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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Phase 1 Sickle Cell

Intervention / Treatment
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* Drug: PDE9i
* Drug: PDE9i
* Drug: placebo for PDE9i
* Drug: PDE9i


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cohort 1 PF-04447943<br> | Drug: PDE9i<br>* oral dose, every 12 hours for 28 days<br>|
| Experimental: cohort 2 PF-04447943<br> | Drug: PDE9i<br>* oral dose, every 12 hours for 28 days<br>|
| Placebo Comparator: placebo comparator<br> | Drug: placebo for PDE9i<br>* oral dose, every 12 hours for 28 days<br>|
| Experimental: optional cohort of PF-04447943<br> | Drug: PDE9i<br>* oral dose, every 12 hours for 28 days<br>Drug: PDE9i<br>* oral dose, every 12 hours for 28 days<br>Drug: PDE9i<br>* oral dose, every 12 hours for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Vital Signs | Number of participants with changes from baseline in vital signs meeting the following criteria is presented: (1) maximum increase from baseline in supine systolic blood pressure (SBP) >=30 millimeters of mercury (mmHg); (2) maximum increase from baseline in supine diastolic blood pressure (DBP) >=20 mmHg; (3) maximum decrease from baseline in supine SBP >=30 mmHg; and (4) maximum decrease from baseline in supine DBP >=20 mmHg. | Baseline up to 30 days post last dose on Day 29 | 
| Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Neurologic Function | Clinical assessment of neurologic functions included cranial nerve function, coordination, deep tendon reflexes, muscle strength, and reflexes (left and right ankles). Clinical importance of neurologic function changes was determined by the investigator. | Baseline up to Day 29 | 
| Number of Participants With Potentially Clinically Important (PCI) Change in Physical Examination Findings | Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Clinical importance of physical examination changes was determined by the investigator. | Baseline up to 30 days post last dose on Day 29 | 
| Number of Participants With Clinically Significant Treatment-Emergent Electrocardiogram (ECG) Findings | Maximum absolute values and increases from baseline were summarized for PR interval (time from the beginning of P wave to the start of QRS complex, corresponding to the end of atrial depolarization and onset of ventricular depolarization), QRS complex (time from Q wave to the end of S wave, corresponding to ventricle depolarization), and QTcF interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula). Number of participants with ECG findings meeting the following criteria is presented: (1) PR interval >=300 msec; (2) QRS complex >=200 msec; (3) QTcF interval: 450 to <480 msec; (4) QTcF interval: 480 to <500 msec; (5) QTcF interval >=500 msec; (6) PR interval percent increase from baseline >=25/50 percent; (7) QRS complex percent increase from baseline >=25/50 percent; (8) QTcF interval increase from baseline: 30 to <60 msec; (9) QTcF interval increase from baseline >=60 msec. | Baseline up to 30 days post last dose on Day 29 | 
| Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Symptoms of Sickle Cell Disease | The following symptoms were assessed: anemia; fatigue; chronic pain; acute pain; infections; fever; swelling hands; swelling feet; abdominal swelling; pale skin; pale nail beds; yellow tint to skin; whites of eyes turned yellow; stroke. Number of participants with changes from baseline deemed potentially clinically important by the investigator is presented. | Baseline up to 30 days post last dose on Day 29 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of its causal relationship with study treatment. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; was life-threatening (immediate risk of death); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs are events between first dose of study drug and up to follow-up visit (30 days post last dose on Day 29) that were absent before treatment or that worsened after treatment. AEs included both serious and non-serious AEs. | Day 1 to 30 days post last dose on Day 29 | 
| Number of Participants With Laboratory Test Abnormalities | The laboratory test included: hematology (hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, absolute total neutrophils, eosinophils, monocytes, basophils, and lymphocytes), chemistry (blood urea nitrogen/urea, serum creatinine, fasting glucose, calcium, sodium, potassium, chloride, total carbon dioxide, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein, and high sensitivity C-reactive protein), urinalysis (pH, qualitative glucose, qualitative protein, qualitative blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin, and microscopy), and other tests (follicle stimulating hormone and serum human chorionic gonadotropin, urine drug screening). Abnormality was determined by the investigator. | Baseline up to 30 days post last dose on Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to 12 Hours Post Dose (AUC(0-12h)) of PF-04447943 | AUC(0-12h) referred to area under the plasma concentration-time curve from 0 to 12 hours post dose. | Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1 | 
| Maximum Observed Plasma Concentration (Cmax) of PF-04447943 |  | Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1 | 
| Time for Maximum Observed Plasma Concentration (Tmax) of PF-04447943 |  | Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1 |