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Clinical Trial Results:
A PHASE 2 MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF THE SAFETY AND EFFICACY OF PF-03049423 IN SUBJECTS WITH ISCHEMIC STROKE

Summary
EudraCT number	2010-021414-32
Trial protocol	HU DE BG CZ
Global end of trial date	20 Dec 2013

Results information
Results version number	v1(current)
This version publication date	09 Feb 2016
First version publication date	09 Jul 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A9541004

ISRCTN number

US NCT number

NCT01208233

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc

Sponsor organisation address

235 E 42nd Street, New York, NY, United States, 10017

Public contact

Clinical Trials.gov Call Centre, Pfizer Inc, 1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Clinical Trials.gov Call Centre, Pfizer Inc, 1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Aug 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Dec 2013

Was the trial ended prematurely?

Yes

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.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Dec 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 35

Country: Number of subjects enrolled

Czech Republic: 1

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Germany: 29

Country: Number of subjects enrolled

Hungary: 33

Country: Number of subjects enrolled

Korea, Republic of: 41

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

India: 6

Country: Number of subjects enrolled

Taiwan: 7

Country: Number of subjects enrolled

United States: 21

Worldwide total number of subjects

178

EEA total number of subjects

102

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 181 subjects were assigned to study treatment, 178 of which received study treatment.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Cohort 1: PF-03049423 1 mg

Arm description

Subjects received PF-03049423 1 mg once daily for 90 days.

Arm type

Experimental

Investigational medicinal product name

PF-03049423

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03049423 1 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

Cohort 1: Placebo

Arm description

Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo 1 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

Cohort 2: PF-03049423 3 mg

Arm description

Subjects received PF-03049423 3 mg once daily for 90 days.

Arm type

Experimental

Investigational medicinal product name

PF-03049423

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03049423 3 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

Cohort 2: Placebo

Arm description

Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo 3 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

Cohort 3: PF-03049423 6 mg

Arm description

Subjects received PF-03049423 6 mg once daily for 90 days.

Arm type

Experimental

Investigational medicinal product name

PF-03049423

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03049423 6 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

Cohort 3: Placebo

Arm description

Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo 6 mg was administered by the appropriate study personnel at Days 1 to 3 and for each of the later assessment days (Days 7, 14, 30, 60 and 90) and for any other days that the subject remained as an in-patient. All other dosing was self- or caregiver-administered once the subject became out-patient.

Number of subjects in period 1	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Started	11	9	11	10	70	67
Completed	6	6	7	9	46	46
Not completed	5	3	4	1	24	21
Adverse event, serious fatal	-	-	-	-	3	5
Consent withdrawn by subject	1	-	-	-	1	2
Did not meet entrance criteria	2	1	1	-	1	-
Study terminated by Sponsor	-	-	-	-	10	7
Adverse event, non-fatal	-	1	2	-	3	5
Subject withdrawn due to Sponsor request	1	1	-	-	-	-
Medication error without adverse event	-	-	-	-	-	1
Took prohibited concomitant medication: digoxin	-	-	-	-	-	1
No longer willing to participate in the trial	-	-	1	1	3	-
Subject took Tamsulosin for urinary disorder	1	-	-	-	-	-
Protocol deviation	-	-	-	-	3	-

Baseline characteristics

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Reporting group title

Cohort 1: PF-03049423 1 mg

Reporting group description

Subjects received PF-03049423 1 mg once daily for 90 days.

Reporting group title

Cohort 1: Placebo

Reporting group description

Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.

Reporting group title

Cohort 2: PF-03049423 3 mg

Reporting group description

Subjects received PF-03049423 3 mg once daily for 90 days.

Reporting group title

Cohort 2: Placebo

Reporting group description

Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.

Reporting group title

Cohort 3: PF-03049423 6 mg

Reporting group description

Subjects received PF-03049423 6 mg once daily for 90 days.

Reporting group title

Cohort 3: Placebo

Reporting group description

Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.

Reporting group values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo	Total
Number of subjects	11	9	11	10	70	67	178
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	5	4	1	5	33	33	81
From 65-84 years	6	5	10	5	36	34	96
85 years and over	0	0	0	0	1	0	1
Age continuous
Units: years
arithmetic mean (standard deviation)	62.3 ± 14.3	64.7 ± 6	69.8 ± 8.3	65.8 ± 13.4	64.2 ± 13.1	65.6 ± 11.3	-
Gender categorical
Units: Subjects
Female	4	2	7	3	28	26	70
Male	7	7	4	7	42	41	108

End points

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Reporting group title

Cohort 1: PF-03049423 1 mg

Reporting group description

Subjects received PF-03049423 1 mg once daily for 90 days.

Reporting group title

Cohort 1: Placebo

Reporting group description

Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.

Reporting group title

Cohort 2: PF-03049423 3 mg

Reporting group description

Subjects received PF-03049423 3 mg once daily for 90 days.

Reporting group title

Cohort 2: Placebo

Reporting group description

Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.

Reporting group title

Cohort 3: PF-03049423 6 mg

Reporting group description

Subjects received PF-03049423 6 mg once daily for 90 days.

Reporting group title

Cohort 3: Placebo

Reporting group description

Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.

Primary: Number of subjects with any abnormal laboratory test results (Part 1* and 2)

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End point title

Number of subjects with any abnormal laboratory test results (Part 1* and 2) ^[1]

End point description

The total number of subjects with laboratory test abnormalities (without regard to baseline abnormality) was assessed. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The Full Analysis Set (FAS) consisted of all randomized subjects who took any study medication (active or placebo).

End point type

Primary

End point timeframe

Day 1 (Baseline) up to Day 90

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[2]	9 ^[3]	10 ^[4]	10 ^[5]	70 ^[6]	66 ^[7]
Units: subjects	8	8	10	9	64	56

Notes
[2] - Subjects analyzed indicated number of subjects evaluated.
[3] - Subjects analyzed indicated number of subjects evaluated.
[4] - Subjects analyzed indicated number of subjects evaluated.
[5] - Subjects analyzed indicated number of subjects evaluated.
[6] - Subjects analyzed indicated number of subjects evaluated.
[7] - Subjects analyzed indicated number of subjects evaluated.

No statistical analyses for this end point

Primary: Number of subjects with vital signs data met criteria of potential clinical concern (Part 1* and 2)

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End point title

Number of subjects with vital signs data met criteria of potential clinical concern (Part 1* and 2) ^[8]

End point description

Vital signs included blood pressure (BP; supine, sitting and standing) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: systolic BP (SBP) greater than or equal to (>=) 30 or 50 millimeters of mercury (mm Hg) change from grand baseline in same posture, systolic less than (<) 90 mm Hg; diastolic BP (DBP) >=20 mm Hg change from grand baseline in same posture, diastolic <50 mm Hg; 2), pulse rate (supine, sitting and standing): <40 or greater than (>) 120 beats per minute (bpm); Standing: <40 or >140 bpm. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo). n=number of evaluable subjects. 99999=No subjects were evaluated.

End point type

Primary

End point timeframe

Day 1 (Baseline) up to follow-up (28 days after Day 90)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[9]	9 ^[10]	11 ^[11]	10 ^[12]	70 ^[13]	67 ^[14]
Units: subjects
Supine SBP <90 mm Hg, n=11,9,11,10,70,67	0	1	1	0	3	0
Sitting SBP <90 mm Hg, n=10,8,9,5,55,59	0	1	1	0	2	2
Standing SBP <90 mm Hg, n=7,7,9,8,49,48	0	0	0	0	1	1
Supine DBP <50 mm Hg, n=11,9,11,10,70,67	0	0	2	1	6	4
Sitting DBP <50 mm Hg, n=10,8,9,5,55,59	0	0	0	0	3	1
Standing DBP <50 mm Hg, n=7,7,9,8,49,48	0	0	0	1	2	3
Supine pulse rate <40 bpm, n=11,9,11,10,70,67	0	0	0	0	1	0
Supine pulse rate >120 bpm, n=11,9,11,10,70,67	0	0	1	0	5	7
Increase:supine SBP >=30 mm Hg, n=11,9,11,10,70,67	2	3	5	3	13	17
Increase: sitting SBP >=30 mm Hg, n=9,6,9,4,48,44	0	2	2	0	10	9
Increase: standing SBP >=30 mm Hg, n=2,3,3,6,19,22	0	0	0	2	2	1
Increase:supine DBP >=20 mm Hg, n=11,9,11,10,70,67	4	2	5	2	16	22
Increase: sitting DBP >=20 mm Hg, n=9,6,9,4,48,44	3	1	2	2	9	12
Increase: standing DBP >=20 mm Hg, n=2,3,3,6,19,22	0	0	0	2	3	3
Decrease:supine SBP >=30 mm Hg, n=11,9,11,10,70,67	7	6	5	4	37	37
Decrease: sitting SBP >=30 mm Hg, n=9,6,9,4,48,44	3	4	6	2	26	18
Decrease: standing SBP >=30 mm Hg, n=2,3,3,6,19,22	2	2	0	2	10	11
Decrease:supine DBP >=20 mm Hg, n=11,9,11,10,70,67	8	6	6	3	32	26
Decrease: sitting DBP >=20 mm Hg, n=9,6,9,4,48,44	1	4	5	1	23	14
Decrease: standing DBP >=20 mm Hg, n=2,3,3,6,19,22	2	2	1	2	6	11
Decrease:supine SBP >=50 mm Hg, n=11,9,11,10,70,67	2	0	1	2	10	9
Decrease: sitting SBP >=50 mm Hg, n=9,6,9,4,48,44	2	1	3	0	7	6
Decrease: standing SBP >=50 mm Hg, n=2,3,3,6,19,22	1	0	0	0	1	2
Sitting pulse rate <40 bpm, n=1,0,2,0,3,2	0	99999	0	99999	0	0
Standing pulse rate <40 bpm, n=0,0,0,2,1,0	99999	99999	99999	0	0	99999
Sitting pulse rate >120 bpm, n=1,0,2,0,3,2	0	99999	0	99999	0	0
Standing pulse rate >140 bpm, n=0,0,0,2,1,0	99999	99999	99999	0	0	99999

Notes
[9] - All randomized and treated subjects in this group.
[10] - All randomized and treated subjects in this group.
[11] - All randomized and treated subjects in this group.
[12] - All randomized and treated subjects in this group.
[13] - All randomized and treated subjects in this group.
[14] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Primary: Number of subjects with electrocardiograms (ECGs) data met criteria of potential clinical concern (Part 1* and 2)

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End point title

Number of subjects with electrocardiograms (ECGs) data met criteria of potential clinical concern (Part 1* and 2) ^[15]

End point description

ECG criteria of potential clinical concern were 1), PR interval: >=300 milliseconds (msec); >=25% increase when baseline >200 msec; or increase >=50% when baseline <=200 msec; 2), QRS interval: >=140 msec; >=50% increase from baseline; 3), QT interval: >=500 msec, QTc interval using Fridericia’s formula (QTcF interval): absolute value >=450 - <480 msec, >=480-<500 msec, >=500 msec; absolute change 30 - <60 msec, >=60 msec. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo). n=number of evaluable subjects.

End point type

Primary

End point timeframe

Day 1 (Baseline) to Day 90

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[16]	9 ^[17]	11 ^[18]	10 ^[19]	70 ^[20]	67 ^[21]
Units: subjects
PR interval >=300 msec, n=11,9,11,10,70,67	0	0	0	0	0	0
QRS interval >=140 msec, n=11,9,11,10,70,67	1	0	1	1	0	1
QT interval >=500 msec, n=11,9,11,10,70,67	0	0	0	0	4	1
QTcF interval 450-480 msec, n=11,9,11,10,70,67	2	3	4	2	14	14
QTcF interval 480-500 msec, n=11,9,11,10,70,67	0	1	0	1	4	3
QTcF interval >=500 msec, n=11,9,11,10,70,67	0	0	1	0	0	1
PR interval increase >=25%/50%, n=10,7,9,9,52,47	0	0	1	0	1	0
QRS interval increase >=50%, n=10,9,11,10,69,66	0	0	0	0	0	1
QTcF increase 30-60 msec, n=10,9,11,10,69,66	2	3	4	2	19	11
QTcF increase >=60 msec, n=10,9,11,10,69,66	0	0	0	1	3	5

Notes
[16] - All randomized and treated subjects in this group.
[17] - All randomized and treated subjects in this group.
[18] - All randomized and treated subjects in this group.
[19] - All randomized and treated subjects in this group.
[20] - All randomized and treated subjects in this group.
[21] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Primary: Number of subjects with significant change in physical examination findings (Part 1* and 2)

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End point title

Number of subjects with significant change in physical examination findings (Part 1* and 2) ^[22]

End point description

The complete physical examination included examination of the skin, eyes, ears, throat, neck, cardiac, respiratory, gastrointestinal, and musculoskeletal systems. The limited physical examination included examination of the cardiac, respiratory, gastrointestinal, and musculoskeletal systems. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo).

End point type

Primary

End point timeframe

Day 1 (Baseline) up to Day 90

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[23]	9 ^[24]	11 ^[25]	10 ^[26]	70 ^[27]	66 ^[28]
Units: subjects	1	1	0	0	2	0

Notes
[23] - Subjects who had physical examinations done at both baseline and last visit in this group.
[24] - Subjects who had physical examinations done at both baseline and last visit in this group.
[25] - Subjects who had physical examinations done at both baseline and last visit in this group.
[26] - Subjects who had physical examinations done at both baseline and last visit in this group.
[27] - Subjects who had physical examinations done at both baseline and last visit in this group.
[28] - Subjects who had physical examinations done at both baseline and last visit in this group.

No statistical analyses for this end point

Primary: Number of subjects with significant change in neurological examination findings (Part 1* and 2)

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End point title

Number of subjects with significant change in neurological examination findings (Part 1* and 2) ^[29]

End point description

The complete neurological examination included an assessment of the motor, sensory, cranial nerves, reflexes, mental status and associated motor functions. The limited neurological exam could examine the same categories of neurologic assessments as the full examination, but would differ by the depth in the examination. The examination was required to be done to the extent needed to assess the subject for any potential changes in neurological status, as determined by the Investigator, but had to always include an assessment of motor, vision and hearing. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo).

End point type

Primary

End point timeframe

Day 1 (Baseline) up to Day 90

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[30]	9 ^[31]	11 ^[32]	10 ^[33]	70 ^[34]	66 ^[35]
Units: subjects	1	1	0	0	4	0

Notes
[30] - Subjects who had neurological examinations done at both baseline and last visit in this group.
[31] - Subjects who had neurological examinations done at both baseline and last visit in this group.
[32] - Subjects who had neurological examinations done at both baseline and last visit in this group.
[33] - Subjects who had neurological examinations done at both baseline and last visit in this group.
[34] - Subjects who had neurological examinations done at both baseline and last visit in this group.
[35] - Subjects who had neurological examinations done at both baseline and last visit in this group.

No statistical analyses for this end point

Primary: Number of subjects with suicidal behavior and/or ideation as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Part 1* and 2)

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End point title

Number of subjects with suicidal behavior and/or ideation as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Part 1* and 2) ^[36]

End point description

Data were mapped to Columbia-Classification Algorithm of Suicide Assessment (C-CASA) event codes. C-SSRS assessed if subject experienced: completed suicide (Code 1), suicide attempt (Code 2), preparatory acts toward imminent suicidal behavior (Code 3), suicidal ideation (Code 4), self-injurious behavior, no suicidal intent (Code 7). Number of subjects with "Yes" response was assessed. *This was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for it were not reported separately, Part 1 and 2 data were reported together. The FAS consisted of all randomized subjects who took any study medication (active or placebo). n=number of subjects who had C-SSRS assessed at that visit. 99999=No subjects had C-SSRS assessed.

End point type

Primary

End point timeframe

Day 7 (Baseline) up to follow up (28 days after Day 90)

Notes
[36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This is a safety endpoint and no statistical analysis was planned and performed for this endpoint.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[37]	9 ^[38]	11 ^[39]	10 ^[40]	70 ^[41]	67 ^[42]
Units: subjects
Day 7, n=0, 0, 1, 1, 64, 57	99999	99999	0	0	1	2
Day 14, n=0, 0, 1, 1, 59, 53	99999	99999	0	0	1	0
Day 30, n=0, 0, 1, 1, 60, 47	99999	99999	0	0	2	0
Day 60, n=0, 0, 1, 1, 55, 44	99999	99999	0	0	2	0
Day 90, n=0, 0, 1, 1, 61, 53	99999	99999	0	0	1	1
Follow-up, n=0, 0, 1, 1, 59, 51	99999	99999	0	0	0	0

Notes
[37] - All randomized and treated subjects in this group.
[38] - All randomized and treated subjects in this group.
[39] - All randomized and treated subjects in this group.
[40] - All randomized and treated subjects in this group.
[41] - All randomized and treated subjects in this group.
[42] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Primary: Percentage of subjects with modified Rankin Scale (mRS) less than or equal to (<=2) at Day 90 (Part 2)

Top of page

End point title

Percentage of subjects with modified Rankin Scale (mRS) less than or equal to (<=2) at Day 90 (Part 2) ^[43]

End point description

The mRS is a 6-point scale of functional recovery. The scale grades subjects as having no symptoms (0), minor symptoms (1), minor handicap (2), moderate handicap (3), moderately severe handicap (4), severe handicap (5), or death (6). n=number of subjects included for comparison between active drug and placebo. The Inferential-Full Analysis Set (I-FAS) consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Primary

End point timeframe

Day 90

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a primary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	68 ^[44]	65 ^[45]
Units: subjects
Last Observation Carried Forward (LOCF), n=68, 65	29	30
Observed Cases (OC), n=51, 52	24	26

Notes
[44] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
[45] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.

PF-03049423 6 mg versus Placebo (LOCF)

Statistical analysis description

LOCF was used to impute missing data.

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4962

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.735

Confidence interval

level

80%

sides

2-sided

lower limit

0.41

upper limit

1.31

PF-03049423 6 mg versus Placebo (OC)

Statistical analysis description

The analysis was based on OC.

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.2517

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.561

Confidence interval

level

80%

sides

2-sided

lower limit

0.29

upper limit

1.07

Notes
[46] - The analysis was based on OC.

Secondary: Change from baseline in Box and Blocks (B&B) Test at Day 90 for paretic and non-paretic hands (Part 2)

Top of page

End point title

Change from baseline in Box and Blocks (B&B) Test at Day 90 for paretic and non-paretic hands (Part 2) ^[47]

End point description

The B&B test is a measure of manual dexterity. The B&B apparatus consists of a box divided into 2 sections and 1-inch hardwood blocks. The blocks began in the compartment of the test box to the dominant side of the subject. The subject was required to transfer the blocks one at a time to the other side of the box as quickly as possible in 1 minute using the non-paretic hand. The box was then turned so all the blocks were in the same side as the paretic hand. The subject was then required to do the test with his/her paretic hand. If more than 1 block was picked up at a time it was counted as 1 block. The subject's fingertips needed to cross the partition for the block to be counted. The performance measure for this task was number of blocks moved within 1 minute. I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group. n=number of subjects included for comparison between active drug and placebo.

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	68 ^[48]	65 ^[49]
Units: blocks moved per minute
least squares mean (standard error)
Paretic Hand, n=21, 24	26.881 ± 3.8667	26.741 ± 3.5627
Non-Paretic Hand, n=45, 41	17.797 ± 2.1676	18.313 ± 2.2407

Notes
[48] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
[49] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.

PF-03049423 6 mg versus Placebo - Paretic Hand

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9716

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.141

Confidence interval

level

80%

sides

2-sided

lower limit

-4.972

upper limit

5.254

Variability estimate

Standard error of the mean

Dispersion value

3.942

PF-03049423 6 mg versus Placebo - Non-Paretic Hand

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8501

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.516

Confidence interval

level

80%

sides

2-sided

lower limit

-4.026

upper limit

2.995

Variability estimate

Standard error of the mean

Dispersion value

2.7201

Secondary: Change from baseline in B&B Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

Top of page

End point title

Change from baseline in B&B Test at Day 90 for paretic to non-paretic hand ratio (Part 2) ^[50]

End point description

he B&B test is a measure of manual dexterity. The B&B apparatus consists of a box divided into 2 sections and 1-inch hardwood blocks. The blocks began in the compartment of the test box to the dominant side of the subject. The subject was required to transfer the blocks one at a time to the other side of the box as quickly as possible in 1 minute using the non-paretic hand. The box was then turned so all the blocks were in the same side as the paretic hand. The subject was then required to do the test with his/her paretic hand. The subject was told that if more than 1 block was picked up at a time it was to only count as 1 block. The subject was also told that their fingertips needed to cross the partition for the block to be counted. The performance measure for this task was the number of blocks moved within 1 minute. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	21 ^[51]	24 ^[52]
Units: percentage change
least squares mean (standard error)	41.83 ± 7.781	31.041 ± 7.1284

Notes
[51] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[52] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Statistical analysis description

This comparison is for paretic to non-paretic hand ratio.

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1417

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

10.789

Confidence interval

level

80%

sides

2-sided

lower limit

1.401

upper limit

20.177

Variability estimate

Standard error of the mean

Dispersion value

7.2392

Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic and non-paretic hands (Part 2)

Top of page

End point title

Change from baseline in Hand Grip Strength Test at Day 90 for paretic and non-paretic hands (Part 2) ^[53]

End point description

The Hand Grip Strength Test measures the maximum isometric strength of the hand and forearm muscles. The subject was required to squeeze the dynamometer with maximum isometric effort while sitting with shoulder adducted and neutrally roated, elbow flexed at 90 degrees and the forearm in neutral position and wrist between 0 to 30 degrees dorsiflexion and a 0 to 15 degrees ulnar deviation. The subject performed this task 3 times with each hand, starting with the non-paretic hand. The performance measure for this task was the average score measured in pounds of pressure exerted. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group. n=number of subjects included for comparison between active drug and placebo.

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	68 ^[54]	65 ^[55]
Units: pounds
least squares mean (standard error)
Paretic Hand, n=26, 26	20.556 ± 4.1829	30.886 ± 3.9964
Non-Paretic Hand, n=46, 41	12.546 ± 2.3612	12.312 ± 2.5029

Notes
[54] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
[55] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.

PF-03049423 6 mg versus Placebo - Paretic Hand

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0611

Method

Mixed models analysis

Parameter type

Median difference (final values)

Point estimate

-10.33

Confidence interval

level

80%

sides

2-sided

lower limit

-17.351

upper limit

-3.31

Variability estimate

Standard error of the mean

Dispersion value

5.4241

PF-03049423 6 mg versus Placebo - Non-Paretic Hand

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9433

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.235

Confidence interval

level

80%

sides

2-sided

lower limit

-4.011

upper limit

4.48

Variability estimate

Standard error of the mean

Dispersion value

3.2899

Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

Top of page

End point title

Change from baseline in Hand Grip Strength Test at Day 90 for paretic to non-paretic hand ratio (Part 2) ^[56]

End point description

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	26 ^[57]	26 ^[58]
Units: percentage change
least squares mean (standard error)	23.949 ± 5.4499	36.761 ± 5.1182

Notes
[57] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[58] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Statistical analysis description

This analysis was for paretic to non-paretic hand ratio.

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0654

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-12.812

Confidence interval

level

80%

sides

2-sided

lower limit

-21.668

upper limit

-3.957

Variability estimate

Standard error of the mean

Dispersion value

6.8448

Secondary: Number of subjects with mRS (0-1) at Day 90 (Part 2)

Top of page

End point title

Number of subjects with mRS (0-1) at Day 90 (Part 2) ^[59]

End point description

The mRS is a 6-point scale of functional recovery. The scale grades subjects as having no symptoms (0), minor symptoms (1), minor handicap (2), moderate handicap (3), moderately severe handicap (4), severe handicap (5), or death (6). The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 90

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	68 ^[60]	65 ^[61]
Units: subjects	17	16

Notes
[60] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
[61] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.951

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.972

Confidence interval

level

80%

sides

2-sided

lower limit

0.54

upper limit

1.76

Secondary: Number of subjects with National Institutes of Health Stroke Scale (NIHSS) (0-1) at Day 90 (Part 2)

Top of page

End point title

Number of subjects with National Institutes of Health Stroke Scale (NIHSS) (0-1) at Day 90 (Part 2) ^[62]

End point description

The NIHSS is a graded 11-item neurological examination rating speech and language, cognition, visual field deficits, motor and sensory impairments and ataxia used for the clinical assessment of acute stroke therapy. The maximum total score is 42 in a subject with a severe neurological deficit; the minimum score is 0 in a subject without gross neurological deficits. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 90

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	68 ^[63]	65 ^[64]
Units: subjects	17	17

Notes
[63] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
[64] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7234

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.854

Confidence interval

level

80%

sides

2-sided

lower limit

0.48

upper limit

1.51

Secondary: Change from baseline in NIHSS at Day 90 (Part 2)

Top of page

End point title

Change from baseline in NIHSS at Day 90 (Part 2) ^[65]

End point description

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	49 ^[66]	47 ^[67]
Units: unit on a scale
least squares mean (standard error)	-6.511 ± 0.5384	-6.228 ± 0.5655

Notes
[66] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[67] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6759

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.283

Confidence interval

level

80%

sides

2-sided

lower limit

-1.156

upper limit

0.589

Variability estimate

Standard error of the mean

Dispersion value

0.6755

Secondary: Number of subjects with Barthel Index (BI) >= 95 and BI =100 at Day 90 (Part 2)

Top of page

End point title

Number of subjects with Barthel Index (BI) >= 95 and BI =100 at Day 90 (Part 2) ^[68]

End point description

The BI is an index of independence to score the ability of a subject with a neuromuscular or musculoskeletal disorder to care for him or herself. The index rates a subject’s ability on the following 10 activities: feeding, moving from wheelchair to bed, personal toilet, getting on and off toilet, bathing self, walking on level surface, ascending and descending stairs, dressing, controlling bowels and controlling bladder. The maximum total score is 100 in a subject without functional impairment; the minimum score is 0 in a subject with major functional impairment. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 90

Notes
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	68 ^[69]	65 ^[70]
Units: subjects
BI >=95	32	26
BI=100	29	23

Notes
[69] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
[70] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.

PF-03049423 6 mg versus Placebo (BI >=95)

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4213

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.433

Confidence interval

level

80%

sides

2-sided

lower limit

0.81

upper limit

2.54

PF-03049423 6 mg versus Placebo (BI=100)

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.276

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.651

Confidence interval

level

80%

sides

2-sided

lower limit

0.92

upper limit

2.98

Secondary: BI at Day 90 (Part 2)

Top of page

End point title

BI at Day 90 (Part 2) ^[71]

End point description

End point type

Secondary

End point timeframe

Day 90

Notes
[71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	49 ^[72]	47 ^[73]
Units: unit on a scale
least squares mean (standard error)	79.151 ± 3.6248	73.552 ± 3.8471

Notes
[72] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[73] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2118

Method

Mixed models analysis

Parameter type

Median difference (final values)

Point estimate

5.599

Confidence interval

level

80%

sides

2-sided

lower limit

-0.15

upper limit

11.348

Variability estimate

Standard error of the mean

Dispersion value

4.4547

Secondary: Domains of Interest: change from baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding Sub Test at Day 90 (Part 2)

Top of page

End point title

Domains of Interest: change from baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding Sub Test at Day 90 (Part 2) ^[74]

End point description

The test uses a reference key, the subject had 90 seconds to pair specific numbers with given geometric figures. Responses could be written or oral. The performance measure for this task was the total number of correct responses. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	33 ^[75]	28 ^[76]
Units: number of correct responses
least squares mean (standard error)	13.748 ± 1.5321	12.686 ± 1.6282

Notes
[75] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[76] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5541

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.062

Confidence interval

level

80%

sides

2-sided

lower limit

-1.252

upper limit

3.375

Variability estimate

Standard error of the mean

Dispersion value

1.7844

Secondary: Domains of Interest: change from baseline in RBANS Naming Sub Test at Day 90 (Part 2)

Top of page

End point title

Domains of Interest: change from baseline in RBANS Naming Sub Test at Day 90 (Part 2) ^[77]

End point description

This test requires the subject to name 10 objects drawn in ink. The tester asked the subject to identify the picture. The subject had 20 seconds to respond to each picture presented. The performance measure was the number of objects named correctly. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[77] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	41 ^[78]	37 ^[79]
Units: number of objects named correctly
least squares mean (standard error)	0.989 ± 0.3676	1.324 ± 0.3666

Notes
[78] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[79] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.426

Method

Mixed models analysis

Parameter type

Median difference (final values)

Point estimate

-0.334

Confidence interval

level

80%

sides

2-sided

lower limit

-0.874

upper limit

0.205

Variability estimate

Standard error of the mean

Dispersion value

0.4178

Secondary: Domains of Interest: change from baseline in Line Cancellation Test [(L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%] at Day 90 (Part 2)

Top of page

End point title

Domains of Interest: change from baseline in Line Cancellation Test [(L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%] at Day 90 (Part 2) ^[80]

End point description

The subject was presented with a page that had lines placed across the page. The subject was required to cross out all the lines on the page using their non-paretic hand after the tester had demonstrated what was required by crossing out the center line. The performance measure for this task was the total number of omissions made expressed as a percentage of the total number of items in the test. The test contains 4 variables: (L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%, and (L-R)/(L+R), where L = number of lines crossed on the left side of the paper; R = number of lines crossed on the right side of the paper. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group. n=number of subjects included for comparison between active drug and placebo for this outcome measure.

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[80] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	68 ^[81]	65 ^[82]
Units: change in percentage of lines crossed
least squares mean (standard error)
(L+R)/28 × 100%, n=39, 35	19.459 ± 4.4433	16.983 ± 4.4551
(L/14) × 100%, n=39, 35	22.824 ± 5.6691	18.95 ± 5.6639
(R/14) × 100%, n=39, 35	16.481 ± 4.3564	15.431 ± 4.3647

Notes
[81] - Subjects who were randomized and treated in PF-03049423 highest dose (6 mg) group.
[82] - Subjects who were randomized and treated in placebo (matched to PF-03049423 6 mg dose) group.

PF-03049423 6 mg versus Placebo - (L+R)/28 × 100%

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.65

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

2.477

Confidence interval

level

80%

sides

2-sided

lower limit

-4.547

upper limit

9.5

Variability estimate

Standard error of the mean

Dispersion value

5.4394

PF-03049423 6 mg versus Placebo - (L/14) × 100%

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5671

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

3.874

Confidence interval

level

80%

sides

2-sided

lower limit

-4.834

upper limit

12.583

Variability estimate

Standard error of the mean

Dispersion value

6.7431

PF-03049423 6 mg versus Placebo - (R/14) × 100%

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.843

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

1.049

Confidence interval

level

80%

sides

2-sided

lower limit

-5.771

upper limit

7.87

Variability estimate

Standard error of the mean

Dispersion value

5.2816

Secondary: Domains of Interest: change from baseline in Recognition Memory Test at Day 90 (Part 2)

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End point title

Domains of Interest: change from baseline in Recognition Memory Test at Day 90 (Part 2) ^[83]

End point description

This test assesses the ability to recognize pictures of objects. The subject was presented a series of pictures, a subset of which were the objects presented in the RBANS Naming Sub Test. After each picture was presented, the subject indicated either manually (ie, affirmative head nod) or verbally whether the picture was seen previously. The subject was given 5 seconds per picture to respond. The performance measure for this task was the total number of pictures correctly identified. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[83] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	44 ^[84]	37 ^[85]
Units: pictures correctly identified
least squares mean (standard error)	-1.135 ± 0.4743	0.144 ± 0.4797

Notes
[84] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[85] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0128

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.279

Confidence interval

level

80%

sides

2-sided

lower limit

-1.929

upper limit

-0.629

Variability estimate

Standard error of the mean

Dispersion value

0.5041

Secondary: Gait Velocity Test at Day 90 (Part 2)

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End point title

Gait Velocity Test at Day 90 (Part 2) ^[86]

End point description

The 10-meter walk test requires a 20 meter straight path, with 5 meters for acceleration, 10 meters for steady state walking, and 5 meters for deceleration. Markers were placed at the 5 and 15 meter positions along the path. The subject began to walk “at a comfortable pace” at 1 end of the path, and continued walking until he/she reached the other end. The rater used a stopwatch to determine how much time it took for the subject to traverse the 10 meter center of the path, starting the stopwatch as soon as the subject’s limb crossed the first marker and stopping the stopwatch as soon as the subject’s limb crossed the second marker. The I-FAS consisted of subjects within the FAS who were randomized to PF-03049423 6 mg or placebo group that was in the same cohort as the 6 mg group.

End point type

Secondary

End point timeframe

Day 90

Notes
[86] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	41 ^[87]	36 ^[88]
Units: meters/second (m/s)
least squares mean (standard error)	1.064 ± 0.104	0.975 ± 0.1128

Notes
[87] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[88] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4713

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.089

Confidence interval

level

80%

sides

2-sided

lower limit

-0.07

upper limit

0.248

Variability estimate

Standard error of the mean

Dispersion value

0.1226

Secondary: Plasma concentrations of PF-03049423 (Part 1 and 2)

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End point title

Plasma concentrations of PF-03049423 (Part 1 and 2) ^[89]

End point description

Pharmacokinetic (PK) concentration population included all subjects who were treated with PF-03049423 who had at least 1 measurable concentration. n=subjects with concentration above lower limit of quantification at the corresponding sampling time. 99999=No sample was collected. 99990=1 subject had concentration above lower limit of quantification, standard deviation cannot be calculated.

End point type

Secondary

End point timeframe

Days 1, 2, 7, 14, 30, 60 and 90

Notes
[89] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The plasma concentration of PF-03049423 can only be reported in those subjects who received active treamtment but not placebo.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 2: PF-03049423 3 mg	Cohort 3: PF-03049423 6 mg
Number of subjects analysed	11 ^[90]	11 ^[91]	70 ^[92]
Units: nanogram/milliliter (ng/mL)
arithmetic mean (standard deviation)
Day 1 (0 hour predose), n=0, 1, 3	99999 ± 99999	0.05245 ± 0.17397	1.42 ± 11.591
Day 1 (1 hour post dose), n=11, 10, 63	5.825 ± 4.3514	17.5 ± 12.814	46.76 ± 36.153
Day 1 (2 hours post dose), n=11, 11, 61	7.063 ± 3.2729	30.18 ± 11.313	58.19 ± 32.837
Day 1 (8 hours post dose), n=11, 11, 68	7.361 ± 2.4032	25.39 ± 8.6644	52.47 ± 23.25
Day 2 (0 hour, predose), n=11, 11, 67	4.521 ± 1.5265	18.05 ± 4.7834	32.07 ± 13.776
Day 7 (0 hour, post dose), n=9, 7, 64	8.601 ± 2.9609	27.79 ± 7.6945	53.08 ± 30.237
Day 7 (1 hour post dose), n=0, 1, 59	99999 ± 99999	51.8 ± 99990	115.9 ± 65.329
Day 7 (2 hours post dose), n=0, 1, 59	99999 ± 99999	58.1 ± 99990	126.3 ± 57.759
Day 7 (6 hours post dose), n=0, 1, 61	99999 ± 99999	51.1 ± 99990	103.8 ± 41.09
Day 14 (0 hour predose), n=10, 8, 59	7.805 ± 2.9278	31.13 ± 9.8243	53.1 ± 28.085
Day 14 (1 hour post dose), n=9, 7, 0	16.47 ± 7.1782	76.71 ± 32.657	99999 ± 99999
Day 14 (2 hours post dose), n=9, 6, 0	17.06 ± 7.3799	70.37 ± 14.795	99999 ± 99999
Day 14 (6 [cohort 3:4] hours post dose), n=9,7,31	17.57 ± 4.1614	58.36 ± 11.72	118.2 ± 41.967
Day 30 (0 hour predose), n=6, 6, 58	5.339 ± 3.5712	29.68 ± 11.015	50.77 ± 31.473
Day 30 (4 hours post dose), n=2, 5, 25	11.55 ± 2.6234	57.08 ± 13.99	96.27 ± 49.929
Day 60 (0 hour predose), n=6, 6, 53	6.36 ± 3.1028	24.55 ± 5.8206	49.37 ± 33.747
Day 60 (4 hours post dose), n=2, 5, 27	13.25 ± 0.7778	47.86 ± 7.3296	112.1 ± 58.56
Day 90 (0 hour predose), n=5, 6, 45	5.252 ± 1.5161	29.18 ± 15.909	47.02 ± 24.065
Day 90 (4 hours post dose), n=2, 5, 20	12.8 ± 0	49.4 ± 13.962	82.69 ± 29.005

Notes
[90] - All randomized and treated subjects in this group.
[91] - All randomized and treated subjects in this group.
[92] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Secondary: Domains of Interest: change from baseline in Line Cancellation Test at Day 90 [(L-R)/(L+R)] (Part 2)

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End point title

Domains of Interest: change from baseline in Line Cancellation Test at Day 90 [(L-R)/(L+R)] (Part 2) ^[93]

End point description

End point type

Secondary

End point timeframe

Day 1 (Baseline), Day 90

Notes
[93] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This is a secondary efficacy endpoint for Part 2 and statistical comparison was conducted in Cohort 3 subjects.

End point values	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	39 ^[94]	34 ^[95]
Units: change in ratio
least squares mean (standard error)
(L-R)/(L+R)	0.083 ± 0.062	-0.023 ± 0.0625

Notes
[94] - Subjects who were in PF-03049423 6 mg group and included in statistical comparison.
[95] - Subjects who were in placebo group (Cohort 3) and included in statistical comparison.

PF-03049423 6 mg versus Placebo

Comparison groups

Cohort 3: PF-03049423 6 mg v Cohort 3: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1512

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.106

Confidence interval

level

80%

sides

2-sided

lower limit

0.011

upper limit

0.201

Variability estimate

Standard error of the mean

Dispersion value

0.0733

Other pre-specified: All-cause mortality (Part 2)

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End point title

All-cause mortality (Part 2)

End point description

Deaths regardless causality were reported. The FAS consisted of all randomized subjects who took any study medication (active or placebo).

End point type

Other pre-specified

End point timeframe

The time began from the subject provided informed consent through 28 calendar days post last administration of investigational product.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[96]	9 ^[97]	11 ^[98]	10 ^[99]	70 ^[100]	67 ^[101]
Units: subjects	0	0	0	0	6	7

Notes
[96] - All randomized and treated subjects in this group.
[97] - All randomized and treated subjects in this group.
[98] - All randomized and treated subjects in this group.
[99] - All randomized and treated subjects in this group.
[100] - All randomized and treated subjects in this group.
[101] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Other pre-specified: Mortality directly related to stroke (Part 2)

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End point title

Mortality directly related to stroke (Part 2)

End point description

Deaths caused by stroke were reported. The FAS consisted of all randomized subjects who took any study medication (active or placebo).

End point type

Other pre-specified

End point timeframe

The time began from the subject provided informed consent through 28 calendar days post last administration of investigational product.

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[102]	9 ^[103]	11 ^[104]	10 ^[105]	70 ^[106]	67 ^[107]
Units: subjects	0	0	0	0	3	0

Notes
[102] - All randomized and treated subjects in this group.
[103] - All randomized and treated subjects in this group.
[104] - All randomized and treated subjects in this group.
[105] - All randomized and treated subjects in this group.
[106] - All randomized and treated subjects in this group.
[107] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Other pre-specified: Treatment-emergent adverse events (AEs) resulting in discontinuation of study drug (Part 2)

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End point title

Treatment-emergent adverse events (AEs) resulting in discontinuation of study drug (Part 2)

End point description

An AE was defined as any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. The FAS consisted of all randomized subjects who took any study medication (active or placebo).

End point type

Other pre-specified

End point timeframe

Day 1 (Baseline) up to follow-up (28 days after Day 90)

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[108]	9 ^[109]	11 ^[110]	10 ^[111]	70 ^[112]	67 ^[113]
Units: subjects	0	1	2	0	3	5

Notes
[108] - All randomized and treated subjects in this group.
[109] - All randomized and treated subjects in this group.
[110] - All randomized and treated subjects in this group.
[111] - All randomized and treated subjects in this group.
[112] - All randomized and treated subjects in this group.
[113] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Other pre-specified: Number of subjects with neuro-worsening (Part 2)

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End point title

Number of subjects with neuro-worsening (Part 2)

End point description

NIHSS change of 4 points or greater. The FAS consisted of all randomized subjects who took any study medication (active or placebo). 99999=No data were reported separately for this outcome measure, which was instead included in routine clinical review of NIHSS data.

End point type

Other pre-specified

End point timeframe

Day 1 (Baseline) up to Day 90

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[114]	9 ^[115]	11 ^[116]	10 ^[117]	70 ^[118]	67 ^[119]
Units: subjects	99999	99999	99999	99999	99999	99999

Notes
[114] - All randomized and treated subjects in this group.
[115] - All randomized and treated subjects in this group.
[116] - All randomized and treated subjects in this group.
[117] - All randomized and treated subjects in this group.
[118] - All randomized and treated subjects in this group.
[119] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Other pre-specified: Number of subjects with SBP <100 mm Hg or SBP decline >=30 mm Hg from immediate pre-dose measurement, with or without neuro-worsening (defined as an NIHSS increase of 4 points or greater) within 2 hours post-dose (Part 2)

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End point title

Number of subjects with SBP <100 mm Hg or SBP decline >=30 mm Hg from immediate pre-dose measurement, with or without neuro-worsening (defined as an NIHSS increase of 4 points or greater) within 2 hours post-dose (Part 2)

End point description

The FAS consisted of all randomized subjects who took any study medication (active or placebo). 99999=No data were reported separately for this outcome measure, which was instead included in routine clinical review of BP data.

End point type

Other pre-specified

End point timeframe

Day 1 (Baseline) up to Day 14

End point values	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Number of subjects analysed	11 ^[120]	9 ^[121]	11 ^[122]	10 ^[123]	70 ^[124]	67 ^[125]
Units: subjects	99999	99999	99999	99999	99999	99999

Notes
[120] - All randomized and treated subjects in this group.
[121] - All randomized and treated subjects in this group.
[122] - All randomized and treated subjects in this group.
[123] - All randomized and treated subjects in this group.
[124] - All randomized and treated subjects in this group.
[125] - All randomized and treated subjects in this group.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the time the subject had taken at least 1 dose of study treatment through last subject visit. For SAEs, the time began from the subject provided informed consent through 28 calendar days post last administration of investigational product.

Adverse event reporting additional description

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Cohort 1: PF-03049423 1 mg

Reporting group description

Subjects received PF-03049423 1 mg once daily for 90 days.

Reporting group title

Cohort 1: Placebo

Reporting group description

Subjects received placebo matched to PF-03049423 1 mg once daily for 90 days.

Reporting group title

Cohort 2: PF-03049423 3 mg

Reporting group description

Subjects received PF-03049423 3 mg once daily for 90 days.

Reporting group title

Cohort 2: Placebo

Reporting group description

Subjects received placebo matched to PF-03049423 3 mg once daily for 90 days.

Reporting group title

Cohort 3: PF-03049423 6 mg

Reporting group description

Subjects received PF-03049423 6 mg once daily for 90 days.

Reporting group title

Cohort 3: Placebo

Reporting group description

Subjects received placebo matched to PF-0304942 6 mg once daily for 90 days.

Serious adverse events	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 11 (18.18%)	1 / 9 (11.11%)	3 / 11 (27.27%)	1 / 10 (10.00%)	15 / 70 (21.43%)	18 / 67 (26.87%)
number of deaths (all causes)	0	0	0	0	6	7
number of deaths resulting from adverse events	0	0	0	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Condition aggravated
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Asphyxia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pneumonia aspiration
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	2 / 67 (2.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Pulmonary embolism
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	3 / 70 (4.29%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Psychiatric disorders
Disorientation
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Electrocardiogram ST-T change
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	2 / 67 (2.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Myocardial infarction
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	2 / 67 (2.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cerebral infarction
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Haematochezia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Sepsis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Urinary tract infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	2 / 67 (2.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 1: PF-03049423 1 mg	Cohort 1: Placebo	Cohort 2: PF-03049423 3 mg	Cohort 2: Placebo	Cohort 3: PF-03049423 6 mg	Cohort 3: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 11 (90.91%)	7 / 9 (77.78%)	7 / 11 (63.64%)	9 / 10 (90.00%)	50 / 70 (71.43%)	47 / 67 (70.15%)
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	0	0
Deep vein thrombosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 67 (1.49%)
occurrences all number	0	0	1	0	1	1
Haematoma
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	1	0
Hypertension
subjects affected / exposed	1 / 11 (9.09%)	4 / 9 (44.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	3 / 70 (4.29%)	2 / 67 (2.99%)
occurrences all number	1	5	0	1	3	2
Hypotension
subjects affected / exposed	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 11 (0.00%)	1 / 10 (10.00%)	4 / 70 (5.71%)	7 / 67 (10.45%)
occurrences all number	1	1	0	3	8	12
General disorders and administration site conditions
Face oedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	0	0
Feeling cold
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	2	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	3 / 70 (4.29%)	3 / 67 (4.48%)
occurrences all number	0	0	2	0	4	3
Pyrexia
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	7 / 70 (10.00%)	6 / 67 (8.96%)
occurrences all number	1	0	3	0	9	6
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	2 / 70 (2.86%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	2	0
Bronchiectasis
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	0	0
Cough
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	4 / 70 (5.71%)	2 / 67 (2.99%)
occurrences all number	0	0	0	0	4	2
Dyspnoea
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	3 / 67 (4.48%)
occurrences all number	1	0	0	0	1	3
Pleural effusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	0	1	1	1	0
Pulmonary congestion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	0	0
Pulmonary embolism
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	1	0
Psychiatric disorders
Depressed mood
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	5 / 70 (7.14%)	3 / 67 (4.48%)
occurrences all number	0	1	0	0	5	3
Depression
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	4 / 70 (5.71%)	4 / 67 (5.97%)
occurrences all number	0	0	0	0	4	4
Insomnia
subjects affected / exposed	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 11 (0.00%)	0 / 10 (0.00%)	7 / 70 (10.00%)	2 / 67 (2.99%)
occurrences all number	0	2	0	0	8	2
Sleep disorder
subjects affected / exposed	3 / 11 (27.27%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	4 / 70 (5.71%)	1 / 67 (1.49%)
occurrences all number	5	0	0	0	5	1
Investigations
Alanine aminotransferase abnormal
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 70 (1.43%)	3 / 67 (4.48%)
occurrences all number	0	0	1	0	1	3
Aspartate aminotransferase abnormal
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	4 / 67 (5.97%)
occurrences all number	0	0	1	0	0	4
Blood bilirubin abnormal
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood potassium decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences all number	0	0	0	1	0	1
Blood pressure increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 70 (1.43%)	2 / 67 (2.99%)
occurrences all number	0	0	0	1	1	4
Hepatic enzyme increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	0	2	0	0
Red blood cells urine positive
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	1	1	1	0	0
Transaminases increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	0	0
White blood cells urine positive
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 70 (1.43%)	1 / 67 (1.49%)
occurrences all number	0	0	1	1	1	1
Excoriation
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	3 / 70 (4.29%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	3	0
Fall
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	2 / 70 (2.86%)	4 / 67 (5.97%)
occurrences all number	0	0	3	0	2	4
Joint dislocation
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	0	0	0	0	0
Laceration
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	2	0	0	0
Limb injury
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	0	0	0	0	0
Lip injury
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	1	0
Radius fracture
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	0	0
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	2 / 67 (2.99%)
occurrences all number	0	2	0	0	1	2
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	2 / 70 (2.86%)	1 / 67 (1.49%)
occurrences all number	0	0	1	0	2	1
Bradycardia
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 70 (2.86%)	1 / 67 (1.49%)
occurrences all number	0	1	0	0	2	1
Coronary artery occlusion
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	1	0
Supraventricular extrasystoles
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	1	0	0	0	1	0
Nervous system disorders
Dementia
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	0	0	0	0	0
Dizziness
subjects affected / exposed	2 / 11 (18.18%)	1 / 9 (11.11%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	3 / 67 (4.48%)
occurrences all number	2	3	1	0	0	3
Haemorrhagic transformation stroke
subjects affected / exposed	2 / 11 (18.18%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences all number	2	1	0	0	0	1
Headache
subjects affected / exposed	4 / 11 (36.36%)	3 / 9 (33.33%)	1 / 11 (9.09%)	0 / 10 (0.00%)	5 / 70 (7.14%)	7 / 67 (10.45%)
occurrences all number	4	6	1	0	5	7
Somnolence
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 70 (2.86%)	2 / 67 (2.99%)
occurrences all number	1	0	0	0	3	2
Syncope
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	2	0	2	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	4 / 70 (5.71%)	3 / 67 (4.48%)
occurrences all number	0	0	0	2	4	3
Leukocytosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	0	0
Neutrophilia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences all number	0	0	1	0	0	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	2 / 70 (2.86%)	0 / 67 (0.00%)
occurrences all number	1	0	1	0	2	0
Eye disorders
Conjunctival hyperaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	1	0
Eye disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 67 (1.49%)
occurrences all number	2	0	0	0	0	1
Abdominal pain upper
subjects affected / exposed	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 11 (0.00%)	1 / 10 (10.00%)	2 / 70 (2.86%)	1 / 67 (1.49%)
occurrences all number	1	1	0	1	4	1
Constipation
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 11 (9.09%)	1 / 10 (10.00%)	8 / 70 (11.43%)	14 / 67 (20.90%)
occurrences all number	0	1	1	1	10	16
Diarrhoea
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	9 / 70 (12.86%)	10 / 67 (14.93%)
occurrences all number	0	0	0	1	10	11
Dyspepsia
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 70 (1.43%)	3 / 67 (4.48%)
occurrences all number	0	1	0	1	1	3
Gastritis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	1	0
Nausea
subjects affected / exposed	1 / 11 (9.09%)	2 / 9 (22.22%)	1 / 11 (9.09%)	0 / 10 (0.00%)	2 / 70 (2.86%)	4 / 67 (5.97%)
occurrences all number	1	3	2	0	2	4
Vomiting
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 70 (1.43%)	4 / 67 (5.97%)
occurrences all number	0	0	4	0	1	7
Skin and subcutaneous tissue disorders
Dermatitis contact
subjects affected / exposed	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	2	0	0	0	0	0
Dermatitis diaper
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	5 / 70 (7.14%)	0 / 67 (0.00%)
occurrences all number	0	0	0	0	5	0
Pruritus
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	1	0
Renal and urinary disorders
Albuminuria
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	0	0	0	0	0
Dysuria
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	5 / 70 (7.14%)	4 / 67 (5.97%)
occurrences all number	1	0	0	0	5	4
Haematuria
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	7 / 70 (10.00%)	2 / 67 (2.99%)
occurrences all number	1	0	0	0	9	2
Renal cyst
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	0	0
Renal failure acute
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 70 (1.43%)	2 / 67 (2.99%)
occurrences all number	0	0	0	1	1	2
Urethral haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	0	0
Urinary retention
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	3 / 70 (4.29%)	1 / 67 (1.49%)
occurrences all number	1	0	0	0	3	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	3 / 70 (4.29%)	3 / 67 (4.48%)
occurrences all number	0	0	0	2	4	4
Back pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 67 (1.49%)
occurrences all number	1	0	4	0	1	2
Gouty arthritis
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	0	1	0	0
Muscular weakness
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	4	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	1 / 11 (9.09%)	1 / 9 (11.11%)	2 / 11 (18.18%)	0 / 10 (0.00%)	3 / 70 (4.29%)	1 / 67 (1.49%)
occurrences all number	1	1	2	0	5	1
Pain in extremity
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 11 (9.09%)	0 / 10 (0.00%)	9 / 70 (12.86%)	4 / 67 (5.97%)
occurrences all number	0	1	1	0	13	4
Infections and infestations
Genitourinary tract infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	0	1	0	0	0
Herpes zoster
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	1	0
Upper respiratory tract infection
subjects affected / exposed	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	3 / 70 (4.29%)	2 / 67 (2.99%)
occurrences all number	1	1	0	0	3	2
Urinary tract infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	8 / 70 (11.43%)	8 / 67 (11.94%)
occurrences all number	1	0	1	1	8	10
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 70 (0.00%)	0 / 67 (0.00%)
occurrences all number	0	1	0	0	0	0
Fluid imbalance
subjects affected / exposed	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 70 (0.00%)	2 / 67 (2.99%)
occurrences all number	0	0	1	0	0	2
Hypokalaemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 11 (9.09%)	1 / 10 (10.00%)	7 / 70 (10.00%)	3 / 67 (4.48%)
occurrences all number	0	1	1	4	11	3

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Were there any global substantial amendments to the protocol? Yes

28 Jul 2010

Addition of a safety Follow-Up visit 14 days after Day 90.

12 Nov 2010

To integrate recording of the time of last meal on PK days to follow an Food and Drug Administration (FDA) recommendation and to add measurement of direct and indirect bilirubin to comply with the corporate recommendations as to detect potential Hy’s law cases.

01 Aug 2011

To reduce the number of procedures: particularly blood pressure measurements to eliminate the visits from Day 8 to Day 13. This change – supported by extrapolation of available data – was subject to review of Cohort 1 patients data and approval by the Data and Safety Monitoring Board (DSMB). Allowed patients with total paresis of the upper extremity to enter the study. Clarified the eligibility criteria on the type of stroke. Updated the suicidality assessments: addition of the Columbia Suicide Severity Rating Scale (C-SSRS). Removed "Criteria for ECG Parameters and Vital Signs of Potential Clinical Concern for Pediatric Subjects".

26 Mar 2012

Addition of digoxin and digitoxin to prohibited concomitant medications list. Study Procedures: Clarification of drug dispensing at day 7 and day 14. The caregiver could not give drug if the subject had an nasogastric tube and further clarification regarding the use of an nasogastric tube. FOR FRANCE ONLY according to local clinical guidelines approved November 2011: 1. Removed option for manual BP measurements, 2. Removed option for BP assessments in standing position, 3. Increased frequency of BP assessments in Part 2 of the study, 4. Required use of an electronic blood pressure measuring device.

24 Aug 2012

Change to inclusion criteria to allow computed tomography (CT) or magnetic resonance imaging (MRI) scan at screening and Day 90 for all subjects (ie, CT was not just for subjects contraindicated for MRI). Change to inclusion criteria to advise that an additional 6 hours (ie, up to a total of 78 hours) could be allowable from stroke onset to initial dose of study drug in exceptional circumstances, such as an unexpected delay in receiving the data to allow randomisation, after consultation with the sponsor. Change to inclusion criteria to expectation that subjects had to remain as in patients for the first 3 days. Subjects could remain as in-patients for the first seven days of dosing if that complies with regional standard of care. Change to the inclusion criterion regarding ECG measurements. If a subject was ineligible on ECG and if it considered likely that there was a temporary perturbation of the subject’s cardiac function related to the stroke, at the discretion of the investigator this ECG analysis could be repeated on one occasion within the 72 hour screening window. If the subject met the ECG eligibility criteria at the second timepoint, this would take precedence over the first analysis. Change to inclusion criteria to note that participation in non-interventional studies (eg, solely involving blood draws for genetic analysis) could be allowable after consultation with the sponsor. Update to the wording on definition of women of child bearing potential to bring into line with revised Pfizer policy. Added wording to advise that the study is now in Part 2 at a 6 mg dose, and to update some procedures to bring them in line with the amended selection criteria.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The study was terminated prematurely due to demonstrated futility at interim analysis. The final results are consistent with interim results.

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Clinical trials

Clinical Trial Results: A PHASE 2 MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF THE SAFETY AND EFFICACY OF PF-03049423 IN SUBJECTS WITH ISCHEMIC STROKE

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with any abnormal laboratory test results (Part 1* and 2)

Primary: Number of subjects with any abnormal laboratory test results (Part 1* and 2)

Primary: Number of subjects with vital signs data met criteria of potential clinical concern (Part 1* and 2)

Primary: Number of subjects with vital signs data met criteria of potential clinical concern (Part 1* and 2)

Primary: Number of subjects with electrocardiograms (ECGs) data met criteria of potential clinical concern (Part 1* and 2)

Primary: Number of subjects with electrocardiograms (ECGs) data met criteria of potential clinical concern (Part 1* and 2)

Primary: Number of subjects with significant change in physical examination findings (Part 1* and 2)

Primary: Number of subjects with significant change in physical examination findings (Part 1* and 2)

Primary: Number of subjects with significant change in neurological examination findings (Part 1* and 2)

Primary: Number of subjects with significant change in neurological examination findings (Part 1* and 2)

Primary: Number of subjects with suicidal behavior and/or ideation as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Part 1* and 2)

Primary: Number of subjects with suicidal behavior and/or ideation as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Part 1* and 2)

Primary: Percentage of subjects with modified Rankin Scale (mRS) less than or equal to (<=2) at Day 90 (Part 2)

Primary: Percentage of subjects with modified Rankin Scale (mRS) less than or equal to (<=2) at Day 90 (Part 2)

Secondary: Change from baseline in Box and Blocks (B&B) Test at Day 90 for paretic and non-paretic hands (Part 2)

Secondary: Change from baseline in Box and Blocks (B&B) Test at Day 90 for paretic and non-paretic hands (Part 2)

Secondary: Change from baseline in B&B Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

Secondary: Change from baseline in B&B Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic and non-paretic hands (Part 2)

Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic and non-paretic hands (Part 2)

Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

Secondary: Change from baseline in Hand Grip Strength Test at Day 90 for paretic to non-paretic hand ratio (Part 2)

Secondary: Number of subjects with mRS (0-1) at Day 90 (Part 2)

Secondary: Number of subjects with mRS (0-1) at Day 90 (Part 2)

Secondary: Number of subjects with National Institutes of Health Stroke Scale (NIHSS) (0-1) at Day 90 (Part 2)

Secondary: Number of subjects with National Institutes of Health Stroke Scale (NIHSS) (0-1) at Day 90 (Part 2)

Secondary: Change from baseline in NIHSS at Day 90 (Part 2)

Secondary: Change from baseline in NIHSS at Day 90 (Part 2)

Secondary: Number of subjects with Barthel Index (BI) >= 95 and BI =100 at Day 90 (Part 2)

Secondary: Number of subjects with Barthel Index (BI) >= 95 and BI =100 at Day 90 (Part 2)

Secondary: BI at Day 90 (Part 2)

Secondary: BI at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding Sub Test at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding Sub Test at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in RBANS Naming Sub Test at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in RBANS Naming Sub Test at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in Line Cancellation Test [(L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%] at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in Line Cancellation Test [(L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%] at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in Recognition Memory Test at Day 90 (Part 2)

Secondary: Domains of Interest: change from baseline in Recognition Memory Test at Day 90 (Part 2)

Secondary: Gait Velocity Test at Day 90 (Part 2)

Secondary: Gait Velocity Test at Day 90 (Part 2)

Secondary: Plasma concentrations of PF-03049423 (Part 1 and 2)

Secondary: Plasma concentrations of PF-03049423 (Part 1 and 2)

Secondary: Domains of Interest: change from baseline in Line Cancellation Test at Day 90 [(L-R)/(L+R)] (Part 2)

Secondary: Domains of Interest: change from baseline in Line Cancellation Test at Day 90 [(L-R)/(L+R)] (Part 2)

Other pre-specified: All-cause mortality (Part 2)

Other pre-specified: All-cause mortality (Part 2)

Other pre-specified: Mortality directly related to stroke (Part 2)

Other pre-specified: Mortality directly related to stroke (Part 2)

Other pre-specified: Treatment-emergent adverse events (AEs) resulting in discontinuation of study drug (Part 2)

Other pre-specified: Treatment-emergent adverse events (AEs) resulting in discontinuation of study drug (Part 2)

Other pre-specified: Number of subjects with neuro-worsening (Part 2)

Other pre-specified: Number of subjects with neuro-worsening (Part 2)

Other pre-specified: Number of subjects with SBP <100 mm Hg or SBP decline >=30 mm Hg from immediate pre-dose measurement, with or without neuro-worsening (defined as an NIHSS increase of 4 points or greater) within 2 hours post-dose (Part 2)

Other pre-specified: Number of subjects with SBP <100 mm Hg or SBP decline >=30 mm Hg from immediate pre-dose measurement, with or without neuro-worsening (defined as an NIHSS increase of 4 points or greater) within 2 hours post-dose (Part 2)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A PHASE 2 MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF THE SAFETY AND EFFICACY OF PF-03049423 IN SUBJECTS WITH ISCHEMIC STROKE