A Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of PF-04958242 in Healthy Subjects

• Sponsor: Biogen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02341482
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arm: 1
• Actual Duration (Months): 1.8
• Patients Per Site Per Month: 7.3

Study Details

Study Description

Brief Summary

The purpose of the current study is to characterize the pharmacokinetic (PK) profile of PF 04958242 when co administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: PF-04958242; Drug: Itraconazole	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: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Fixed-sequence Study To Estimate The Effects Of Multiple-dose Administration Of Itraconazole On The Pharmacokinetics Of Pf 04958242 In Healthy Adult Subjects
• Actual Study Start Date: Feb 5, 2015
• Actual Primary Completion Date: Mar 31, 2015
• Actual Study Completion Date: Mar 31, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: PF-04958242 and itraconazole PF-04958242 will be provided in a capsule. Participants will receive a 0.10 mg loading dose of PF-04958242 twice daily (BID) on Day 1 then 0.025 mg BID on Day 2-Day 16, with the last dose occurring in the morning on Day 17. Itraconazole will be provided as a solution starting on Day 4. On Day 4, a 200 mg dose of itraconazole will be administered approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4-Day 17).

Drug: PF-04958242; Administered as specified in the treatment arm; Drug: Itraconazole; Administered as specified in the treatment arm

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242 [Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21]

   AUCtau = area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau = 12 hours. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

2. Maximum Observed Plasma Concentration (Cmax) of PF-04958242 [Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21]

   Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

Secondary Outcome Measures

1. Time for Cmax (Tmax) of PF-04958242 [Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21]

   Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

2. Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242 [Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21]

3. Predose Concentration (Ctrough) of PF-04958242 [0 hour at Day 1, Day 2, Day 3, Day 4, Day 7, Day 10, Day 13, Day 16, and Day 17 (pre-dose)]

4. Apparent Oral Clearance (CL/F) of PF-04958242 [Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21]

   Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

5. Number of Participants With Abnormal Clinical Laboratory Measurements [Baseline up to Day 21]

   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], urine cotinine, and urine drug screening).

6. Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern [Baseline up to Day 21]

   Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate more than (<)40 or less than (>)120 beats per minute (bpm); systolic blood pressure (SBP) more than or equal to (>=)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.

7. Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern [Baseline up to Day 21]

   Electrocardiogram (ECG) parameters included time from ECG Q wave to the end of the T wave corresponding to electrical systole (QT) interval, beginning of the P wave until the beginning of the QRS complex (PR) interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) interval, QT interval corrected for heart rate (QTc) interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval >=300 milliseconds (msec) or >=25% increase when baseline is >200 msec and >=50% increase when baseline is less than or equal to (=<)200 msec; QRS interval >=140 msec or >=50% increase from baseline; and QTcF >=450 to <480, 480 to <500 and >=500 msec or >=30 to 60 msec increase and also >=60 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.

8. Number of Participants With Significant Change in Neurological Examination From Previous Examination [Baseline up to Day 21]

   The extended neurological examination, performed by a board certified neurologist, included observations 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).

9. Number of Participants With Significant Change in Physical Examination From Previous Examination [Baseline up to Day 21]

   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.

10. Number of Participants With 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.

11. Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS) [Baseline up to Day 21]

    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").

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 male subjects and female subjects of non childbearing with a Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >55 kg (121 lbs).

Key Exclusion Criteria:

• Subjects with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat, if deemed necessary:

• Aspartate transaminase (AST)/serum glutamic oxaloacetic transminase (SGOT) or alanine transaminase (ALT)/serum glutamic pyruvic transminase (SGPT) >=1 x upper limit of normal (ULN);

• Total bilirubin >=1.5 x ULN; subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is <= ULN.

• Subjects with epilepsy, or history of epilepsy, or conditions that lower seizure threshold, seizures of any etiology (including substance or drug withdrawal), or who have increased risk of seizures as evidenced by self reported history of electroencephalogram (EEG) with epileptiform activity. Subjects with a history of childhood seizures and history of head trauma with loss of consciousness requiring hospitalization overnight will be excluded as well.

• Subjects who had a history of allergy or intolerance to azole antifungal drugs.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer 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: NCT02341482
• Other Study ID Numbers: B1701021; DDI
• First Posted: Jan 19, 2015
• Last Update Posted: Jan 9, 2020
• Last Verified: Dec 1, 2019

• Keywords provided by Biogen: Itraconazole; Healthy Volunteers; Drug-drug interaction; PF-04958242
• Additional relevant MeSH terms: Itraconazole

Study Results

Participant Flow

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 milligram (mg) loading dose was administered orally twice daily (BID) on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), once daily (QD).
Period Title: Overall Study
STARTED	13
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.5 (8.5)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	13 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242
Description	AUCtau = area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau = 12 hours. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.

Arm/Group Title	PF-04958242 0.025 mg	PF-04958242 0.025 mg + Itraconazole 200 mg
Arm/Group Description	All participants who received PF-04958242 0.025 mg BID orally.	All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Measure Participants	13	12
Geometric Mean (Geometric Coefficient of Variation) [picogram*hours per milliliter pg*h/mL]	4242 (30)	4073 (25)

2. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of PF-04958242
Description	Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21

Outcome Measure Data

Analysis Population Description

All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.

Arm/Group Title	PF-04958242 0.025 mg	PF-04958242 0.025 mg + Itraconazole 200 mg
Arm/Group Description	All participants who received PF-04958242 0.025 mg BID orally.	All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Measure Participants	13	12
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]	553.4 (27)	541.6 (20)

3. Secondary Outcome

Title	Time for Cmax (Tmax) of PF-04958242
Description	Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.

Arm/Group Title	PF-04958242 0.025 mg	PF-04958242 0.025 mg + Itraconazole 200 mg
Arm/Group Description	All participants who received PF-04958242 0.025 mg BID orally.	All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Measure Participants	13	12
Median (Full Range) [hours]	1.50	1.50

4. Secondary Outcome

Title	Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242
Time Frame	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21

Outcome Measure Data

Analysis Population Description

All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.

Arm/Group Title	PF-04958242 0.025 mg	PF-04958242 0.025 mg + Itraconazole 200 mg
Arm/Group Description	All participants who received PF-04958242 0.025 mg BID orally.	All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Measure Participants	13	12
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]	256.5 (35)	238.2 (30)

5. Secondary Outcome

Title	Predose Concentration (Ctrough) of PF-04958242
Time Frame	0 hour at Day 1, Day 2, Day 3, Day 4, Day 7, Day 10, Day 13, Day 16, and Day 17 (pre-dose)

Outcome Measure Data

Analysis Population Description

All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.

Arm/Group Title	PF-04958242 0.025 mg	PF-04958242 0.025 mg + Itraconazole 200 mg
Arm/Group Description	All participants who received PF-04958242 0.025 mg BID orally.	All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Measure Participants	13	12
Geometric Mean (Geometric Coefficient of Variation) [pg/mL]	289.3 (37)	255.0 (29)

6. Secondary Outcome

Title	Apparent Oral Clearance (CL/F) of PF-04958242
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Time Frame	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21

Outcome Measure Data

Analysis Population Description

The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.

Arm/Group Title	PF-04958242 0.025 mg	PF-04958242 0.025 mg + Itraconazole 200 mg
Arm/Group Description	All participants who received PF-04958242 0.025 mg BID orally.	All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.
Measure Participants	13	12
Geometric Mean (Geometric Coefficient of Variation) [milliliters per minute (mL/min)]	98.25 (30)	102.3 (25)

7. Secondary Outcome

Title	Number of Participants With Abnormal Clinical Laboratory Measurements
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], urine cotinine, and urine drug screening).
Time Frame	Baseline up to Day 21

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of the study medication.

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Measure Participants	13
Number [participants]	1 7.7%

8. Secondary Outcome

Title	Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern
Description	Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate more than (<)40 or less than (>)120 beats per minute (bpm); systolic blood pressure (SBP) more than or equal to (>=)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 21

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of the study medication.

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Measure Participants	13
Supine SBP <90 mmHg	0 0%
Supine DBP <50 mmHg	0 0%
Supine Pulse Rate <40 BPM	0 0%
Supine Pulse Rate >120 BPM	0 0%
Supine SBP >=30 mmHg IFB	2 15.4%
Supine DBP >=20 mmHg IFB	1 7.7%
Supine SBP >=30 mmHg DFB	0 0%
Supine DBP >=20 mmHg DFB	0 0%

9. Secondary Outcome

Title	Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern
Description	Electrocardiogram (ECG) parameters included time from ECG Q wave to the end of the T wave corresponding to electrical systole (QT) interval, beginning of the P wave until the beginning of the QRS complex (PR) interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) interval, QT interval corrected for heart rate (QTc) interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval >=300 milliseconds (msec) or >=25% increase when baseline is >200 msec and >=50% increase when baseline is less than or equal to (=<)200 msec; QRS interval >=140 msec or >=50% increase from baseline; and QTcF >=450 to <480, 480 to <500 and >=500 msec or >=30 to 60 msec increase and also >=60 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.
Time Frame	Baseline up to Day 21

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of the study medication.

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Measure Participants	13
Number [participants]	0 0%

10. Secondary Outcome

Title	Number of Participants With Significant Change in Neurological Examination From Previous Examination
Description	The extended neurological examination, performed by a board certified neurologist, included observations 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 21

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of the study medication.

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Measure Participants	13
Number [participants]	0 0%

11. Secondary Outcome

Title	Number of Participants With Significant Change in Physical Examination From Previous Examination
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 21

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of the study medication.

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Measure Participants	13
Number [participants]	0 0%

12. Secondary Outcome

Title	Number of Participants With 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.
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 at least 1 dose of the study medication.

Arm/Group Title	PF-04958242 0.025 mg	PF-04958242 0.025 mg + Itraconazole 200 mg	PF-04958242 0.1 mg
Arm/Group Description	All participants who received PF-04958242 0.025 mg BID orally.	All participants who received PF-04958242 0.025 mg BID combined with Itraconazole 200 mg QD orally.	All participants who received PF-04958242 0.1 mg BID orally.
Measure Participants	13	13	13
AEs	2 15.4%	7 NaN	1 NaN
SAEs	0 0%	0 NaN	0 NaN

13. Secondary Outcome

Title	Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS)
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 21

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least 1 dose of the study medication.

Arm/Group Title	All Subjects
Arm/Group Description	PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.
Measure Participants	13
Number [participants]	0 0%

Adverse Events

Time Frame	Baseline up to 28 days after last dose of study drug.
Arm/Group Title	PF-04958242 0.1 mg		PF-04958242 0.025 mg		PF-04958242 0.025 mg Combined With Itraconazole 200 mg
Arm/Group Description	All participants who received PF-04958242 0.1 mg BID orally.		All participants who received PF-04958242 0.025 mg BID orally.		All participants who received PF-04958242 0.025 mg combined with itraconazole 200 mg orally.
All Cause Mortality
	PF-04958242 0.1 mg		PF-04958242 0.025 mg		PF-04958242 0.025 mg Combined With Itraconazole 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PF-04958242 0.1 mg		PF-04958242 0.025 mg		PF-04958242 0.025 mg Combined With Itraconazole 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	PF-04958242 0.1 mg		PF-04958242 0.025 mg		PF-04958242 0.025 mg Combined With Itraconazole 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		2/13 (15.4%)		7/13 (53.8%)
Gastrointestinal disorders
Abdominal discomfort	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Change of bowel habit	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Diarrhoea	0/13 (0%)		0/13 (0%)		2/13 (15.4%)
Flatulence	0/13 (0%)		1/13 (7.7%)		0/13 (0%)
General disorders
Drug intolerance	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Fat tissue increased	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Oedema peripheral	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Thirst	0/13 (0%)		0/13 (0%)		2/13 (15.4%)
Injury, poisoning and procedural complications
Contusion	0/13 (0%)		1/13 (7.7%)		1/13 (7.7%)
Joint injury	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Investigations
Urine output decreased	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Weight increased	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Back pain	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Pain in extremity	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Nervous system disorders
Dizziness	1/13 (7.7%)		0/13 (0%)		0/13 (0%)
Headache	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Paraesthesia	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Somnolence	0/13 (0%)		0/13 (0%)		2/13 (15.4%)
Reproductive system and breast disorders
Penile swelling	0/13 (0%)		0/13 (0%)		2/13 (15.4%)
Skin and subcutaneous tissue disorders
Pruritus	0/13 (0%)		0/13 (0%)		1/13 (7.7%)
Rash maculo-papular	0/13 (0%)		0/13 (0%)		1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.