ISCHEMIC STROKE

Objectives for Part 1: Safety Dose-Ranging Study Primary Objectives  To evaluate the safety and tolerability of PF-03049423 following multiple dose administration to subjects with ischemic stroke following 14 days of dosing. Secondary Objectives  To explore the PK-PD relationship of PF-03049423 and blood pressure (supine and standing) in ischemic stroke subjects following 14 days of dosing. Objectives for Part 2: Proof-of-Concept study Primary Objectives To assess the efficacy of PF-03049423, relative to placebo, using the modified Rankin Score (mRS) in subjects with ischemic stroke at Day 90. Secondary Objectives  To evaluate the safety and tolerability of PF-03049423, relative to placebo, in subjects with ischemic stroke.  To evaluate the effects of PF-03049423, relative to placebo, in subjects with ischemic stroke, on other clinically relevant measures of stroke recovery, specific upper extremity motor (Box and Blocks (B&B), hand grip strength test) and lower (gait velocity) motor endpoints as well as neurological outcomes (NIHSS) and functional outcomes (Barthel Index - BI) at Day 90.  To evaluate the pharmacokinetics of PF-03049423 in subjects with ischemic stroke.

PF-03049423

PF-03049423

tablet

1mg, 5mg

Endpoints for Part 1: Safety Dose-Ranging Study
Primary Endpoints
Safety Measurement/Parameters:
 Safety and tolerability in all cohorts as assessed from baseline to Day 14 by an
independent Data and Safety Monitoring Board (DSMB) using study data, including
SAEs, AEs and vital signs. Additional AE data will be collected including brain
Magnetic Resonance Imaging (MRI), ECG, physical (including neurological)
examination, National Institute for Health Stroke Scale (NIHSS) scores, laboratory tests
(including hematology, blood chemistry, urinalysis), C-SSRS. Specific stopping rules for
individuals and for each cohort are in Section 3.1.
Secondary Endpoints
Plasma concentrations of PF-03049423

Endpoints for Part 2: Proof-of-Concept study
Primary Endpoint for Part 2
 Proportion of subjects with Modified Rankin Scale (mRS) 2 at Day 90.
Key Secondary Endpoints
 Box and Blocks, Hand Grip Strength Test at Day 90.
Secondary Endpoints
 Proportion of subjects with minimal disability (mRS 0-1) at Day 90.
 Proportion of subjects with NIHSS (0-1) at Day 90.
 NIHSS on Day 90.
 Barthel Index (BI) at Day 90.
 Proportion of subjects with BI 95 at Day 90.
 Proportion of subjects with BI =100 at Day 90.
 Domains of Interest: RBANS Coding Sub Test, RBANS Naming Sub Test, Line
Cancellation, Recognition Memory Test at Day 90.
 Gait Velocity at Day 90.

1. Men or women (women must be of non-child bearing potential), age 18-85 years,
inclusive.
2. Supratentorial ischemic (non-hemorrhagic) infarct involving the cortex, as documented
by neurological exam and Magnetic Resonance Imaging (MRI) scan (or Computed
Tomography (CT) scan if MRI scan contraindicated). Strokes involving more than one
area will be allowed as long as there is documented ischemic cortical involvement.
3. Baseline NIHSS of 6-20 inclusive.
4. New onset of upper extremity paresis or paralysis on the affected side (NIHSS Item 5,
score between 1 and 4 inclusive).
5. Enrolled in the study so that initial dose of study drug is administered 24-72 hours from
stroke onset (time of onset is when symptoms began; for stroke that occurred during
sleep, time of onset is when subject was last seen or was self-reported to be normal).
6. Able to receive study medication orally after stroke onset. If dysphagia precludes oral
intake, the subject consents to placement of a nasogastric tube to receive study
medication (NOTE: administration of study drug through a gastrostomy tube is allowed if
the tube is positioned within the stomach).
7. Adequate gastrointestinal function for oral drug absorption.
8. Expectation that the subject will remain as an in-patient for at least the first 7 days of
dosing (eg, acute care, rehabilitation, long-term care facility or nursing home).
9. Subjects must participate in a rehabilitation program. Reasonable expectation that the
subject will receive the full course of post-stroke rehabilitation as per standard of care (to
include physical, occupational, speech, and cognitive therapy as indicated), and to be
available for subsequent follow-up visits.
10. Willing and reasonably able to participate in the evaluation process to the point of
accurate assessment.
11. Evidence of a signed and dated informed consent document indicating that the subject (or
a legally acceptable representative) has been informed of all pertinent aspects of the
study.
12. Reasonable likelihood to comply with scheduled visits, lifestyle guidelines, treatment
plan, laboratory tests, and other study procedures.
13. Subjects who have received thrombolytic therapy (within 4.5 hours or 6 hours post onset
of acute ischemic stroke if given intravenously or intra-arterially, respectively) may be
enrolled as long as the subject has been stable to improving post treatment and if an MRI
or CT (if MRI contraindicated) at least 18-24 hours post thrombolysis does not
demonstrate any significant new findings. As a guideline, using ECASS [24] criteria: PH
II: dense blood clot(s) exceeding 30% of the infarct volume with significant space
occupying effect would serve as an exclusion criteria.
14. Use of antiplatelet and/or anti-thrombotic agents is acceptable.
15. No previous stroke in the 90 days prior to enrollment (except index stroke). A previous
stroke >90 days from the time of enrollment may be allowed if it is confirmed that there
were no clinically significant deficits from prior stroke(s) (example: mRS 0-1) and the
investigator, in consultation with the Sponsor has concluded that all other inclusion
criteria have been met.

1. Women of child-bearing potential are excluded even if contraception is being used. For
definition of child-bearing potential, see Section 4.4.1. Serum FSH level must be
obtained for women aged 40-60 who have experienced amenorrhea for at least 2 years.
2. NIHSS item 5 score of 0 for the upper extremity that may be involved with the stroke.
3. Impaired level of consciousness (National Institutes of Health Stroke Scale [NIHSS]
section 1a score 2 points).
4. Stroke that is primarily hemorrhagic, or ischemic stroke that does not involve the
supratentorial cortex. This includes - but is not limited to - the following examples: subcortical, lacunar, cerebellar or brainstem stroke that do not involve the supratentorial
cortex.
5. Previous stroke unless >90 days and well recovered as defined by mRS 0-1.
6. Significant cerebral edema, clinically significant hematoma, hemorrhagic transformation
or presence of clinically significant midline shift with effacement that is likely to cause
further clinical deterioration in the opinion of the investigator in consultation with the
sponsor.
7. Subjects expected to undergo carotid endarterectomy (CEA; intra- or extra-cranial) or
any other vascular, but not limited to carotid stenting procedures, or intracranial
procedure during the 3 month study period; these procedures are acceptable if they are
performed before enrolment and if the patient’s condition is stabilized 24 hours before
randomization.
8. Intracranial pathology other than cerebral infarction on any admission imaging tests
(eg, Intracranial Hemorrhage (ICH) or Subarachnoid Hemorrhage (SAH), Arteriovenous
malformation (AVM), cerebral aneurysm, or cerebral neoplasm) that would preclude
participation in this study.
9. Known CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy) or Moyamoya Disease.
10. 12-lead ECG demonstrating QTcF >450 msec or a QRS interval >120 msec at screening.
If QTc exceeds 450 msec or QRS exceeds 120 msec, the ECG should be repeated two
more times and the average of the three QTc or QRS values should be used to determine
the subject’s eligibility.
11. Abnormal blood glucose thought to significantly contribute to the neurological deficit.
12. Any medical condition that, in the opinion of the investigator, may preclude full
participation in this clinical study.
13. Abnormally labile BP or uncontrolled hypertension that, in the opinion of the
investigator, may preclude full participation in this clinical study. Uncontrolled
hypertension is defined in the context of acute stroke as blood pressure persistently above
220 mm Hg systolic or 120 mm Hg diastolic despite antihypertensive therapy.
14. Supine BP at baseline of either <100 mm Hg systolic or <70 mm Hg diastolic.
15. Total body weight <90 lb (40.9 kg).
16. Medications in any of the following categories:
 Nitrates (current or considered a potential for use during the study).
 Alpha blockers. This includes but is not limited to the following medications:
terazosin HCl, tamsulosin HCl, doxazosin mesylate, prazosin HCl or alfuzosin HCl.
 Strong CYP3A4 inhibitors. This includes but is not limited to the following
medications: clarithromycin, itraconazole, ketoconazole, nefazodone, telithromycin
and HIV protease inhibitors, including: atazanavir, indinavir, nelfinavir, ritonavir,
saquinavir.
 CYP3A4 inducers. This includes but is not limited to the following medications:
rifampin and carbamazepine. Concomitant use of other PDE5i. This includes but is
not limited to the following medications: sildenafil, tadalafil, vardenafil.
17. Abnormal liver enzymes/hepatic function (Serum bilirubin >1.5 Upper Limit of Normal
(ULN); Alkaline phosphatase >2.5 ULN; AST or ALT >2.5 ULN).
18. Abnormal renal function (Creatinine >2.0 ULN).
19. Significant pulmonary disease (eg, Chronic Obstructive Pulmonary Disease (COPD) with
oxygen-requirement at rest or with ambulation, moderate to severe asthma) such that full
participation in rehabilitation would not be possible in the opinion of the investigator.
20. Subjects living in a nursing home or incapable of independent living prior to the stroke.
21. Subjects with a known medical history of severe hearing loss/deafness or nonarteritic
ischemic optic neuropathy (NAION).
22. Subjects with hereditary degenerative retinal disorders (eg, retinitis pigmentosa).
23. Subjects with a history of or risk for priapism, sickle-cell disease, multiple myeloma and
myeloprofilerative disorders (eg, myeloid leukemia, polycythemia, thrombocythemia) or
serious skin reactions.
24. Blood donation of approximately 1 pint (500 mL) within 56 days prior to dosing and
14 days after the end of study.
25. Known hypersensitivity to any PDE5i.
26. Known left ventricular (LV) outlet obstruction.
27. Known diagnosis of cancer, except for localized, non-invasive or metastatic cancers of
any type that are stable, and not currently treated and not expected to influence life
expectancy over the 6 months post screening.
28. History of seizure disorder or current seizure disorder.
29. Pre-existing and active major psychiatric or other chronic neurological disease that would
unduly influence the assessments in the study
30. Participation in a previous clinical study within 30 days or currently participating in
another study.
31. Positive urine drug screen (see Section 7.2.1).
32. Any other severe acute or chronic medical (eg, unstable ischemic heart disease) or
psychiatric condition or laboratory abnormality that may significantly 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.
33. Subjects who are investigational site staff members or subjects who are Pfizer employees
directly involved in the conduct of the study.