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

July 17, 2017 updated by: Pfizer

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.

Study Overview

Status

Completed

Conditions

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Masking: Triple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
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.
Baseline up to Day 29
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.
Baseline up to 30 days post last dose on Day 29
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.
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
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.
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)
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.
Day 1 to 30 days post last dose on Day 29
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.
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
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.
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
Time Frame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1
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
Time Frame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1
Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2014

Primary Completion (Actual)

September 1, 2016

Study Completion (Actual)

September 1, 2016

Study Registration Dates

First Submitted

April 7, 2014

First Submitted That Met QC Criteria

April 11, 2014

First Posted (Estimate)

April 15, 2014

Study Record Updates

Last Update Posted (Actual)

December 14, 2017

Last Update Submitted That Met QC Criteria

July 17, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Other Study ID Numbers

  • B0401016
  • 2014-001677-13 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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