A Study of Nicotinamide With Oral Tetrahydrouridine and Decitabine to Treat High Risk Sickle Cell Disease
A Study of Nicotinamide With Oral Tetrahydrouridine and Decitabine to Treat High Risk Sickle Cell Disease
A randomized control trial in 20 subjects with sickle cell disease comparing oral
 THU-decitabine to nicotinamide and in combination (THU, decitabine and nicotinamide).
A randomized control trial comparing oral THU-decitabine to nicotinamide (1:1 randomization),
 and then comparing the effects of the combination of nicotinamide with THU-decitabine vs
 either treatment alone. Treatment with each agent alone is for 12 weeks followed by the
 combination for a further 12 weeks. Patients have the option to enter an extension phase of
 combination treatment for an additional 24 weeks (total of 48 weeks)
Inclusion Criteria:

 -  Age 18 years or older.

 -  Written informed consent provided by the subject before study entry.

 -  Confirmed sickle cell disease (SCD) as determined by hemoglobin electrophoresis or
 liquid chromatography.

 -  Subject is in his/her steady state and not having any acute complication due to SCD
 (i.e., hospitalization, acute pain, or acute chest syndrome in the past 14 days).

 -  Weight at least 40kg

 -  Regular compliance with comprehensive care and previous therapy.

 -  Symptomatic SCD is defined as having one of following, despite at least 6 months of
 hydroxyurea therapy, or refuse to take hydroxyurea for personal reasons: fetal
 hemoglobin <0.5 g/dL, or 3 or more pain episodes per year requiring parenteral
 narcotics, or 1 or more acute chest syndrome episodes, or Hemoglobin <9 g/dL and
 absolute reticulocyte count <250,000/mm3.

 Exclusion Criteria:

 -  Inability to give informed consent.

 -  Experienced severe sepsis or septic shock within the previous 12 weeks.

 -  Last HU dose was ingested within the previous 4 weeks.

 -  Currently pregnant or breast-feeding.

 -  Alanine Aminotransferase (ALT) ≥ 3 times the upper limit of normal or albumin <2.0
 mg/dL or direct (conjugated) bilirubin ≥ 1.5 mg/dl.

 -  Serum creatinine >2.9 mg/dL and calculated creatinine clearance <30 mL/min.

 -  Platelet count >800 x 109/L.

 -  Absolute neutrophil count <1.5 x 109/L.

 -  Female of active childbearing potential who is unwilling to use at least one of the
 two following forms of birth control: (i) not having heterosexual sexual contact
 beginning at the screening visit and continuing until 4 weeks after the last dose of
 decitabine OR (ii) intrauterine device (IUD).

 -  Sexually active male who is unwilling to use a condom when engaging in any sexual
 contact with a female with child-bearing potential, beginning at the screening visit
 and continuing until 4 weeks after taking the last dose of THU and decitabine. This
 requirement applies also to males who have had a successful vasectomy.

 -  Altered mental status or recurrent seizures requiring anti-seizure medications.

 -  Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such
 severity that death within 24 weeks is likely.

 -  Concurrent diagnosis of malignancy including known Myelodysplastic syndrome, leukemia,
 or an abnormal karyotype.

 -  New York Heart Association (NYHA) class III/IV status.

 -  Eastern Co-operative Oncology Group (ECOG) performance status ≥3.

 -  Participant is on chronic transfusion therapy

 -  Known history of illicit drug or alcohol abuse within the past 12 months.

 -  Other experimental or investigational drug therapy in the past 28 days.

 -  Taking l-glutamine within the last 28 days

 -  Being positive for HIV infection