Study To Evaluate The Safety, Tolerability And Pharmacokinetics Of Single Doses Of PF-04958242 In Healthy Volunteers

• Sponsor: Biogen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02228395
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arms: 3
• Actual Duration (Months): 1.7
• Patients Per Site Per Month: 7

Study Details

Study Description

Brief Summary

This study aims to assess the safety, tolerability, and pharmacokinetics of PF-04958242 at a number of single ascending doses in healthy volunteers

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: PF-04958242; Drug: Placebo	Phase 1

Detailed Description

This study was previously posted by Pfizer, Inc. Sponsorship of the trial was transferred to Biogen.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: A Phase 1, Randomized, Subject- And Investigator-blind, Sponsor Open, Placebo Controlled, Single Ascending Dose Escalation Study To Evaluate The Safety, Tolerability And Pharmacokinetics Of Pf-04958242 Following Oral Dose Capsules in Healthy Subjects
• Actual Study Start Date: Sep 22, 2014
• Actual Primary Completion Date: Nov 13, 2014
• Actual Study Completion Date: Nov 13, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Participants received 1 single dose of placebo, PF-04958242 0.6 mg, and PF-04958242 0.8 mg orally during 3 periods, respectively. There was at least a 10-day washout period between each dosing.	Drug: PF-04958242; Administered as specified in treatment arm; Drug: Placebo; Administered as specified in treatment arm
Experimental: Cohort 2 Participants received 1 single dose of PF-04958242 0.35 mg, placebo, and PF-04958242 0.8 mg orally during 3 periods, respectively. There was at least a 10-day washout period between each dosing.	Drug: PF-04958242; Administered as specified in treatment arm; Drug: Placebo; Administered as specified in treatment arm
Experimental: Cohort 3 Participants received 1 single dose of PF-04958242 0.35 mg, PF-04958242 0.6 mg, and placebo orally during 3 periods, respectively. There was at least a 10-day washout period between each dosing.	Drug: PF-04958242; Administered as specified in treatment arm; Drug: Placebo; Administered as specified in treatment arm

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) Post-Baseline [Baseline up to Day 10]

   The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment [C-CASA]) is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced the following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has participant engaged in non-suicidal self-injurious behavior").

2. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to 28 days after last study drug administration.]

   An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are 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. AEs included both SAEs and non-SAEs.

3. Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern [Baseline up to Day 10]

   The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen [BUN], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin and microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (follicle stimulating hormone [FSH], and urine drug screening).

4. Number of Participants With Potentially Clinically Significant Vital Signs Findings [Baseline up to Day 10]

   Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate <40 or >120 beats per minute (bpm), standing pulse rate <40 or >140 bpm; systolic blood pressure (SBP) >=30 millimeters of mercury (mm Hg) change from baseline in same posture or SBP <90 mm Hg, diastolic blood pressure (DBP) >=20 mm Hg change from baseline in same posture or DBP <50 mm Hg. IFB = increase from baseline; DFB = decrease from baseline.

5. Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings [Baseline up to Day 10]

   ECG parameters included pulse rate (PR) interval, QRS interval, corrected QT interval using Bazett's formula (QTcB)and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval greater than or equal to (>=)300 milliseconds (msec) or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (=<)200 msec; QRS interval >=140 msec or >=50% increase from baseline (IFB); and QTcF >=450 msec or >=30 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.

6. Number of Participants With Abnormal Physical Examination Findings [Baseline up to Day 10]

   A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The brief physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.

7. Number of Participants With Abnormal Neurological Examination Findings [Baseline up to Day 10]

   The extended neurological examination, performed by a board certified neurologist, included observation for cerebellar (intention) tremor and for non-cerebellar tremors (eg, resting or positional), finger nose, heel shin, Romberg, tandem walking, positional and gaze evoked nystagmus, reflexes, muscle strength, cranial nerves, sensory function of upper and lower extremities. The brief neurological examination included an assessment of motor and sensory function, cranial nerves, reflexes, non-cerebellar tremor (eg, resting or positional) and cerebellar function. The assessment of cerebellar function were complemented by the Scale for Assessment and Rating of Ataxia (SARA)

Secondary Outcome Measures

1. Maximum Observed Plasma Concentration (Cmax) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

2. Time to Reach Maximum Observed Plasma Concentration (Tmax) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

3. Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

4. Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

5. Apparent Clearance (CL/F) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

6. Apparent Volume of Distribution (Vz/F) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

7. Terminal Elimination Half-Life (t1/2) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

   Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.

8. Dose Normalized Cmax (Cmax[dn]) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

9. Dose Normalized AUClast (AUClast[dn]) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

10. Dose Normalized AUCinf (AUCinf[dn]) [0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Key Inclusion Criteria:

• Healthy female subjects of non-childbearing potential and/or male subjects between the ages of 18 and 55 years, inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests).

• Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >55 kg

Key Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).

• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New Haven Clinical Research Unit	New Haven	Connecticut	United States	06511

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02228395
• Other Study ID Numbers: B1701016; SAD-MAD
• First Posted: Aug 29, 2014
• Last Update Posted: Jan 7, 2020
• Last Verified: Dec 1, 2019

• Keywords provided by Biogen: Single ascending doses; pharmacokinetics; safety; tolerability; healthy volunteers; cognitive impairment associated with schizophrenia (CIAS)

Study Results

Participant Flow

Pre-assignment Detail	Twelve participants were assigned study treatment. All participants received the assigned PF-04958242 doses during 3 periods (6 participants each received 0.35 mg, 0.6 mg and 0.8 mg doses, respectively). Nine participants received placebo. Three participants did not complete the study and they were replaced during the conduct of the study.

Arm/Group Title	Placebo, PF-04958242 0.6 Milligrams (mg), PF-04958242 0.8 mg	PF-04958242 0.35 mg, Placebo, PF-04958242 0.8 mg	PF-04958242 0.35 mg, PF-04958242 0.6 mg, Placebo
Arm/Group Description	Participants received 1 single dose of placebo, PF-04958242 0.6 mg, and PF-04958242 0.8 mg orally during 3 periods, respectively. There was at least a 10-day washout period between each dosing.	Participants received 1 single dose of PF-04958242 0.35 mg, placebo, and PF-04958242 0.8 mg orally during 3 periods, respectively. There was at least a 10-day washout period between each dosing.	Participants received 1 single dose of PF-04958242 0.35 mg, PF-04958242 0.6 mg, and placebo orally during 3 periods, respectively. There was at least a 10-day washout period between each dosing.
Period Title: First Intervention Period
STARTED	3	3	3
COMPLETED	2	2	2
NOT COMPLETED	1	1	1
Period Title: First Intervention Period
STARTED	3	3	3
COMPLETED	3	3	3
NOT COMPLETED	0	0	0
Period Title: First Intervention Period
STARTED	3	3	3
COMPLETED	3	3	3
NOT COMPLETED	0	0	0
Period Title: First Intervention Period
STARTED	3	3	3
COMPLETED	3	3	3
NOT COMPLETED	0	0	0
Period Title: First Intervention Period
STARTED	3	3	3
COMPLETED	3	3	3
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Included all participants who received at least 1 dose of study treatment in any of the intervention periods
Overall Participants	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.8 (11.1)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	12 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS) Post-Baseline
Description	The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment [C-CASA]) is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced the following: completed suicide (1), suicide attempt (2) (response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (3)("Yes" on "preparatory acts or behavior"), suicidal ideation (4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (7)("Yes" on "Has participant engaged in non-suicidal self-injurious behavior").
Time Frame	Baseline up to Day 10

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received the study medication.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg	Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
Measure Participants	6	6	6	9
Complete suicide	0 0%	0 NaN	0 NaN	0 NaN
Suicide attempt	0 0%	0 NaN	0 NaN	0 NaN
Preparatory acts to imminent suicidal behavior	0 0%	0 NaN	0 NaN	0 NaN
Suicidal ideation	0 0%	0 NaN	0 NaN	0 NaN
Self-injurious behavior, no suicidal intent	0 0%	0 NaN	0 NaN	0 NaN

2. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are 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. AEs included both SAEs and non-SAEs.
Time Frame	Baseline up to 28 days after last study drug administration.

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received the study medication.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg	Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
Measure Participants	6	6	6	9
AEs	4 33.3%	4 NaN	2 NaN	4 NaN
SAEs	0 0%	0 NaN	0 NaN	0 NaN

3. Primary Outcome

Title	Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern
Description	The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen [BUN], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin and microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (follicle stimulating hormone [FSH], and urine drug screening).
Time Frame	Baseline up to Day 10

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received the study medication.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg	Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
Measure Participants	6	6	6	9
Number [participants]	1 8.3%	2 NaN	1 NaN	3 NaN

4. Primary Outcome

Title	Number of Participants With Potentially Clinically Significant Vital Signs Findings
Description	Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate <40 or >120 beats per minute (bpm), standing pulse rate <40 or >140 bpm; systolic blood pressure (SBP) >=30 millimeters of mercury (mm Hg) change from baseline in same posture or SBP <90 mm Hg, diastolic blood pressure (DBP) >=20 mm Hg change from baseline in same posture or DBP <50 mm Hg. IFB = increase from baseline; DFB = decrease from baseline.
Time Frame	Baseline up to Day 10

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received the study medication.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg	Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
Measure Participants	6	6	6	9
Supine SBP <90 mm Hg	0 0%	0 NaN	0 NaN	0 NaN
Standing SBP <90 mm Hg	0 0%	0 NaN	0 NaN	0 NaN
Supine DBP <50 mm Hg	0 0%	0 NaN	0 NaN	0 NaN
Standing DBP <50 mm Hg	0 0%	0 NaN	0 NaN	0 NaN
Supine Pulse Rate <40 bpm	0 0%	1 NaN	0 NaN	0 NaN
Supine Pulse >120 bpm	0 0%	0 NaN	0 NaN	0 NaN
Standing Pulse Rate <40 bpm	0 0%	0 NaN	0 NaN	0 NaN
Standing Pulse Rate >140 bpm	0 0%	0 NaN	0 NaN	0 NaN
Supine SBP >=30 mm Hg IFB	0 0%	0 NaN	0 NaN	0 NaN
Standing SBP >=30 mm Hg IFB	0 0%	0 NaN	1 NaN	0 NaN
Supine DBP >=20 mm Hg IFB	0 0%	0 NaN	0 NaN	0 NaN
Standing DBP >=20 mm Hg IFB	1 8.3%	0 NaN	0 NaN	1 NaN
Supine SBP >=30 mm Hg DFB	0 0%	0 NaN	0 NaN	0 NaN
Standing SBP >=30 mm Hg DFB	0 0%	1 NaN	0 NaN	0 NaN
Supine DBP >=20 mm Hg DFB	0 0%	0 NaN	0 NaN	0 NaN
Standing DBP >=20 mm Hg DFB	0 0%	0 NaN	0 NaN	0 NaN

5. Primary Outcome

Title	Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
Description	ECG parameters included pulse rate (PR) interval, QRS interval, corrected QT interval using Bazett's formula (QTcB)and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval greater than or equal to (>=)300 milliseconds (msec) or >=25% increase when baseline is greater than (>)200 msec and >=50% increase when baseline is less than or equal to (=<)200 msec; QRS interval >=140 msec or >=50% increase from baseline (IFB); and QTcF >=450 msec or >=30 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.
Time Frame	Baseline up to Day 10

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received the study medication; n=number of participants evaluated against criteria.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg	Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
Measure Participants	6	6	6	9
PR Interval >=300 msec	0 0%	0 NaN	0 NaN	0 NaN
QRS Complex >=140 msec	0 0%	0 NaN	0 NaN	0 NaN
QTcF Interval 450-<480 msec	0 0%	0 NaN	0 NaN	0 NaN
QTcF Interval 480-<500 msec	0 0%	0 NaN	0 NaN	0 NaN
QTcF Interval >=500 msec	0 0%	0 NaN	0 NaN	0 NaN
QTcB Interval >=500 msec	0 0%	0 NaN	0 NaN	0 NaN
PR Interval >=25/50% IFB	0 0%	0 NaN	0 NaN	0 NaN
QRS Interval >=50% IFB	0 0%	0 NaN	0 NaN	0 NaN
QTcF Interval 30-<60 msec IFB	0 0%	0 NaN	0 NaN	0 NaN
QTcF Interval >=60 msec IFB	0 0%	0 NaN	0 NaN	0 NaN

6. Primary Outcome

Title	Number of Participants With Abnormal Physical Examination Findings
Description	A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The brief physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.
Time Frame	Baseline up to Day 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg	Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
Measure Participants	6	6	6	9
Number [participants]	0 0%	0 NaN	0 NaN	0 NaN

7. Primary Outcome

Title	Number of Participants With Abnormal Neurological Examination Findings
Description	The extended neurological examination, performed by a board certified neurologist, included observation for cerebellar (intention) tremor and for non-cerebellar tremors (eg, resting or positional), finger nose, heel shin, Romberg, tandem walking, positional and gaze evoked nystagmus, reflexes, muscle strength, cranial nerves, sensory function of upper and lower extremities. The brief neurological examination included an assessment of motor and sensory function, cranial nerves, reflexes, non-cerebellar tremor (eg, resting or positional) and cerebellar function. The assessment of cerebellar function were complemented by the Scale for Assessment and Rating of Ataxia (SARA)
Time Frame	Baseline up to Day 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg	Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
Measure Participants	6	6	6	9
Number [participants]	0 0%	0 NaN	0 NaN	0 NaN

8. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax)
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) parameter analysis set included all participants randomized and treated who had at least 1 of the PK parameters of interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [nanograms per milliliter (ng/mL)]	3.119 (22)	5.602 (29)	6.193 (24)

9. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Median (Full Range) [hours]	1.29	1.80	1.50

10. Secondary Outcome

Title	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [nanograms*hours per milliliter (ng*h/mL)]	42.79 (36)	76.00 (22)	88.27 (23)

11. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	45.34 (40)	79.34 (28)	90.78 (26)

12. Secondary Outcome

Title	Apparent Clearance (CL/F)
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [milliliters per minute (mL/min)]	128.6 (40)	126.0 (28)	146.9 (26)

13. Secondary Outcome

Title	Apparent Volume of Distribution (Vz/F)
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [liters]	367.9 (45)	327.0 (40)	337.2 (43)

14. Secondary Outcome

Title	Terminal Elimination Half-Life (t1/2)
Description	Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Mean (Standard Deviation) [hours]	37.33 (27.170)	34.10 (20.533)	29.07 (14.691)

15. Secondary Outcome

Title	Dose Normalized Cmax (Cmax[dn])
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [mg/mL/mg]	8.923 (23)	9.331 (29)	7.745 (24)

16. Secondary Outcome

Title	Dose Normalized AUClast (AUClast[dn])
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL/mg]	122.4 (37)	126.6 (22)	110.5 (24)

17. Secondary Outcome

Title	Dose Normalized AUCinf (AUCinf[dn])
Time Frame	0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, 120, 168 and 216 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.

Arm/Group Title	PF-04958242 0.35 mg	PF-04958242 0.6 mg	PF-04958242 0.8 mg
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.	All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.
Measure Participants	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL/mg]	129.7 (40)	132.3 (28)	113.6 (26)

Adverse Events

Time Frame	Baseline up to 28 days after last study drug administration.
Arm/Group Title	PF-04958242 0.35 mg		PF-04958242 0.6 mg		PF-04958242 0.8 mg		Placebo
Arm/Group Description	All participants who received a single-dose of PF-04958242 0.35 mg capsule orally in any of the intervention periods.		All participants who received a single-dose of PF-04958242 0.6 mg capsule orally in any of the intervention periods.		All participants who received a single-dose of PF-04958242 0.8 mg capsule orally in any of the intervention periods.		All participants who received a single-dose of placebo matching capsule orally in any of the intervention periods.
All Cause Mortality
	PF-04958242 0.35 mg		PF-04958242 0.6 mg		PF-04958242 0.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PF-04958242 0.35 mg		PF-04958242 0.6 mg		PF-04958242 0.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	PF-04958242 0.35 mg		PF-04958242 0.6 mg		PF-04958242 0.8 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		4/6 (66.7%)		2/6 (33.3%)		4/9 (44.4%)
Cardiac disorders
Sinus bradycardia	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/9 (0%)
Ear and labyrinth disorders
Vertigo	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/9 (11.1%)	1
Gastrointestinal disorders
Constipation	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/9 (0%)
Diarrhoea	0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/9 (0%)
Faeces hard	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/9 (11.1%)
Nausea	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/9 (11.1%)
General disorders
Fatigue	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/9 (11.1%)
Injury, poisoning and procedural complications
Contusion	2/6 (33.3%)		0/6 (0%)		0/6 (0%)		2/9 (22.2%)
Musculoskeletal and connective tissue disorders
Muscular weakness	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/9 (0%)
Musculoskeletal pain	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/9 (0%)
Myalgia	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		1/9 (11.1%)
Nervous system disorders
Dizziness postural	0/6 (0%)		2/6 (33.3%)		1/6 (16.7%)		1/9 (11.1%)
Headache	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/9 (0%)
Presyncope	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/9 (0%)
Reproductive system and breast disorders
Penis disorder	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/9 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/9 (0%)
Skin and subcutaneous tissue disorders
Pruritus	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/9 (11.1%)
Rash	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/9 (11.1%)
Skin lesion	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/9 (0%)

Limitations/Caveats

The participants received PF-04958242 0.35 milligrams (mg), 0.6 mg and 0.8 mg instead of the proposed doses of 0.35 mg, 0.55 mg and 0.75 mg based on the review conducted after each dosing period prior to proceeding to next dosing level.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.