Multiple Ascending Doses of PF-04958242 in Subjects With Stable Schizophrenia (MAD)

A Randomized, Double-blind, Placebo Controlled, Sponsor Open, Parallel Group Phase 1b Study To Examine The Safety, Tolerability And Pharmacokinetics Of Multiple Ascending Doses Of Pf-04958242 In Subjects With Stable Schizophrenia

This study aims to assess the safety, tolerability and pharmacokinetics of PF-04958242 in multiple ascending doses in subjects with stable schizophrenia.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: PF-04958242; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90806
      • Collaborative Neuroscience Network, LLC.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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/Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: PF-04958242 0.25 mg; All participants who received PF-04958242 0.25 milligram (mg) twice daily (BID) for 14 consecutive days with the last dose occurring in the morning on Day 14.	Drug: PF-04958242; Administered as specified in the treatment arm
EXPERIMENTAL: 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.	Drug: PF-04958242; Administered as specified in the treatment arm
PLACEBO_COMPARATOR: Matching Placebo; All participants who received placebo BID for 14 consecutive days with the last dose occurring in the morning on Day 14.	Drug: Placebo; Administered as specified in the treatment arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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").	Baseline up to Day 21
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)	Cmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.	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
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)	Tmax steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.	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
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)	AUCτ steady state for PF-04958242 0.25 mg group and PF-04958242 0.475 mg group at Day 14 were presented.	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
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.	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
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.	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 (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.	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
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.	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
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.	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
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.	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
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).	Baseline up to Day 21
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.	Baseline up to Day 21
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.	Baseline up to Day 21
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).	Baseline up to Day 21
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.	Baseline up to Day 21
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.	Baseline up to 28 days after last study drug administration

Collaborators and Investigators

• Sponsor: Biogen

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 6, 2015
• Primary Completion (ACTUAL): April 15, 2015
• Study Completion (ACTUAL): April 15, 2015

Study Registration Dates

• First Submitted: December 5, 2014
• First Submitted That Met QC Criteria: January 5, 2015
• First Posted (ESTIMATE): January 7, 2015

Study Record Updates

• Last Update Posted (ACTUAL): October 25, 2021
• Last Update Submitted That Met QC Criteria: October 4, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: tolerability; safety; pharmacokinetics; Multiple ascending doses; cognitive impairment associated with schizophrenia (CIAS)
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia
• Other Study ID Numbers: B1701017; MAD (OTHER: Alias Study Number)