Poland,  Russian Federation,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of subject with development of inhibitors	Development of neutralizing antibodies (inhibitors) will be followed during the regular visits, average of 3 months.	evert 3 months, up to 18 months	Yes
Secondary	Describe the PK profile of GreenGene™ F	AUC, AUMC, Half-life, Incremental recovery, Mean residence time (MRT), Clearance, Volume of distribution - steady state, Cmax, Tmax	Pre-dose, 0~48hours post-dose	No