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

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ClinicalTrials.gov Identifier: NCT02114203
Recruitment Status : Completed
First Posted : April 15, 2014
Results First Posted : December 14, 2017
Last Update Posted : December 14, 2017
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief 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.

Condition or disease Intervention/treatment Phase
Phase 1 Sickle Cell Drug: PDE9i Drug: placebo for PDE9i Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: 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
Actual Study Start Date : December 2014
Actual Primary Completion Date : September 2016
Actual Study Completion Date : September 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Hydroxyurea

Arm Intervention/treatment
Experimental: cohort 1 PF-04447943 Drug: PDE9i
oral dose, every 12 hours for 28 days

Experimental: cohort 2 PF-04447943 Drug: PDE9i
oral dose, every 12 hours for 28 days

Placebo Comparator: placebo comparator Drug: placebo for PDE9i
oral dose, every 12 hours for 28 days

Experimental: optional cohort of PF-04447943 Drug: PDE9i
oral dose, every 12 hours for 28 days

Drug: PDE9i
oral dose, every 12 hours for 28 days

Drug: PDE9i
oral dose, every 12 hours for 28 days




Primary Outcome Measures :
  1. Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Vital Signs [ Time Frame: Baseline up to 30 days post last dose on Day 29 ]
    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.

  2. Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Neurologic Function [ Time Frame: Baseline up to Day 29 ]
    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.

  3. Number of Participants With Potentially Clinically Important (PCI) Change in Physical Examination Findings [ Time Frame: Baseline up to 30 days post last dose on Day 29 ]
    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.

  4. Number of Participants With Clinically Significant Treatment-Emergent Electrocardiogram (ECG) Findings [ Time Frame: Baseline up to 30 days post last dose on Day 29 ]
    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.

  5. Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Symptoms of Sickle Cell Disease [ Time Frame: Baseline up to 30 days post last dose on Day 29 ]
    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.

  6. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 to 30 days post last dose on Day 29 ]
    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.

  7. Number of Participants With Laboratory Test Abnormalities [ Time Frame: Baseline up to 30 days post last dose on Day 29 ]
    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.


Secondary Outcome Measures :
  1. Area Under the Curve From Time Zero to 12 Hours Post Dose (AUC(0-12h)) of PF-04447943 [ Time Frame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1 ]
    AUC(0-12h) referred to area under the plasma concentration-time curve from 0 to 12 hours post dose.

  2. Maximum Observed Plasma Concentration (Cmax) of PF-04447943 [ Time Frame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1 ]
  3. Time for Maximum Observed Plasma Concentration (Tmax) of PF-04447943 [ Time Frame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02114203


Locations
United States, Illinois
University of Illinois Hospital and Health Sciences System
Chicago, Illinois, United States, 60612-5836
University of Illinois at Chicago Clinical Research Center
Chicago, Illinois, United States, 60612
University of Illinois Hospital and Health Sciences System
Chicago, Illinois, United States, 60612
United States, Massachusetts
Boston Medical Center E7E
Boston, Massachusetts, United States, 02118
Boston Medical Center
Boston, Massachusetts, United States, 02118
Boston University Medical Center
Boston, Massachusetts, United States, 02118
United States, New York
Interfaith Medical Center
Brooklyn, New York, United States, 11213
Interfaith Medical Center
Brooklyn, New York, United States, 11238
United States, North Carolina
UNC Hospitals' Investigational Drug Service Pharmacy
Chapel Hill, North Carolina, United States, 27514
UNC School of Medicine Clinical and Translational Research Center
Chapel Hill, North Carolina, United States, 27599
United States, Virginia
Investigational Drug Services
Richmond, Virginia, United States, 23298
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Belgium
Pfizer Clinical Research Unit
Brussels, Belgium, B-1070
Italy
Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico
Milano, Italy, 20122
A.O.O.R Villa Sofia - V. Cervello
Palermo, Italy, 90146
Netherlands
Centre for Human Drug Research
Leiden, Netherlands, 2333 CL
United Kingdom
Royal Liverpool and Broadgreen University Hospital Trust
Liverpool, Merseyside, United Kingdom, L7 8XP
Guy's and St Thomas' NHS Foundation Trust
London, United Kingdom, SE1 9RT
King's College Hospital NHS Foundation Trust
London, United Kingdom, SE5 9RS
Imperial College Healthcare NHS Trust
London, United Kingdom, W12 0HS
Central Manchester University Hospitals NHS Foundation Trust
Manchester, United Kingdom, M13 9WL
Manchester Royal Infirmary
Manchester, United Kingdom, M13 9WL
Oxford University Hospitals NHS Trust
Oxford, United Kingdom, OX3 7LE
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02114203     History of Changes
Other Study ID Numbers: B0401016
2014-001677-13 ( EudraCT Number )
First Posted: April 15, 2014    Key Record Dates
Results First Posted: December 14, 2017
Last Update Posted: December 14, 2017
Last Verified: July 2017

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors