| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055221 |
| E.1.2 | Term | Ischemic stroke |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective for Part 1: Safety Dose-Ranging Study
To evaluate the safety and tolerability of PF-03049423 following multiple dose administration to subjects with ischemic stroke following 14 days of dosing.
Primary Objective for Part 2: Proof-of-Concept study
To assess the efficacy of PF-03049423, relative to placebo, using the modified Rankin Score (mRS) in subjects with ischemic stroke at Day 90. |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objective for Part 1: Safety Dose-Ranging Study
To explore the PK-PD relationship of PF-03049423 and blood pressure (supine and standing) in ischemic stroke subjects following 14 days of dosing.
Secondary Objective for Part 2: Proof-of-Concept study
•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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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. 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). In exceptional circumstances, such as unexpected delays in receiving the data to allow randomisation, an additional 6 hours, ie, up to 78 hours, may be allowed after consultation with the sponsor.
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 3 days of dosing (eg, acute care, rehabilitation, long-term care facility or nursing home). Subjects may remain as in-patients for the first seven days of dosing if that complies with
regional standard of care.
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 legal 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 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 |
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| E.4 | Principal exclusion criteria |
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. of the protocol. Serum FSH level must be obtained for women aged 45-60 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 (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 does 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, severe hemorrhagic transformation (please refer to inclusion criterion 13 of the protocol), presence of clinically significant
midline shift with effacement or the presence of any brain abnormality that, in the opinion of the investigator, may significantly increase the risk associated with study participation.
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 or Subarachnoid Hemorrhage, Arteriovenous malformation, cerebral aneurysm, or cerebral neoplasm) that would preclude participation in this study
9. Known CADASIL or Moyamoya Disease
10. 12-lead ECG demonstrating QTcF >450 msec or a QRS interval >120 msec at screening. This ECG is always performed in triplicate and the average of the three QTc or QRS values should be used to determine the subject’s eligibility. If a subject is ineligible on ECG and if it considered likely that there is a temporary perturbation of the subject’s cardiac function related to the stroke, at the discretion of the investigator this ECG analysis may be repeated on one occasion within the 72 hour screening window. If the subject meets the ECG eligibility criteria at the second timepoint, this will take precedence over the first analysis.
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
•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 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, 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 incapable of independent living prior to the stroke.
21. Subjects with a known medical history of severe hearing loss/deafness or nonarteritic 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
This is a shortened list of the exclusion criteria, the protocol should be reviewed for the full list. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints for Part 1: Safety Dose-Ranging Study
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 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 of the protocol
Primary Endpoints for Part 2: Proof-of-Concept study
•Proportion of subjects with Modified Rankin Scale (mRS) ≤2 at Day 90 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints for Part 1: Safety Dose-Ranging Study:
Plasma concentrations of PF-03049423
Secondary Endpoints for Part 2: Proof-of-Concept study:
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. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| India |
| Korea, Republic of |
| Mexico |
| Taiwan |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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