Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open Label Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector (scAAV 2/8-LP1-hFIXco) For Gene Transfer in Hemophilia B
Brief Summary: The purpose of this study is to determine the safety of giving a normal factor IX gene to treat individuals who have an abnormal or no factor IX gene. Recruitment will be limited to adults (≥ 18 years) with a confirmed diagnosis of hemophilia B (HB), resulting from a missense mutation in the coagulation factor IX (FIX) gene or a nonsense mutation that has not been associated with an inhibitor. Only subjects who have no evidence of active hepatitis or anti-hFIX antibodies, and who have been treated/exposed to Factor IX concentrates for at least ten years and have had an average of 3 bleeding episodes per year requiring FIX administration will be enrolled. Patients will be recruited within the United States for treatment at St. Jude Children's Research Hospital, and patients will be recruited in England and other countries for treatment in London by our British collaborators.


Options:
A: Inclusion Criteria:

* The subject is male and is 18 to 65 years of age at the time of screening
* The subject has severe hemophilia A (factor VIII level \< 1%)
* The subject was previously treated with plasma-derived factor VIII (FVIII) concentrates or recombinant FVIII for at least 150 exposure days (EDs)

Exclusion Criteria:

* The subject has a detectable FVIII inhibitor at screening, with a titer \>= 0.6 BU
* The subject has a documented history of FVIII inhibitors with a titer \>= 0.4 BU at any time prior to screening
* The subject has a known hypersensitivity towards mouse or hamster proteins or to polyethylene glycol (PEG)
B: Inclusion Criteria:

* Males ≥ 18 years of age with established severe HB (FIX:C\<1u/dl),
* Treated/exposed to FIX products (e.g., concentrates or fresh frozen plasma) for at least 10 years or 50 exposure days.
* A minimum of an average of 3 bleeding episodes per year requiring FIX infusions or prophylactic FIX infusions because of frequent prior bleeding episodes
* Able to give informed consent and comply with requirements of the trial
* Currently free of inhibitor and have no history of inhibitors to FIX protein
* A negative family history for the development of an inhibitor,
* Willing to practice a reliable barrier method of contraception until 3 sequential samples are negative for vector genomes using our PCR assay.

Exclusion Criteria:

* Evidence of active infection with Hepatitis B or C virus as reflected by HBsAg or NCV RNA positivity, respectively. To be considered negative for active infection, two negative assays at a minimum of a six month interval are required.
* Exposure to Hepatitis B or C who are currently on antiviral therapy.
* Serological evidence of HTLV or active HIV infection. Individuals who are effectively being treated with antiretroviral therapy are eligible. Specific criteria for effectiveness of treatment include the following:

  * Documented CD4+ T-cell count of \> 350 cells/mm\^3.
  * HIV-1 RNA viral load \< 400 copy/ml for at least the past 12 months, including at least 2 viral load test results of \< 400 copy/ml during the immediate 12 month interval prior to screening.
  * Screening HIV-RNA viral load \< 400 copies/ml.
  * Stable HAART regimen (drugs of at least 2 different classes) for at least 12 months prior to study entry. Treatment regimen changes for dosing convenience and in response to toxicity are permitted.
  * Documented and confirmed (repeated) viral loads of ≥ 400 copies/ml during the 12 month time interval prior to screening are bases for exclusion although a single, unconfirmed, "glimpse" of ≥ 400 copies/ml are permitted.
* Significant liver dysfunction as defined by an abnormal ALT (alanine transaminase), bilirubin, alkaline phosphatase or INR. Potential participants who have had a liver biopsy in the past 3 years will be excluded if they have significant fibrosis of 3 or 4 as rated on a scale of 0-4.
* Coronary artery disease as a co-morbid condition
* Platelet count of \<50 x 10\^9/l
* Creatinine ≥ 1.5 mg/dl
* Hypertension with systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg
* History of active tuberculosis, fungal disease or other chronic infection
* History of chronic disease that would adversely affect performance other than hemophilic arthropathy
* Detectable antibodies reactive with AAV8
* Subjects who are unwilling to provide the required semen samples
* Poor performance status (WHO performance status score \>1) or
* Received an AAV vector or any other gene transfer agent in the previous 6 months
* Presence of lung nodule(s) suspicious of malignancy on screening chest tomography
* Presence of liver abnormalities suspicious of malignancy on screening liver ultrasound
C: Main Inclusion Criteria:

* Participant and/or legal representative has/have voluntarily provided signed informed consent
* Participant is 12 to 65 years old at the time of screening
* Participant is male with severe hemophilia A (Factor VIII (FVIII) clotting activity \< 1%) as confirmed by central laboratory at screening after the appropriate washout period or a documented FVIII clotting activity \<1%
* Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥150 documented exposure days (EDs)
* Participant is currently receiving prophylaxis or on-demand therapy with FVIII
* Participant is willing and able to comply with the requirements of the protocol

Main Exclusion Criteria:

* Participant has detectable FVIII inhibitory antibodies (≥ 0.6 Bethesda Units (BU) using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening
* Participant has history of FVIII inhibitory antibodies (≥ 0.4 BU using the Nijmegen modification of the Bethesda assay or ≥ 0.6 BU using the Bethesda assay) at any time prior to screening
* Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
D: Inclusion Criteria:

* Able to provide informed consent and comply with requirements of the study
* Males ≥18 y.o. with confirmed diagnosis of hemophilia B (≤2 IU/dL or ≤2% endogenous factor IX)
* Received ≥50 exposure days to factor IX products
* A minimum average of 4 bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions
* No measurable factor IX inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor IX protein
* Agree to use reliable barrier contraception until 3 consecutive samples are negative for vector sequences

Exclusion Criteria:

* Evidence of active hepatitis B or C
* Currently on antiviral therapy for hepatitis B or C
* Have significant underlying liver disease
* Have serological evidence\* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 (\* subjects who are HIV+ and stable with CD4 count \>200/mm3 and undetectable viral load are eligible to enroll)
* Neutralizing antibodies reactive with AAV-Spark100 above and/or below a defined titre
* Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational drug within the last 12 weeks
* Unable or unwilling to comply with study assessments

Answer: B