Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Study Of PF-04447943, Co-Administered With And Without Hydroxyurea, In Subjects With Stable Sickle Cell Disease
Condition: Phase 1 Sickle Cell
MeSH terms: Anemia, Sickle Cell
Intervention: PDE9i; PDE9i; placebo for PDE9i; PDE9i
Intervention description: oral dose, every 12 hours for 28 days; oral dose, every 12 hours for 28 days; oral dose, every 12 hours for 28 days; oral dose, every 12 hours for 28 days
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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.