Clinical trial NCT02114203: Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Study Of PF-04447943, Co-Administered With And Without Hydroxyurea, In Subjects With Stable Sickle Cell Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Phase 1 Sickle Cell
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2014-04-15
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: BASIC_SCIENCE

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.


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.

Primary outcomes:
measure: Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Vital Signs
timeFrame: Baseline up to 30 days post last dose on Day 29
measure: Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Neurologic Function
timeFrame: Baseline up to Day 29
measure: Number of Participants With Potentially Clinically Important (PCI) Change in Physical Examination Findings
timeFrame: Baseline up to 30 days post last dose on Day 29
measure: Number of Participants With Clinically Significant Treatment-Emergent Electrocardiogram (ECG) Findings
timeFrame: Baseline up to 30 days post last dose on Day 29
measure: Number of Participants With Potentially Clinically Important (PCI) Change From Baseline in Symptoms of Sickle Cell Disease
timeFrame: Baseline up to 30 days post last dose on Day 29
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Day 1 to 30 days post last dose on Day 29
measure: Number of Participants With Laboratory Test Abnormalities
timeFrame: Baseline up to 30 days post last dose on Day 29
Secondary outcomes:
measure: Area Under the Curve From Time Zero to 12 Hours Post Dose (AUC(0-12h)) of PF-04447943
timeFrame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1
measure: Maximum Observed Plasma Concentration (Cmax) of PF-04447943
timeFrame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1
measure: Time for Maximum Observed Plasma Concentration (Tmax) of PF-04447943
timeFrame: Prior to 0 hour, and 0.5, 1, 2, 4, 8, and 12 hours post dose on Day 1
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Illinois Hospital and Health Sciences System
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Clinical Research Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois Hospital and Health Sciences System
state: Illinois
city: Boston
country: United States
facility: Boston Medical Center E7E
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Brooklyn
country: United States
facility: Interfaith Medical Center
state: New York
city: Brooklyn
country: United States
facility: Interfaith Medical Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Hospitals' Investigational Drug Service Pharmacy
state: North Carolina
city: Chapel Hill
country: United States
facility: UNC School of Medicine Clinical and Translational Research Center
state: North Carolina
city: Richmond
country: United States
facility: Investigational Drug Services
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Brussels
country: Belgium
facility: Pfizer Clinical Research Unit
city: Milano
country: Italy
facility: Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico
city: Palermo
country: Italy
facility: A.O.O.R Villa Sofia - V. Cervello
city: Leiden
country: Netherlands
facility: Centre for Human Drug Research
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen University Hospital Trust
state: Merseyside
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospitals NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Charnigo RJ, Beidler D, Rybin D, Pittman DD, Tan B, Howard J, Michelson AD, Frelinger AL , III, Clarke N. PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study. Clin Transl Sci. 2019 Mar;12(2):180-188. doi: 10.1111/cts.12604. Epub 2018 Dec 31.