Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Study Of PF-04447943, Co-Administered With And Without Hydroxyurea, In Subjects With Stable Sickle Cell Disease

A Phase 1b, Randomized, Double-blind (Sponsor Open), Placebo Controlled Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Pf 04447943, Co-administered With And Without Hydroxyurea, In Subjects With Stable Sickle Cell Disease

This study is being conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an investigational drug, PF-04447943, in subjects with stable sickle cell disease with and without co-administration with hydroxyurea. This study will also aid in selecting the doses for future studies and evaluation of substances in the blood which may help access the effectiveness of the drug.

Inclusion Criteria:

• Male and female subjects with a confirmed diagnosis of sickle cell disease (HbSS or HBS-β0 thalassemia) between the ages of 18 and 65 years, inclusive
• Subjects who are being treated with hydroxyurea must be on a stable dose for at least 8 weeks, with the intent of remaining on the same dose of hydroxyurea throughout the clinical trial including the protocol-specified follow-up period. Subjects who are not treated with hydroxyurea should not plan to begin treatment during the study period.
• Body Mass Index (BMI) of 17.5 to 35 kg/m2; and a total body weight >40 kg (88 lbs

Exclusion Criteria:

• History of a recent major surgery, within 3 months of baseline visit.

• Serious infection (requiring hospitalization or parenteral antibiotics) within 1 month of baseline visit.

• History of cerebrovascular accident or seizure disorder.

• Subjects with a history of clinically significant orthostatic blood pressure (BP) changes or clinically significant orthostatic symptoms.

• Known previous diagnosis of acute hepatitis of any aetiology Hepatitis B or C or Human immunodeficiency virus (HIV) infection.

• History of any malignancy except for subjects who had a basal or squamous cell cancer which has been treated and fully resolved for a minimum of 5 years.

• History or evidence of cardiac disease including: myocardial infarction, cardiac arrhythmia

• Systemic therapy with any of the following medications that are strong or moderate CYP3A4 inhibitors within 7 days or 5 half-lives (whichever is longer) or CYP3A inducers within 28 days prior to the first dose of the trial medication, or during the trial.

• Use of PDE5 inhibitors within 7 days prior to the first dose of the trial medication, or at any time during the trial.

• Creatinine clearance <30ml/min.

• Hemoglobin level <6 gm/dL.

• Alanine transaminase (ALT/SGPT) and Aspartate aminotransferase (AST/SGOT) >2x upper limit of normal, (based on clinic laboratory normal range).

• Any condition possibly affecting drug absorption (eg, gastrectomy).

• A positive urine drug screen for illicit drug.

• History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.

• Treatment with an investigational drug within 2 months (or as determined by the local requirement, whichever is longer) or 5 half-lives preceding the first dose of study medication.

• 12-lead ECG demonstrating QTc >450 or a QRS interval >120 msec msec at Screening.

• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

• A family history of long QT syndrome and/or ECG abnormalities at screening or randomization, including those listed below:

  • Subjects with pre-randomization evidence of QTcF prolongation (defined as >450 ms) at screening or baseline are not eligible for randomization.
  • Predominant heart rhythm other than normal sinus rhythm eg, atrial fibrillation, atrial flutter, supraventricular tachycardia.
  • Atrioventricular (AV) block greater than first degree.

• Use of concomitant medications that prolong the QT/QTc interval

• Pregnant females and, breast feeding females and females of childbearing potential; male and female subjects of childbearing potential who are unwilling or unable to use highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 30 days after the last dose of investigational product.

• Subjects who lack the capacity to consent for themselves.