Schizophrenia
Conditions
Keywords
Multiple ascending doses, safety, tolerability, pharmacokinetics, cognitive impairment associated with schizophrenia (CIAS)
Brief summary
This study aims to assess the safety, tolerability and pharmacokinetics of PF-04958242 in multiple ascending doses in subjects with stable schizophrenia.
Detailed description
This study aims to assess the safety, tolerability and pharmacokinetics of PF-04958242 compared to placebo over 14 days twice a day dosing in multiple ascending doses in subjects with stable schizophrenia. This study was previously posted by Pfizer, Inc. Sponsorship of the trial was transferred to Biogen.
Interventions
DRUGPF-04958242
Administered as specified in the treatment arm
DRUGPlacebo
Administered as specified in the treatment arm
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Psychiatrically stable (≥3 months) male and female subjects with schizophrenia of non-childbearing potential between the ages of 18 and 55 years, inclusive. * Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>55 kg (121 lbs). * DSM-IV Diagnosis of Schizophrenia; on stable medication treatment regimen ≥2 months. Key
Exclusion criteria
* Suicide attempt within 3 months prior to screening. * History of or risk of seizures; head injury with long term abnormal resulting condition, abnormal EEG, clinically significant additional diseases or conditions, current medication with a significant risk of seizures, currently receiving antipsychotic medications. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) (Single Dose) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 12 hours post-dose) | — |
| Cmax (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | Cmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Time for Cmax (Tmax) (Single Dose) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 12 hours post-dose) | — |
| Tmax (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | Tmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Area Under the Concentration-Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 12 Hours (AUCτ) (Single Dose) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 12 hours post-dose) | — |
| AUCτ (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | AUCτ steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Apparent Oral Clearance (CL/F) (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, 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 pharmacokinetic modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Apparent Volume of Distribution (Vz/F) (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. Vz/F steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Terminal Half-Life (t1/2) (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | Terminal half-life is the time measured for the plasma concentration to decrease by one half. t1/2 steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Observed Accumulation Ratio (Rac) (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | Accumulation ratio was calculated as, Rac obtained from Area Under the Concentration Time Curve (AUC) from time 0-t (Day X) divided by AUC from time 0-t (Day 1). Rac steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 (ie. X = 14) were presented. |
| Observed Accumulation Ratio for Cmax (Rac, Cmax) (Steady State) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | Accumulation ratio based on Cmax was calculated as: Rac,Cmax = Cmax at steady state (ss) divided by Cmax at first dose. Rac, Cmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Peak-to-Trough Ratio at Steady State (PTR) | Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21 | PTR was calculated as Cmax divided by Cmin (that is defined as lowest concentration observed during the dosing interval). PTR steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented. |
| Number of Participants With Abnormal Clinical Laboratory Measurements | Baseline up to Day 21 | The following laboratory parameters were reported: 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, phosphorus, cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), bicarbonate, uric acid, albumin, and total protein); urinalysis (color, appearance, specific gravity, pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, and microscopy); others (follicle stimulating hormone \[FSH\], and urine drug screening). |
| 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 less than (\<) 40 or greater than (\>) 120 beats per minute (bpm), standing pulse rate \<40 or \>140 bpm; systolic blood pressure (SBP) greater 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. |
| Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern | Baseline up to Day 21 | Electrocardiogram (ECG) parameters included 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, and QTc 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 (IFB); and and QTcF \>=450 to \<480, 480 to \<500 and \>=500 msec. The number of participants with potentially clinically significant ECG findings at any visit were reported. |
| Number of Participants With Abnormalities in Neurological Examination | Baseline up to Day 21 | 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). |
| Number of Participants With Abnormalities in Physical 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. |
| 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. 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. |
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-04958242 0.25 mg All participants who received PF-04958242 0.25 mg BID for 14 consecutive days with the last dose occurring in the morning on Day 14. | 13 |
| PF-04958242 0.475 mg All participants who received PF-04958242 0.475 mg BID for 14 consecutive days with the last dose occurring in the morning on Day 14. | 14 |
| Placebo All participants who received placebo BID for 14 consecutive days with the last dose occurring in the morning on Day 14. | 12 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal Laboratory Findings | 1 | 0 | 0 |
| Overall Study | Positive Urine Drug Test | 0 | 1 | 0 |
| Overall Study | Unwilling to Participate in Study | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | PF-04958242 0.25 mg | PF-04958242 0.475 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 45.6 years STANDARD_DEVIATION 5.9 | 41.6 years STANDARD_DEVIATION 7.5 | 45.8 years STANDARD_DEVIATION 10.5 | 44.3 years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 13 Participants | 11 Participants | 10 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 13 | 9 / 14 | 4 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 14 | 0 / 12 |
Outcome results
Primary
Apparent Oral Clearance (CL/F) (Steady State)
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 pharmacokinetic modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Apparent Oral Clearance (CL/F) (Steady State) | 169.5 milliliter per minute (mL/min) | Geometric Coefficient of Variation 18 |
| PF-04958242 0.475 mg | Apparent Oral Clearance (CL/F) (Steady State) | 157.9 milliliter per minute (mL/min) | Geometric Coefficient of Variation 34 |
Primary
Apparent Volume of Distribution (Vz/F) (Steady State)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. Vz/F steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Apparent Volume of Distribution (Vz/F) (Steady State) | 545.7 Liter (L) | Geometric Coefficient of Variation 31 |
| PF-04958242 0.475 mg | Apparent Volume of Distribution (Vz/F) (Steady State) | 530.2 Liter (L) | Geometric Coefficient of Variation 26 |
Primary
Area Under the Concentration-Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 12 Hours (AUCτ) (Single Dose)
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 12 hours post-dose)
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Area Under the Concentration-Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 12 Hours (AUCτ) (Single Dose) | 9.570 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 19 |
| PF-04958242 0.475 mg | Area Under the Concentration-Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 12 Hours (AUCτ) (Single Dose) | 17.72 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 18 |
Primary
AUCτ (Steady State)
AUCτ steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | AUCτ (Steady State) | 24.57 ng*h/mL | Geometric Coefficient of Variation 19 |
| PF-04958242 0.475 mg | AUCτ (Steady State) | 50.09 ng*h/mL | Geometric Coefficient of Variation 34 |
Primary
Cmax (Steady State)
Cmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK concentration population is defined as all enrolled subjects treated who received at least one dose of PF-04958242 and have at least 1 measureable concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Cmax (Steady State) | 3.174 ng/mL | Geometric Coefficient of Variation 18 |
| PF-04958242 0.475 mg | Cmax (Steady State) | 7.139 ng/mL | Geometric Coefficient of Variation 37 |
Primary
Maximum Observed Plasma Concentration (Cmax) (Single Dose)
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 12 hours post-dose)
Population: The pharmacokinetic (PK) concentration population is defined as all enrolled subjects treated who received at least one dose of PF-04958242 and have at least 1 measureable concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Maximum Observed Plasma Concentration (Cmax) (Single Dose) | 1.920 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 23 |
| PF-04958242 0.475 mg | Maximum Observed Plasma Concentration (Cmax) (Single Dose) | 3.830 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 21 |
Primary
Number of Participants With Abnormal Clinical Laboratory Measurements
The following laboratory parameters were reported: 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, phosphorus, cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), bicarbonate, uric acid, albumin, and total protein); urinalysis (color, appearance, specific gravity, pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, and microscopy); others (follicle stimulating hormone \[FSH\], and urine drug screening).
Time frame: Baseline up to Day 21
Population: The safety analysis population included all participants who received at least 1 dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04958242 0.25 mg | Number of Participants With Abnormal Clinical Laboratory Measurements | 4 participants |
| PF-04958242 0.475 mg | Number of Participants With Abnormal Clinical Laboratory Measurements | 4 participants |
| Placebo | Number of Participants With Abnormal Clinical Laboratory Measurements | 7 participants |
Primary
Number of Participants With Abnormalities in Neurological Examination
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 21
Population: The safety analysis population included all participants who received at least 1 dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04958242 0.25 mg | Number of Participants With Abnormalities in Neurological Examination | 0 participants |
| PF-04958242 0.475 mg | Number of Participants With Abnormalities in Neurological Examination | 0 participants |
| Placebo | Number of Participants With Abnormalities in Neurological Examination | 0 participants |
Primary
Number of Participants With Abnormalities in Physical Examination
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
Population: The safety analysis population included all participants who received at least 1 dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04958242 0.25 mg | Number of Participants With Abnormalities in Physical Examination | 0 participants |
| PF-04958242 0.475 mg | Number of Participants With Abnormalities in Physical Examination | 0 participants |
| Placebo | Number of Participants With Abnormalities in Physical Examination | 0 participants |
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drug. 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
Population: The safety analysis population included all participants who received at least 1 dose of the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-04958242 0.25 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 10 participants |
| PF-04958242 0.25 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF-04958242 0.475 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 9 participants |
| PF-04958242 0.475 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
Primary
Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern
Electrocardiogram (ECG) parameters included 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, and QTc 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 (IFB); and and QTcF \>=450 to \<480, 480 to \<500 and \>=500 msec. The number of participants with potentially clinically significant ECG findings at any visit were reported.
Time frame: Baseline up to Day 21
Population: The safety analysis population included all participants who received at least 1 dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04958242 0.25 mg | Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern | 0 participants |
| PF-04958242 0.475 mg | Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern | 0 participants |
| Placebo | Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern | 0 participants |
Primary
Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS)
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
Population: The safety analysis population included all participants who received at least 1 dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-04958242 0.25 mg | Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 participants |
| PF-04958242 0.475 mg | Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 participants |
| Placebo | Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 participants |
Primary
Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern
Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate less than (\<) 40 or greater than (\>) 120 beats per minute (bpm), standing pulse rate \<40 or \>140 bpm; systolic blood pressure (SBP) greater 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
Population: The safety analysis population included all participants who received at least 1 dose of the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP <90 mmHg | 0 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP <90 mmHg | 0 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP >=30 mmHg IFB | 0 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP >=30 mmHg IFB | 2 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine DBP >=20 mmHg IFB | 0 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing DBP >=20 mmHg IFB | 2 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP >=30 mmHg DFB | 2 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP >=30 mmHg DFB | 2 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine DBP >=20 mmHg DFB | 2 participants |
| PF-04958242 0.25 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing DBP >=20 mmHg DFB | 5 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing DBP >=20 mmHg IFB | 2 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP <90 mmHg | 2 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine DBP >=20 mmHg IFB | 2 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing DBP >=20 mmHg DFB | 2 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP <90 mmHg | 1 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine DBP >=20 mmHg DFB | 0 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP >=30 mmHg DFB | 1 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP >=30 mmHg IFB | 0 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP >=30 mmHg DFB | 1 participants |
| PF-04958242 0.475 mg | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP >=30 mmHg IFB | 1 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP >=30 mmHg DFB | 1 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP >=30 mmHg IFB | 1 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing DBP >=20 mmHg DFB | 4 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine DBP >=20 mmHg IFB | 1 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing DBP >=20 mmHg IFB | 0 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine DBP >=20 mmHg DFB | 3 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP >=30 mmHg DFB | 0 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP <90 mmHg | 0 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Standing SBP <90 mmHg | 0 participants |
| Placebo | Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern | Supine SBP >=30 mmHg IFB | 1 participants |
Primary
Observed Accumulation Ratio for Cmax (Rac, Cmax) (Steady State)
Accumulation ratio based on Cmax was calculated as: Rac,Cmax = Cmax at steady state (ss) divided by Cmax at first dose. Rac, Cmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Observed Accumulation Ratio for Cmax (Rac, Cmax) (Steady State) | 1.645 Ratio | Geometric Coefficient of Variation 23 |
| PF-04958242 0.475 mg | Observed Accumulation Ratio for Cmax (Rac, Cmax) (Steady State) | 1.797 Ratio | Geometric Coefficient of Variation 51 |
Primary
Observed Accumulation Ratio (Rac) (Steady State)
Accumulation ratio was calculated as, Rac obtained from Area Under the Concentration Time Curve (AUC) from time 0-t (Day X) divided by AUC from time 0-t (Day 1). Rac steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 (ie. X = 14) were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Observed Accumulation Ratio (Rac) (Steady State) | 2.524 Ratio | Geometric Coefficient of Variation 20 |
| PF-04958242 0.475 mg | Observed Accumulation Ratio (Rac) (Steady State) | 2.815 Ratio | Geometric Coefficient of Variation 31 |
Primary
Peak-to-Trough Ratio at Steady State (PTR)
PTR was calculated as Cmax divided by Cmin (that is defined as lowest concentration observed during the dosing interval). PTR steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Peak-to-Trough Ratio at Steady State (PTR) | 2.323 Ratio | Geometric Coefficient of Variation 19 |
| PF-04958242 0.475 mg | Peak-to-Trough Ratio at Steady State (PTR) | 2.531 Ratio | Geometric Coefficient of Variation 28 |
Primary
Terminal Half-Life (t1/2) (Steady State)
Terminal half-life is the time measured for the plasma concentration to decrease by one half. t1/2 steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF-04958242 0.25 mg | Terminal Half-Life (t1/2) (Steady State) | 39.64 hours | Standard Deviation 14.878 |
| PF-04958242 0.475 mg | Terminal Half-Life (t1/2) (Steady State) | 42.18 hours | Standard Deviation 14.421 |
Primary
Time for Cmax (Tmax) (Single Dose)
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 12 hours post-dose)
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PF-04958242 0.25 mg | Time for Cmax (Tmax) (Single Dose) | 1.65 hours |
| PF-04958242 0.475 mg | Time for Cmax (Tmax) (Single Dose) | 1.33 hours |
Primary
Tmax (Steady State)
Tmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.
Time frame: Day 1 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 hours post-dose), Day 2, Day 7 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 8, Day 10, Day 14 (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours post-dose), Day 15, Day 17, Day 21
Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters interest measured.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PF-04958242 0.25 mg | Tmax (Steady State) | 1.65 hours |
| PF-04958242 0.475 mg | Tmax (Steady State) | 1.33 hours |