Conditions: Cognitive Impairment Associated With Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 195
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the efficacy of BIIB104 in participants with CIAS, using the Working Memory Domain of the MATRICS Consensus Cognitive Battery (MCCB).

The secondary objectives of this study are to evaluate the safety and tolerability of BIIB104 in participants with CIAS, and to evaluate the efficacy of BIIB104 in participants with CIAS on measures of cognition, functioning, and psychiatric symptomology.

Detailed description:

Arms:
arm 1: Participants will receive 0.5 mg of BIIB104 twice a day, orally, for 12 weeks. arm 2: Participants will receive 0.15 mg of BIIB104 twice a day, orally, for 12 weeks. arm 3: Participants will receive matching placebo twice a day, orally, for 12 weeks.

Interventions: intervention 1: BIIB104 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm intervention 2: Administered as specified in the treatment arm

Protocol document:
Prot_000.pdf: 




Protocol 263CS201
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Phase 2 Safety and Efficacy Study of BIIB104 in Subjects With CIAS
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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SYNOPSIS .................................................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................14
3.
SPONSOR INFORMATION .....................................................................................17
4.
INTRODUCTION......................................................................................................18
4.1.
Schizophrenia and Cognitive Defects.........................................................................18
4.1.1.
AMPA Receptors and Cognition................................................................................19
4.1.2.
AMPA Potentiators in Clinical Trials.........................................................................20
4.2.
Current Therapies for CIAS........................................................................................21
21
21
21
21
23
23
23
25
4.4.
Study Rationale...........................................................................................................26
26
5.
SCHEDULES OF ACTIVITIES ................................................................................27
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................36
7.
STUDY DESIGN .......................................................................................................38
7.1.
Study Duration for Subjects........................................................................................40
7.2.
Rater Qualifications....................................................................................................40
7.3.
Study Stopping Rules .................................................................................................40
7.4.
End of Study ...............................................................................................................41
8.
SELECTION OF SUBJECTS ....................................................................................42
8.1.
Inclusion Criteria ........................................................................................................42
8.2.
Exclusion Criteria.......................................................................................................44
8.3.
Lifestyle Guidelines....................................................................................................47
8.3.1.
Meals and Diet............................................................................................................47


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8.3.2.
Alcohol, Caffeine, and Tobacco .................................................................................47
8.3.3.
Activity .......................................................................................................................48
8.3.4.
Contraception..............................................................................................................48
9.
SCREENING AND RANDOMIZATION .................................................................49
9.1.
Screening ....................................................................................................................49
9.1.1.
Screening Assessments...............................................................................................49
9.1.1.1.
Validated Reading Test...............................................................................................50
9.1.1.2.
Mini-International Neuropsychiatric Interview for Psychotic Disorders 7.0.2..........50
9.1.1.3.
Independent Telemedicine Interview .........................................................................50
9.2.
Placebo Lead-In..........................................................................................................50
9.3.
Subject Rescreening....................................................................................................51
9.4.
Subject Eligibility Review..........................................................................................51
9.5.
Sponsor Screening Verification Process.....................................................................51
9.6.
Randomization............................................................................................................51
9.7.
Blinding Procedures....................................................................................................52
10.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY........................................................................53
10.1.
Discontinuation of Study Treatment...........................................................................53
10.2.
Subject Early Termination/Withdrawal......................................................................54
10.3.
Lost to Follow-Up.......................................................................................................54
11.
STUDY TREATMENT USE .....................................................................................55
11.1.
Regimen......................................................................................................................55
11.2.
Modification of Dose and/or Treatment Schedule......................................................55
11.3.
Compliance.................................................................................................................55
11.4.
Concomitant Therapy and Procedures........................................................................56
11.4.1.
Concomitant Therapy .................................................................................................56
11.4.2.
Concomitant Procedures.............................................................................................59
12.
STUDY TREATMENT MANAGEMENT................................................................60
12.1.
BIIB104 Study Treatment...........................................................................................60
12.1.1.
BIIB104 Preparation and Dispensing.........................................................................60
12.1.2.
BIIB104 Storage.........................................................................................................60
12.1.3.
BIIB104 Handling and Disposal.................................................................................61


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12.1.4.
BIIB104 Accountability..............................................................................................61
12.2.
Placebo........................................................................................................................62
13.
EFFICACY AND 
 ASSESSMENTS...................................63
13.1.
Clinical Efficacy Assessments....................................................................................63
13.1.1.
MATRICS Consensus Cognitive Battery...................................................................63
63
63
63
13.1.5.
Structured Clinical Interview for Positive and Negative Syndrome Scale.................64
13.1.6.
University of California, San Diego, Performance-Based Skills Assessment 
– Brief, international version......................................................................................64
13.1.7.
Schizophrenia Cognition Rating Scale .......................................................................64
13.1.8.
Clinical Global Impression of Severity ......................................................................65
13.1.9.
Clinical Global Impression of Improvement ..............................................................65
65
66
66
66
67
67
67
14.
SAFETY ASSESSMENTS ........................................................................................69
14.1.
Clinical Safety Assessments.......................................................................................69
14.1.1.
Physical Examinations................................................................................................69
14.1.2.
Neurological Examinations ........................................................................................69
14.1.3.
Scale for the Assessment and Rating of Ataxia..........................................................69
14.1.4.
Columbia-Suicide Severity Rating Scale....................................................................70
14.1.5.
Blood Pressure and Pulse Rate ...................................................................................71
14.1.6.
Electrocardiogram.......................................................................................................71
14.2.
Laboratory Safety Assessments..................................................................................72
14.2.1.
Pregnancy Testing ......................................................................................................72
14.2.2.
Antipsychotic Medication Monitoring .......................................................................73


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14.3.
Japan-Specific Safety Assessment on Day 8..............................................................73
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................74
15.1.
Definitions ..................................................................................................................74
15.1.1.
Adverse Event.............................................................................................................74
15.1.2.
Serious Adverse Event................................................................................................74
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................75
15.2.
Safety Classifications..................................................................................................75
15.2.1.
Investigator Assessment of Events.............................................................................75
15.2.2.
Relationship of Events to Study Treatment................................................................76
15.2.3.
Severity of Events.......................................................................................................76
15.2.4.
Expectedness of Events ..............................................................................................76
15.3.
Monitoring and Recording Events..............................................................................76
15.3.1.
Adverse Events ...........................................................................................................76
15.3.2.
Adverse Events of Special Interest.............................................................................77
15.3.3.
Serious Adverse Events..............................................................................................77
15.3.4.
Immediate Reporting of Serious Adverse Events.......................................................77
15.3.4.1.
Deaths .........................................................................................................................78
15.3.5.
Suspected Unexpected Serious Adverse Reactions....................................................78
15.4.
Procedures for Handling Special Situations ...............................................................78
15.4.1.
Pregnancy ...................................................................................................................78
15.4.2.
Overdose.....................................................................................................................79
15.4.3.
Medical Emergency....................................................................................................79
15.4.3.1.
Unblinding for Medical Emergency...........................................................................79
15.5.
Contraception Requirements ......................................................................................79
15.6.
Safety Responsibilities................................................................................................81
15.6.1.
The Investigator..........................................................................................................81
15.6.2.
The Sponsor................................................................................................................81
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........82
16.1.
Efficacy.......................................................................................................................82
16.1.1.
Analysis Population....................................................................................................82
16.1.2.
Methods of Analysis...................................................................................................82


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16.1.2.1.
Analysis of the Primary Endpoint...............................................................................82
16.1.2.2.
Analysis of the Secondary Endpoints.........................................................................83
83
.83
16.2.1.
Analysis Population....................................................................................................83
16.2.2.
Methods of Analysis...................................................................................................83
83
16.4.
Safety..........................................................................................................................83
16.4.1.
Analysis Population....................................................................................................83
16.4.2.
Methods of Analysis...................................................................................................84
16.4.2.1.
Adverse Events ...........................................................................................................84
16.4.2.2.
Clinical Laboratory Results........................................................................................84
16.4.2.3.
Vital Signs ..................................................................................................................84
16.4.2.4.
C-SSRS.......................................................................................................................84
16.5.
Interim Analyses.........................................................................................................84
16.6.
Sample Size Considerations .......................................................................................85
17.
ETHICAL REQUIREMENTS ...................................................................................86
17.1.
Declaration of Helsinki...............................................................................................86
17.2.
Ethics Committee........................................................................................................86
17.3.
Subject Information and Consent ...............................................................................87
17.4.
Subject Data Protection ..............................................................................................87
17.5.
Compensation for Injury.............................................................................................88
17.6.
Conflict of Interest......................................................................................................88
17.7.
Registration of Study and Disclosure of Study Results..............................................88
18.
ADMINISTRATIVE PROCEDURES.......................................................................89
18.1.
Study Site Initiation....................................................................................................89
18.2.
Quality Control and Quality Assurance......................................................................89
18.3.
Monitoring of the Study..............................................................................................89
18.4.
Study Funding.............................................................................................................90
18.5.
Publications.................................................................................................................90
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................91
19.1.
External Contract Organizations.................................................................................91


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19.1.1.
Contract Research Organization.................................................................................91
19.1.2.
Interactive Response Technology...............................................................................91
19.1.3.
Electronic Data Capture..............................................................................................91
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................91
19.1.5.
Central Facility for Other Assessments ......................................................................92
19.2.
Study Committees.......................................................................................................92
19.2.1.
Independent Data Monitoring Committee..................................................................92
19.3.
Changes to Final Study Protocol ................................................................................92
19.4.
Ethics Committee Notification of Study Completion or Termination........................92
19.5.
Retention of Study Data..............................................................................................92
19.6.
Study Report Signatory...............................................................................................93
20.
REFERENCES ...........................................................................................................94
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................98


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LIST OF TABLES
23
24
Table 3:
Schedule of Activities – Screening.............................................................................27
Table 4:
Schedule of Activities – Placebo-Controlled Treatment and Safety 
Follow-Up...................................................................................................................30
35
Table 6:
Study Objectives and Endpoints.................................................................................36
LIST OF FIGURES
Figure 1:
Study 263CS201 Schematic .......................................................................................39


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1.
SYNOPSIS
Protocol Title:
A Phase 2, Randomized, Double-Blind, Multiple-Dose, Placebo-
Controlled Study to Evaluate the Safety and Efficacy of BIIB104 in 
Subjects With Cognitive Impairment Associated With Schizophrenia 
(CIAS)
Protocol Number:
263CS201
Version Number:
4
Name of Study 
Treatment:
BIIB104
Study Phase:
2
Study Indication:
Cognitive impairment associated with schizophrenia
Study Rationale:
This Phase 2 study is being conducted to evaluate the safety and 
efficacy of BIIB104 (0.15 and 0.5 mg doses) administered orally, twice 
daily (BID), for 12 weeks in subjects with CIAS who are receiving 
antipsychotic background therapy. 
Rationale for 
Starting Dose and 
Maximum 
Exposure:
A maximum dose of BIIB104 0.5 mg administered BID was chosen to 
provide exposure within the expected clinically relevant range with 
mean concentration levels not exceeding stopping limits set for this 
study. After correction for species differences in plasma protein 
binding and the safety factor, BIIB104 exposure limits are 8.1 ng/mL 
for mean Cmax and 122 ng•h/mL for mean AUC24. This is based on the 
no observed adverse effect level (NOAEL) for convulsions in the rat, 
the most sensitive nonclinical species, which is 5× (unbound 
Cmax-based) the human mean Cmax of 8.1 ng/mL. In addition, the 
NOAEL for intercostal muscle degeneration/regeneration in the rat is 
1× (unbound AUC-based) the human mean AUC24 of 122 ng•h/mL.
The BIIB104 maximum exposure at steady state (Cmax,ss) and AUC24,ss
from the top dosing regimen (7.47 ng/mL and 89.5 ng × h/mL) are 
expected to be in the exposures that have been previously shown to be 
safe and well tolerated in schizophrenia patients, with approximately 
90% of subjects having minimum exposure at steady state (Cmin,ss) 
equivalent to or greater than predicted clinically efficacious total 
plasma concentration (Ceff) [2.3 ng/mL]. To minimize the overlap in 
exposure and allow identification of the minimum efficacious dose, a 
0.15 mg BID dose was also selected. At steady state, the mean Cmax,ss


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from the low dose is expected to be equivalent to Ceff, and within the 
clinically relevant range.
Study Objectives 
and Endpoints:
The primary objective of the study is to evaluate the efficacy of 
BIIB104 in subjects with CIAS using the Working Memory Domain of 
the MATRICS Consensus Cognitive Battery (MCCB). 
The primary endpoint that relates to this objective is the change from 
baseline in the MCCB Working Memory Domain score to Week 12.
Secondary objectives are as follows: 

To evaluate the safety and tolerability of BIIB104 in 
subjects with CIAS.

To evaluate the efficacy of BIIB104 in subjects with CIAS 
on measures of cognition, functioning, and psychiatric 
symptomology, as measured by:

University of California, San Diego Performance Based 
Skills Assessment–Brief, international version 
(UPSA-Bi)

Schizophrenia Cognition Rating Scale (SCoRS) 

MCCB

Structured Clinical Interview Positive and Negative 
Syndrome Scale (SCI-PANSS) 

Clinical Global Impression–Severity (CGI-S) and 
Clinical Global Impression–Improvement (CGI-I) 
Secondary endpoints are as follows:

Incidence of adverse events (AEs) and serious adverse 
events (SAEs) reported during the study, Scale for the 
Assessment and Rating of Ataxia (SARA), Columbia
Suicide Severity Rating Scale (C-SSRS)

Change from baseline in UPSA-Bi to Week 12

Change from baseline in SCoRS to Week 12

Change from baseline in MCCB Composite scores and 
Individual Domain scores (excluding Working Memory 
Domain) to Week 12


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
Change from baseline in SCI-PANSS total score and 
subscale scores to Week 12 

Change from baseline in CGI-S to Week 12 

CGI-I at Week 12
Study Design:
This is a Phase 2, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the safety, tolerability, and efficacy of 
BIIB104 in subjects with CIAS.
Treatment Groups:
Subjects will be randomized in a 1:1:1 ratio into 1 of 3 treatment 
groups. The randomization will be stratified by region. 

Placebo group: Up to 73 subjects to receive oral dosing BID 
with placebo for 12 weeks.

BIIB104 0.15 mg group: Up to 73 subjects to receive oral 
dosing BID with BIIB104 0.15 mg for 12 weeks.

BIIB104 0.5 mg group: Up to 73 subjects to receive oral 
dosing BID with BIIB104 0.5 mg for 12 weeks.
Study Location:
This study will be conducted at approximately 80 sites globally.
Number of 
Planned Subjects:
Approximately 219 subjects are planned to be enrolled, randomized, 
and dosed in this study.
Study Population:
This study will be conducted in subjects from age 18 to 55 years, 
inclusive, with a Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition, diagnosis of schizophrenia of at least 2 years’ 
duration as confirmed by the Mini-International Neuropsychiatric 
Interview (MINI) Version 7.0.2 for Psychotic Disorders. Subjects must 
have stable disease (e.g., no hospitalizations or worsening symptoms) 
for at least 12 weeks prior to randomization and must not have any 
other significant psychiatric comorbid diagnoses. Subjects must also be 
receiving ongoing maintenance atypical antipsychotic therapy for at 
least 8 weeks prior to randomization.
Detailed criteria are described in Section 8.
Duration of 
Treatment and 
Follow-up:
The maximum total duration of study participation for each subject will 
be approximately 19 weeks, including a screening phase of 
approximately 5 weeks, a treatment phase of approximately 12 weeks, 


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and a safety follow-up phase of approximately 2 weeks.
Sample Size 
Determination:
Fifty-one subjects per treatment group will have approximately 
80% power to detect a true mean difference of 3.5 in change from 
baseline MCCB Working Memory Domain score to Week 12 between 
the treatment and placebo groups. With an assumed drop-out rate of 
30%, 73 subjects are required from each group to maintain the 80% 
power. This power calculation is based on a 2-sided t-test assuming 
equal variance with a final significance level of 0.1, and a standard 
deviation (SD) of 7. The statistical software EAST 6.3® is used for 
sample size calculation. The sample size may be re-estimated based on 
blinded data review and evolving development of this study.
Statistical 
Methods:
Continuous variables will be summarized using descriptive statistics 
(number of subjects [n], mean, standard deviation, median, minimum, 
and maximum) by treatment group, and categorical variables will be 
presented using frequency distributions by timepoint and treatment 
group. Point estimates and 90% CIs will be provided where applicable.
The primary endpoint is the change in MCCB Working Memory 
Domain score from baseline to Week 12. A mixed model repeated 
measures (MMRM) model will be used as the primary analysis to 
analyze change from baseline in MCCB Working Memory Domain 
score using fixed effects of treatment, visit, treatment-by-visit 
interaction, baseline Working Memory Domain score, baseline 
Working Memory Domain score by visit interaction, and region.
The secondary endpoints are defined in Table 6. The population for the 
analysis will be subjects in the intent-to-treat (ITT) population with a 
baseline and at least 1 postbaseline value. For all continuous endpoints, 
an MMRM model will be used to analyze change from baseline to the 
Week 12 Visit using fixed effects of treatment, visit, treatment-by-visit 
interaction, baseline, baseline-by-visit interaction, and region. 
Sensitivity analyses based on different missing mechanisms will also 
be performed (imputation methods are defined in the statistical analysis 
plan).
 The endpoints will be 
summarized by MMRM model, as well as reported by standard 
descriptive statistics.


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2.
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine transaminase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
AMPAR
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
AST
aspartate transaminase
AUC
area under the plasma drug concentration-time curve
AUC24
area under the plasma drug concentration-time curve from 0 to 24 hours
AUCinf
area under the plasma drug concentration-time curve from 0 to infinity
AUClast
area under the plasma drug concentration-time curve from 0 to the time of 
last measurement
AUCtau
area under the concentration-time curve within a dosing interval
BID
twice daily
BUN
blood urea nitrogen
CGI-I
Global Clinical Impression–Improvement
CGI-S
Global Clinical Impression–Severity
CIAS
cognitive impairment associated with schizophrenia
Cb,u
unbound brain drug concentration
Ceff
efficacious plasma drug concentration
Cmax
maximum observed plasma concentration
Cmin
minimum plasma drug concentration
CNS
central nervous system
CRF
case report form
CSF
cerebrospinal fluid
Css,av
average steady-state drug plasma concentration
C-SSRS
Columbia Suicide Severity Rating Scale
CV
coefficient of variation
CYP
cytochrome P450 
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EQ-VAS
EuroQol-Visual Analog Scale
ET
early termination


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FDG
2-deoxy-2-[18F]fluoro-D-glucose
fMRI
functional magnetic resonance imaging
HBsAg
hepatitis B surface antigen 
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
ID
identification
IDMC
independent data monitoring committee
IQ
intelligence quotient
IRB
institutional review board
IRT
interactive response technology
ITT
intent to treat
MAD
multiple ascending dose
MAR
missing at random
MATRICS
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia
MCCB
MATRICS Consensus Cognitive Battery
MGH
Massachusetts General Hospital
MHP
mental health professional
MINI
Mini-International Neuropsychiatric Interview for Psychotic Disorders
MMRM
mixed model repeated measures 
MTD
maximum tolerated dose
NMDA
N-methyl-D-aspartate
NMDAR
N-methyl-D-aspartate receptor
NOAEL
no observable adverse effect level
NOEL
no observable effect level
NPI
Neuropsychiatric Inventory
PD
pharmacodynamics
PK
pharmacokinetics
QD
once daily
QTcF
QT interval corrected for heart rate using Fridericia’s correction
RNA
ribonucleic acid
SAE
serious adverse event
SAFER 
(criteria)
State versus trait, Accessibility, Face validity, Ecological validity, Rule of 3 
Ps (pervasive, persistent, and pathological)
SAP
statistical analysis plan
SARA
Scale for the Assessment and Rating of Ataxia
SCI-PANSS
Structured Clinical Interview for Positive and Negative Syndrome Scale
SCID
Structured Clinical Interview for DSM disorders
SCoRS
Schizophrenia Cognition Rating Scale


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SD
standard deviation
SFU
safety follow-up
SM
safety margin
TID
3 times daily
UCSD
University of California, San Diego
ULN
upper limit of normal
UPSA-Bi
UCSD Performance-Based Skills Assessment – Brief, international version


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3.
SPONSOR INFORMATION
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
Biogen Japan Ltd. 
Nihonbashi 1-chome 
Mitsui Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku, Tokyo 
103-0027 Japan
For urgent medical issues in which the study Medical Director should be contacted, please refer 
to the Study Reference Manual’s Official Study Contact List for complete contact information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities.


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4.
INTRODUCTION 
BIIB104 (formerly known as PF-04958242 under the previous Sponsor, Pfizer Inc.) is a positive 
allosteric modulator (potentiator) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
receptor (AMPAR) that represents a mechanistically novel approach to the treatment of cognitive 
impairment associated with schizophrenia (CIAS).
BIIB104 has been safe and well tolerated in the approximately 300 subjects exposed to date, with 
no serious adverse events (SAEs) or severe adverse events (AEs). A maximum tolerated dose 
(MTD) has not been achieved in the 11 completed clinical studies (conducted by Pfizer Inc.) in 
healthy volunteers, subjects with schizophrenia, and older subjects (55 to 75 years old, inclusive) 
with presbycusis. BIIB104 has been evaluated at exposures up to its current clinical cap of mean 
total maximum observed plasma concentration (Cmax) of 8.1 ng/mL, or one-fifth the no observed 
effect level (NOEL).
BIIB104 has demonstrated pharmacological activity both functionally (via a functional magnetic 
resonance imaging [fMRI]-detected reduction in activity in the left inferior parietal cortex of 
healthy subjects undergoing a cognitive task [Study B1701003]) and behaviorally (via an 
approximate 20% attenuation of ketamine-mediated disruptions in verbal learning performance 
in healthy subjects [Study B1701013]). Most recently, exploratory efficacy data in Study 
B1701017 (multiple ascending dose [MAD]) demonstrated a statistically significant 
improvement on the MATRICS Consensus Cognitive Battery (MCCB) Working Memory 
Domain after 2 weeks of dosing (0.475 mg twice daily [BID]) in subjects with schizophrenia. 
These results are supported by a statistically significant relationship between average plasma 
BIIB104 concentration at steady state (Cav,ss) and MCCB Working Memory Domain (change 
from baseline to Day 14) observed in Studies B1701017 and B1701004 (MAD in subjects with 
schizophrenia). 
Together, these data, which are consistent with the hypothesized and preclinical effects of 
BIIB104, suggest the potential effectiveness of BIIB104 to improve cognitive function in 
subjects with CIAS.
4.1.
Schizophrenia and Cognitive Defects 
Schizophrenia is a chronic, highly debilitating psychiatric disorder with a point prevalence 
worldwide ranging from 2.7 to 8.3 per 1000 population [Eaton and Chen 2006]. Schizophrenia 
includes positive symptoms (hallucinations, paranoia, delusions), negative symptoms (apathy, 
alogia, affective flattening), and cognitive symptoms (deficits in memory, attention, executive 
function) [Javitt and Laruelle 2006]. At an individual level, almost all patients with 
schizophrenia have cognitive impairments relative to what would be expected had they never 
developed schizophrenia [Kremen 2000]. Impaired cognition is now seen as a feature of 
schizophrenia that precedes, accompanies, and then outlasts a patient’s symptoms and medical 
regimen [Heinrichs 2005]. Measurable deficits in thought and language, perception, memory, 
and attention appear in vulnerable children long before psychosis appears [Erlenmeyer-Kimling 


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2000]. Patients experiencing their first psychotic episodes are cognitively impaired, and this 
impairment is relatively stable over time [Albus 2002]. Studies suggest little or no relation 
between symptoms and cognitive performance early in the illness, and cognitive deficits remain 
when symptoms remit in response to treatment [Hughes 2003; Rund 2004]. Thus, neurocognitive 
deficits do not correlate with positive symptom severity and only modestly correlate with 
negative symptom severity (r=0.13-0.27) [Keefe 2006].
Effective treatment of cognitive deficits in schizophrenia remains a critical unmet medical need. 
Current antipsychotic treatments most effectively treat positive symptoms, modestly improve 
negative symptoms, and have little to no effect on the cognitive deficits [Keefe 2007; Stroup 
2006]. Effective treatment of cognitive deficits would enable patients with schizophrenia to live 
more fulfilling and productive lives in society. 
4.1.1.
AMPA Receptors and Cognition
BIIB104 is a potent and highly selective AMPAR positive allosteric modulator (i.e., AMPAR 
potentiator) that represents a mechanistically novel approach to the treatment of CIAS. In 
response to glutamate, postsynaptic AMPARs produce a rapid membrane depolarization that 
removes the magnesium block from colocalized N-methyl-D-aspartate (NMDA) receptor-gated 
ion channels and allows calcium influx into the cell [Malinow and Malenka 2002]. The resulting 
intracellular cascade activates kinases and transcription factors, which induce long-term 
potentiation and gene expression [Pláteník 2000]. This process, which produces changes in 
synaptic morphology and strength, is believed to underlie learning and memory [Bliss and 
Collingridge 1993]. Pharmacologic NMDAR antagonism in healthy humans [Krystal 1994], as 
well as genetic manipulation of NMDAR in rodents [Mohn 1999], produce cognitive impairment 
and behavioral effects suggestive of schizophrenia. High-impact AMPAR potentiators, including 
BIIB104, have been found to significantly attenuate the NMDAR antagonist-induced cognitive 
disruptions in these preclinical [Kiss 2013; Roberts 2010; Shaffer 2018; Shaffer 2013; Shaffer 
2015] and clinical [Ranganathan 2017; Shaffer 2018] models. Furthermore, postmortem studies 
have found decreased hippocampal AMPAR density in patients with schizophrenia versus 
age-matched controls, suggesting some of the strongest evidence for dysregulation of 
glutamatergic transmission in schizophrenia [Meador-Woodruff and Healy 2000].
Unlike orthosteric agonists, AMPAR potentiators lack intrinsic activity. However, in the 
presence of glutamate, they augment agonism by modulating the biophysical properties of the 
receptor. It has been demonstrated that AMPAR potentiators binding at different allosteric sites 
can attenuate either receptor deactivation (increasing synaptic current amplitude) or both 
receptor deactivation and desensitization (increasing and prolonging synaptic current). 
Distinctive modes of allosteric activation are possible as indicated by experiments demonstrating 
that potentiators can differentially affect receptor deactivation and desensitization to enhance 
receptor signaling [Partin 1996].
A diverse array of chemotypes, distinguished by their receptor interactions, have been reported 
to potentiate AMPARs [Grove 2010]. One group of compounds, characterized by the 
benzamides (e.g., CX516, CX717, and farampator [Org24448, CX691]) and benzothiadiazines 
(e.g., S18986) [Rosi 2004], attenuate receptor deactivation with minimal-to-modest effects on 


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receptor desensitization to afford increased amplitude in AMPAR-mediated synaptic currents. 
These are known as low-impact compounds. Another group of potentiators, exemplified by the 
biarylpropylsulfonamides (e.g., LY450108 and LY451395) [Jhee 2006] and aminoindane 
sulfonamides (e.g., GSK729327) [Ward 2011], impede receptor deactivation and desensitization 
that increases both the amplitude and duration of AMPAR-mediated synaptic currents. Such 
compounds are classified as high-impact compounds. Based on its common allosteric binding 
site with biarylpropylsulfonamides like LY451395, along with its electrophysiological 
properties, BIIB104 is considered a high-impact AMPAR potentiator.
4.1.2.
AMPA Potentiators in Clinical Trials
Numerous AMPAR potentiators have been evaluated in humans. The low-impact potentiator 
CX516, has undergone both small and large clinical trials for its procognitive potential in 
schizophrenia patients stabilized on concomitant antipsychotics (900 mg three times daily [TID] 
for 4 weeks) [Goff 2001], in healthy young and elderly subjects [Lynch 1997; Lynch 1996] and 
in patients with Fragile-X Syndrome (600 mg TID for 1 week + 900 mg TID for 3 weeks) 
[Berry-Kravis 2006]. Although safe and well-tolerated in these populations, a Phase 2 study of 
adjunctive therapy in 105 schizophrenic patients (4 weeks of treatment) with CX516 added to 
clozapine (N = 52), olanzapine (N = 40), or risperidone (N = 13) found no difference from 
placebo on a composite cognitive score or any cognitive test after 4 weeks or 8 weeks (i.e., 
4 weeks after end of treatment) [Goff 2008]. While site methodology was a potential problem 
(e.g., small size, inadequate dosing duration and/or regimen, potential cognitive battery 
insensitivity), it should be noted that CX516 is a “low-impact” AMPAR potentiator with a short 
pharmacokinetic (PK) half-life, which likely also addresses these negative CIAS findings. Single 
doses of the low-impact potentiator CX717 (300-1,000 mg) have been reported to increase 
wakefulness and improve performance in sleep-deprived male healthy subjects. CX717 (800 mg 
twice daily [BID] for 4 weeks) was also reported to be significantly more effective versus 
placebo on the total Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale (p=0.0024) 
and on both the hyperactivity (p=0.0168) and inattentiveness (p=0.0273) subscales [Cortex 
2006]. CX717 was shown to be efficacious in treating drug induced respiratory depression 
caused by opioids or certain anesthetics [Business Wire 2008]. In a small clinical trial, a single 
dose (500 mg) of the low-impact potentiator farampator (Org24448, CX691) improved 
short-term memory, but impaired episodic memory in elderly subjects [Wezenberg 2007].
More recently, numerous clinical trials have occurred with high-impact AMPAR potentiators. 
For example, both single (0.25 to 6 mg) and multiple (0.1 mg once daily [QD] for 28 days) doses 
of GSK729327 were well tolerated in healthy subjects, with no safety issues raised or 
withdrawals due to AEs [Ward 2011]. Similarly, the high-impact potentiators LY450108 (8 to 
30 mg BID for 3 days) and LY451395 (5 to 18 mg BID for 3 days) were studied in patients with 
probable Alzheimer’s disease [Jhee 2002]. LY450108 was well tolerated at 30 mg BID with 
dizziness being the most frequent AE; no MTD was determined. LY451395 was well tolerated 
up to 12 mg BID, but dizziness and nervousness were dose limiting at 15 and 18 mg BID; 15 mg 
BID was deemed the MTD. Subsequently, the steady-state plasma and cerebrospinal fluid (CSF) 
concentrations of LY450108 and LY451395 (both at 1 and 5 mg BID for 6 to 8 days) were 
determined in healthy subjects [Jhee 2006]. All doses were found to be safe and well tolerated in 
healthy subjects, and both drugs had equivalent unbound plasma and CSF concentrations at 














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5.
SCHEDULES OF ACTIVITIES
Study activities for the Screening and Treatment Periods are presented in Table 3 and Table 4, 
respectively. 
The Investigator may schedule visits (unplanned visits) in addition to those listed on the schedule 
of activities, in order to conduct evaluations or assessments required to protect the well-being of 
the subject.
Table 3:
Schedule of Activities – Screening 
Study Phase:
Screening 
Protocol Activity
Screening Visit 1 
(Day -35 to Day -8)1       
Screening Visit 2       
Placebo Lead-In
(7-day Placebo Lead-In 
must begin between     Day
-9 and Day -7, inclusive)14
Informed Consent Form
X
Informant Consent Form2
X
Validated Reading Test 
X
Demographics  
X
Site Inclusion/Exclusion Criteria Verification
X----------------------------------------------------------------
Sponsor Inclusion/Exclusion Criteria 
Verification and Confirmation3
X----------------------------------------------------------------
Independent Telemedicine Review 
(SAFER)4
X
Medical, Neurological, Psychiatric, and 
Medication History
X
MINI 7.0.2 Diagnostic Interview
X
SCI-PANSS1
X
C-SSRS5, 6
X
X
Study Guidelines Review7
X
X
Contraception Check8
X
X
Concomitant Psychiatric Medication Check6
X
X
Height6
X
Weight6
X
Full Physical and Neurological 
X






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Table 4:
Schedule of Activities – Placebo-Controlled Treatment and Safety Follow-Up
Study Phase:
Baseline
Treatment
SFU
Protocol Activity
Day 11
Week 1/   
Day 82
Week 2/    
Day 151, 2
Week 4/   
Day 292
Week 6/    
Day 431, 2
Week 8/   
Day 572
Week10
/ Day 
712
Week 12/ 
Day 851, 2
/ET3
14 Days 
After
Last 
Dose2
Inclusion/Exclusion Criteria 
Review
X4
Randomization
X
Medical, Neurological, 
Psychiatric, and Medication 
History
X
C-SSRS5, 6
X
X
X
X
X
X
X
X
X
Study Guidelines Review7
X
X
X
X
X
X
X
X
Contraception Check8
X
X
X
X
X
X
X
X
Concomitant Psychiatric 
Medication Check
X
X
X
X
X
X
X
X
X
Weight6
X
X
X
X
X
X
Full Physical and Neurological 
Examination6
X
Brief Physical and Neurological 
Examination6
X9, 10
X10
X
X
X
SARA6
X9, 10
X10
X
X
X
X
12-Lead ECG6
X10
X10
X
X
X
X
X
12-Lead ECG, Triplicate6
X








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However, the 
 assessments must be administered on the same day as their respective immediate recall 
assessments (contained in MCCB). The same rater should administer these assessments whenever possible. See the Study Reference Manual for 
additional information.
16 The informant will provide input for completing study rating scales (e.g., Informant Questionnaire for PANSS, SCoRS). This may be performed 
remotely (i.e., by phone) after the Screening Visit. See Table 3 and the Study Reference Manual for information about informant consent and 
interview.
17 CGI-S and CGI-I scales should be rated after all other study efficacy assessments are completed. The same rater should administer these 
assessments whenever possible.
18 Study treatment is to be dispensed after all visit assessments have been completed. The first dose of study treatment will be supervised by the 
site staff at the Baseline/Day 1 Visit. Study treatment will be administered BID over the course of the study. Antipsychotic background 
medication will not be administered or provided by the Sponsor or the study site.








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7.
STUDY DESIGN
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the safety, tolerability, and efficacy of BIIB104 in subjects with CIAS. Approximately 219 male 
and female subjects with stable schizophrenia from age 18 to 55 years, inclusive, will be 
recruited. Dosing with BIIB104 0.15 mg BID and 0.5 mg BID versus placebo will be evaluated 
over a treatment phase of 12 weeks. The study will be conducted at approximately 80 sites 
globally. 
The study includes a screening phase, a placebo lead-in phase, a randomized treatment phase, 
and a safety follow-up (SFU) phase to begin after the last dose of study treatment. The primary 
analysis will be conducted after 12 weeks of placebo-controlled treatment.
Screening evaluation will occur up to 35 days prior to randomization. Once eligibility has been 
established, a 7-day Placebo Lead-In evaluation will be conducted to assess the subject’s ability 
to comply with dosing requirements; this evaluation must be completed no earlier than 3 days 
prior to the Baseline/Day 1 Visit. After Sponsor reconfirmation of eligibility and completion of 
baseline measurements at the Baseline/Day 1 Visit, subjects will be randomized in a 1:1:1 ratio 
to receive BIIB104 0.5 mg, BIIB104 0.15 mg, or placebo (planned for 73 subjects per treatment 
group). The randomization will be stratified by region. Subjects will be dosed at approximately 
12-hour intervals for approximately 12 weeks. Total duration of subject participation will be 
approximately 19 weeks from screening to final follow-up visit.
See Figure 1 for a schematic presentation of the study design.




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7.1.
Study Duration for Subjects
The maximum total duration of study participation for each subject will be approximately 
19 weeks including a screening phase of approximately 5 weeks, a treatment phase of 
approximately 12 weeks, and a safety follow-up phase of approximately 2 weeks.
The end of study date for a subject may be the last study visit, last follow-up telephone 
conversation, or last protocol-specified assessment. If the subject has ongoing AEs that are being 
followed, the end of study date may be the date of AE resolution.
7.2.
Rater Qualifications
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
subjects in this study. The minimum qualifications a rater must meet for each study rating 
assessment will be outlined in the Study Reference Manual. It is recommended that, whenever 
possible, subjects and informants be interviewed and assessed throughout the study by the same 
rater. Reasons for changes in certified raters should be documented in the source. The Study 
Reference Manual provides a detailed description of specific study assessment information.
7.3.
Study Stopping Rules
The Sponsor can terminate this study, after informing the Investigator, at any time. The 
Investigator will be notified by the Sponsor if the study is placed on hold, completed, or closed.
Stopping criteria for a seizure event are as follows:

The study may be stopped if 1 subject experiences a seizure (postdosing and 
confirmed following unblinding to be on active study treatment), with a diagnosis of 
seizure confirmed by an independent panel of neurologists where no other cause has 
been identified. The process is described as follows: 

If any subject has a suspected seizure event, individual dosing will be stopped 
immediately. 

All available information regarding the seizure event including a Diagnostic 
Interview for Seizure Identification form will be provided to an independent panel 
of neurologists for review and adjudication as to the diagnosis and the possible 
relationship to the blinded study treatment.

The Sponsor will provide the outcome of the adjudication to the Independent Data 
Monitoring Committee (IDMC). If the IDMC recommends terminating the study, 
the Sponsor will unblind the treatment allocation for the subject who experienced 
the seizure. The study may be terminated by the Sponsor on recommendation of 
the IDMC. 


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The Sponsor and the IDMC will review safety data on an ongoing basis. The study may be 
modified or terminated based on recommendation of the IDMC or at the discretion of the 
Sponsor.
7.4.
End of Study
The end of study is last subject, last visit.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of randomization, or at the timepoint specified in the individual eligibility criterion 
listed:
1. Evidence of a personally signed and dated informed consent document at the time of 
Screening indicating that the subject has been informed of all pertinent aspects of the 
study.
2. Evidence of a personally signed and dated informed consent for the informant indicating 
the informant has been informed of all pertinent aspects of the study. Informant consent 
must be signed prior to the in-person informant interview conducted during Screening.
3. Otherwise healthy male and/or female subjects from age 18 to 55 years, inclusive, with a 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), diagnosis 
of schizophrenia of at least 2 years duration as confirmed by the MINI 7.0.2 for Psychotic 
Disorders. The MINI 7.0.2 for Psychotic Disorders will also be used to exclude comorbid 
diagnoses. In addition, diagnosis of schizophrenia must be deemed “valid” by remote, 
independent raters using prespecified criteria (see Section 9.1.1.3).
4. Evidence of stable schizophrenia symptomatology ≥12 weeks (e.g., no hospitalizations 
for schizophrenia, no increase in level of psychiatric care due to worsening of 
schizophrenia symptoms). 
5. Subjects must be receiving ongoing maintenance atypical antipsychotic therapy (except 
clozapine), on a stable treatment regimen for ≥8 weeks prior to Baseline/Day 1, including 
concomitant psychiatric medications. Doses of background atypical antipsychotics should
be within the recommended dose range listed in the approved product labeling of the 
country where the study is being conducted. Doses exceeding the recommended dose 
range are not permitted and doses below the recommended dose range should be 
discussed with the Sponsor's Medical Monitor (see Section 11.4.1).

Treatment regimen stability is defined as maintaining the same dosage of 
treatments except for minor adjustments (≤25%) to manage medication-specific 
tolerability issues. Recognizing that physicians outside of the study may be 
managing the subject’s background antipsychotic and other psychiatric 
medications, changes in background antipsychotic and psychiatric medications 
should be discussed with the Sponsor’s Medical Monitor.

Stable concomitant treatment with a second atypical antipsychotic, at doses that 
do not exceed the range listed in the approved product labeling of the country 
where the study is being conducted, is permissible if used for a targeted symptom 


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(e.g., insomnia) or an adverse effect from the primary maintenance antipsychotic 
treatment, but not if it is used for refractory psychotic symptoms. Treatment 
regimen stability as defined above applies to the second antipsychotic. Subjects 
should be taking no more than 2 background antipsychotics.

Note that hypnotics are an exception to the treatment regimen stability 
requirement; prohibited hypnotics may be substituted with allowed hypnotics 
administered as described in Section 11.4.1.
6. Must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
7. Must have an identified informant (e.g., family member, social worker, caseworker, or 
nurse who interacts [in person or by telephone] with the subject at least 2 times per week) 
who should, whenever possible, be consistent throughout the study and considered 
reliable by the Investigator.
8. Must reside in a stable living situation, in the opinion of the Investigator, for at least 
12 weeks prior to Screening and be expected to remain in a stable living situation for the 
duration of the study. 
9. Must have oral fluency in the test language confirmed by a standard score of ≥70 at 
Screening on a validated reading assessment test (please refer to the Study Reference 
Manual for appropriate reading test). Non-native speakers of the test language must have 
at least 7 years of formal education in this language.
10. All women of childbearing potential and all men must practice highly effective 
contraception during the study and for at least 30 days after the last dose of study 
treatment. For further details of contraceptive requirements for this study, refer to 
Section 15.5.
11. Body mass index of 17.5 to 45.0 kg/m2 and total body weight >50 kg (110 lb). Subjects 
with a BMI >40.5 kg/m2 must be discussed with the Sponsor’s Medical Monitor to 
determine subject eligibility.
12. SCI-PANSS: No more than moderate-severe rating (score ≤5) on delusions, hallucinatory 
behavior, grandiosity, suspiciousness/persecution, and hostility (i.e., PANSS, positive 
symptom items P1, P3, P5, P6, P7), or unusual thought content (G9); and no more than a 
moderate rating (score ≤4) on conceptual disorganization (P2). 
13. At least 80% dosing regimen compliance during the Placebo Lead-In period. 


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8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening, or at the timepoint specified in the individual criterion as listed:
1. Individuals who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
Investigator, or Sponsor employees directly involved in the conduct of the study.
2. Participation in other studies involving treatment with an investigational drug within 
30 days or 5 half-lives (whichever is longer) prior to randomization and/or during study 
participation.
3. Participation in a trial that uses any component or version of the MCCB or the UCSD 
Performance-Based Skills Assessment test within the previous 6 months. 
4. Participation in cognitive remediation therapy within 6 months prior to randomization.
5. Participation in ongoing cognitive behavioral therapy that was initiated <8 weeks prior to 
Baseline/Day 1.
6. Screening MCCB Working Memory Domain T-score ≥60.
7. Current DSM-5 diagnosis of schizoaffective disorder on the MINI 7.0.2 for Psychotic 
Disorders. 
8. Current DSM-5 diagnosis of major depressive episode, manic and hypomanic episode, 
panic disorder, agoraphobia, social anxiety disorder, obsessive-compulsive disorder, 
post-traumatic stress disorder, and/or generalized anxiety disorder on the MINI 7.0.2 for 
Psychotic Disorders.
9. Lifetime DSM-5 diagnosis of antisocial personality disorder, anorexia nervosa, bulimia 
nervosa, and/or binge-eating disorder on the MINI 7.0.2 for Psychotic Disorders. 
10. Meets the DSM-5 diagnosis of moderate or severe substance use disorder (excluding 
nicotine dependence) within 12 months of screening on the MINI 7.0.2 for Psychotic 
Disorders interview.
11. DSM-5 diagnosis of Intellectual Disability (intellectual developmental disorder).
12. 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 that 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.
13. Pregnant or breastfeeding female subjects; male subjects with partners who are currently 
pregnant.


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14. Evidence or history of current clinically significant hematological, renal, endocrine 
(excluding adequately controlled hypothyroidism or hyperthyroidism), pulmonary 
(excluding chronic bronchitis, mild emphysema or chronic obstructive pulmonary 
disease), gastrointestinal (including conditions that can affect drug absorption, e.g., 
gastrectomy), oncological, dermatological, immunological disease, as determined by the 
Investigator in discussion with the Sponsor. Medical conditions not specifically 
addressed in this section may be discussed with the Sponsor’s Medical Monitor to 
determine subject eligibility. Note that controlled type 2 diabetes (HbA1c ≤7%) will not 
be considered a significant medical illness and will not exclude subjects from the study; 
type 1 diabetes is exclusionary.
15. Evidence or history of current clinically significant cardiovascular disease, including 
uncontrolled hypertension (standing or supine diastolic pressure >95 mmHg and/or 
standing or supine systolic pressure >170 mmHg with or without treatment); ischemic 
heart disease; or uncompensated heart failure, acute myocardial infarction, bypass 
surgery within 6 months of screening. Controlled essential hypertension and nonclinically 
significant sinus bradycardia and sinus tachycardia will not be considered significant 
medical illnesses and would not exclude a subject from the study.
16. History of seizures or of a condition with risk of seizures; as an exception, a history of 
1 febrile seizure in childhood will not exclude a subject from the study.
17. Lifetime history of head injury with clinically significant sequelae (e.g., loss of 
consciousness for >15 minutes).
18. History of hyponatremia, syndrome of inappropriate antidiuretic hormone secretion or 
psychogenic polydipsia.
19. Treatment with electroconvulsive therapy within the 6 months prior to randomization.
20. History of neuroleptic malignant syndrome as determined by the Principal Investigator 
with consultation from the Sponsor.
21. Significant extrapyramidal symptoms that have not been stabilized with anticholinergics.
22. Onset of schizophrenia symptoms prior to age 12.
23. Positive urine drug screen for illicit drugs or drugs that cannot be explained by prescribed 
treatments (however, it should be noted that marijuana is prohibited whether prescribed 
or recreational).
24. Use of prohibited treatments (see Section 11.4.1) and inability to discontinue these 
concomitant treatments after the Screening Visit. These treatments must be discontinued 
(or tapered if medically indicated) for a minimum of 5 half-lives prior to randomization at 
the Baseline/Day 1 Visit. Note that psychiatric medications (excluding psychiatric 
medications prescribed for non-psychiatric conditions and hypnotics) cannot be 


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discontinued to address this criterion due to the treatment regimen stability requirements 
listed in inclusion criterion 5, above.
25. Use of concomitant treatment that can impair cognition, (e.g., centrally acting 
antihistamines) as determined by the Investigator in consultation with the Sponsor.
26. Use of concomitant treatment with a significant risk associated with seizures (see 
Section 11.4.1).
27. Use of typical antipsychotic treatments, including prochlorperazine, haloperidol, 
loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine, trifluoperazine, 
chlorpromazine, and perphenazine. This list is not all inclusive; the Investigator should 
discuss the use of any concomitant treatment associated with typical antipsychotic 
treatments with the Sponsor’s Medical Monitor prior to randomizing a subject.
28. Use of off-label treatments for schizophrenia (including, but not limited to, donepezil and 
modafinil).
29. Screening laboratory test results that deviate from the upper or lower limits of the 
reference range, except for nonclinically significant values, as determined by the 
Investigator in consultation with the Sponsor’s Medical Monitor, including the following:

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be 
≤2 times the upper limit of reference range, and total bilirubin must be ≤1.5 times the 
upper limit of the reference range at screening.

Impaired renal function at screening (e.g., repeated values of creatinine and blood 
urea nitrogen [BUN] ≥1.5 × upper limit of normal (ULN) or estimated glomerular 
filtration rate [GFR] <45 mL/min/1.73 m2 and corroborating medical history and 
physical examination). See the Study Laboratory Manual for details of GFR 
calculation. 
30. Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] 
and/or total hepatitis B core antibody [anti-HBc]). Subjects with immunity to hepatitis B 
from previous natural infection (defined as negative HBsAg, positive anti-HBc, and 
positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative 
HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
31. Current hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody and 
detectable HCV ribonucleic acid [RNA]). Subjects with positive HCV antibody and 
undetectable HCV RNA are eligible to participate in the study (United States Centers for 
Disease Control and Prevention).
32. History of or positive test result at Screening for human immunodeficiency virus (HIV). 
The requirement for testing at screening may be omitted if it is not permitted by local 
regulations.


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33. History of regular alcohol consumption exceeding 7 drinks/week for females or 
14 drinks/week for males (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of
beer or 1.5 ounces [45 mL] of hard liquor) within 6 months of screening.
34. Use of tobacco- or nicotine-containing products in excess of the equivalent of 
40 cigarettes per day.
35. Triplicate 12-lead ECGs demonstrating average QTcF >450 msec for men and 
>470 msec for women or an average QRS interval >120 msec at the Screening or 
Baseline /Day 1 Visit. 
36. History of risk factors of QT prolongation or torsades de pointes (e.g., heart disease, 
congestive heart failure, hypokalemia, hypomagnesaemia, congenital long QT syndrome, 
myocardial ischemia, or infarction), congenital deafness, and family history of sudden 
death before age 60 as determined by the Investigator.
37. Suicide attempt within the last 2 years. Subjects who, in the Investigator’s judgment, pose 
a significant suicide risk, or who have suicidal ideation associated with actual intent and a 
method or plan in the past 6 months (i.e., “Yes” answers on items 4 or 5 of the C-SSRS) 
will be excluded from the study.
38. Evidence or history of current clinically significant medical or psychiatric illness that 
could preclude the subject from completing all aspects of this clinical trial, as determined 
by the Investigator in discussion with the Sponsor.
Subject eligibility should be reviewed and documented in the source documents by an 
appropriately qualified member of the Investigator’s study team before subjects are 
reviewed by the Sponsor for confirmation of eligibility.
8.3.
Lifestyle Guidelines
The following lifestyle guidelines are provided:
8.3.1.
Meals and Diet  
There are no meal or dietary restrictions. Study treatment can be taken with or without food; 
however, subjects should remain fasted for 2 hours before and after taking the dose of study 
treatment associated with 
 
. Time and date of food consumption should be recorded in the source 
documentation if the study treatment is taken at the clinical sites. All 
 are 
dependent on individual subject availability and it will not be considered a protocol deviation if 
the subject is not able to comply with recommended 
.
8.3.2.
Alcohol, Caffeine, and Tobacco
Because the potential for interactions between the study treatment and alcohol have not yet been 
evaluated, subjects are prohibited from consuming alcohol for the duration of the study. Urine 


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drug and alcohol testing is performed at Screening and other timepoints during the study (see 
Table 4). In addition, subjects may undergo an alcohol breath test or blood alcohol test at the 
discretion of the Investigator. Subjects should adhere to their usual regime of caffeine and 
tobacco (to maximum of 40 cigarettes or equivalent per day) as appropriate.
8.3.3.
Activity
Subjects should avoid driving or operating potentially hazardous machinery until it is clear they 
are not experiencing adverse treatment effects that might interfere with their ability to drive or 
operate potentially hazardous machinery.
Subjects will abstain from strenuous exercise (e.g., heavy lifting, weight training, calisthenics,
and aerobics) for at least 48 hours prior to each blood collection for clinical laboratory tests. 
Walking at a normal pace will be permitted.
8.3.4.
Contraception
The Investigator or designee, in consultation with the subject, will confirm that the subject has 
selected an appropriate method of contraception for the individual subject from the permitted list 
of contraception methods (see Section 15.5) and will instruct the subject in its consistent and 
correct use. Subjects need to affirm that they meet the criteria for the correct use of at least 1 of 
the selected methods of contraception. The Investigator or designee will discuss with the subject 
the need for using highly effective contraception consistently and correctly, per the Schedule of 
Activities tables (Section 5) and will document the conversation in the subject’s record. 
Contraception and pregnancy testing requirements must also be consistent with the 
contraception/pregnancy testing guidance for any background antipsychotic medication a subject 
is taking (as stated within their approved product labels). In addition, the Investigator or designee 
will instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or the subject’s partner.


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9.
SCREENING AND RANDOMIZATION
9.1.
Screening
Subjects must provide informed consent before any screening tests are performed (see 
Section 17.3). Participating study sites are required to document all screened candidates initially 
considered for inclusion in the study. 
The interactive response technology (IRT) system will provide the subject identification number 
at the end of the IRT subject screening transaction. This unique subject identification number is 
assigned sequentially to each subject who has signed the informed consent form (ICF). This 
identifying number will be retained throughout the duration of the study participation.
Screen failures are defined as subjects who sign the ICF but are not subsequently randomized. If 
a subject is considered a screen failure, this must be registered in the IRT; the reasons for 
exclusion must be documented in the subject’s source documents and on the screening log. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure subjects to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs. Individuals who do not 
meet the criteria for participation in this study (i.e., a screen failure) may be rescreened at the 
discretion of the Investigator and approval by the Sponsor (see Section 9.3).
Site screening procedures need to be completed within 3 out of 5 consecutive working days from 
the beginning of screening procedures to enable Sponsor Eligibility Verification. At screening, 
the informant interview must be conducted in person; however, the interview does not need to be 
conducted at the study site. The informant interview does not have to occur on the same day as 
the subject interview; however, the informant interview should, wherever possible, be completed 
within 3 days of the relevant subject screening procedures (e.g., SCI-PANSS, SCoRS). The 
Screening Visit should be scheduled as close as possible to when the informed consent is signed 
to allow maximum time for the subject eligibility process.
In order to prevent subject fatigue during assessments, it is acceptable for subjects to take a short 
break between assessments. Screening procedures may be completed over a maximum of 3 out 
of 5 consecutive days for feasibility and subject comfort.
9.1.1.
Screening Assessments
For a list of all screening assessments and procedures, see Table 3. Assessments that are 
conducted at screening and at other timepoints during the study are described in the appropriate 
sections, e.g., Clinical Efficacy Assessments (Section 13.1), Clinical Safety Assessments 
(Section 14.1). Some screening assessments may be recorded (see Study Reference Manual for 
further details). Assessments that are performed only at screening are described below. 


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9.1.1.1.
Validated Reading Test 
A validated reading test can provide an intelligence quotient (IQ) estimate. A standard score of 
≥70 on such an assessment is required for participation in the study.
9.1.1.2.
Mini-International Neuropsychiatric Interview for Psychotic Disorders 7.0.2
The MINI 7.0.2 for Psychotic Disorders is a short, structured diagnostic interview that was 
developed for DSM-5 and International Statistical Classification of Mental and Behavioral 
Disorders, 10th revision (ICD-10) psychiatric disorders and has been validated against the 
Structured Clinical Interview for DSM (SCID) diagnoses. It will be used to assess diagnosis of 
schizophrenia for study inclusion and will also be used to assess for excluded psychiatric 
conditions outlined in the study exclusion criteria.
9.1.1.3.
Independent Telemedicine Interview
Following the initial Screening Visit, a telemedicine interview with an independent research 
interviewer will be performed to confirm that each subject meets criteria for diagnosis of 
schizophrenia. This assessment will be based on the Massachusetts General Hospital (MGH) 
SAFER criteria (State versus trait, Accessibility, Face validity, Ecological validity, Rule of 3 p’s 
[pervasive, persistent, and pathological]) [Desseilles 2013]. The subject’s illness must be deemed 
"valid" according to SAFER criteria in order to participate in the study. 
9.2.
Placebo Lead-In
This study will employ a medication adherence monitoring platform for all subjects in the study. 
The platform uses an application for smart phones to confirm medication ingestion in addition to 
built-in reminders and a communication system that allows real-time intervention in case of drug 
interruptions. See the Study Reference Manual for further description and detailed instructions 
on training for and use of the monitoring platform.
As part of the screening and eligibility process, in order to assess overall compliance with the 
planned dosing regimen and to assess the subject’s ability to operate the monitoring platform, a 
7-day placebo lead-in evaluation will take place after the initial screening is completed (see 
Table 3). A Placebo Lead-In Visit will be scheduled to start the 7-day test, at which time the 
subject will be instructed on the use of the monitoring platform. A 7-day supply of placebo will 
be issued to the subject with instructions for dosing over the test period, which must be 
completed no earlier than 3 days prior to the Baseline/Day 1 Visit. 
At the Baseline/Day 1 Visit, confirmation of compliance will be documented. Compliance during 
the lead-in period is defined as at least 80% of the medication ingested within the allowable time 
frames and recorded using the monitoring platform. 


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9.3.
Subject Rescreening
A subject may be considered for rescreening in this study. As a general rule, depending on the 
timing of rescreening relative to the original screening procedures, the battery of screening safety 
assessments to be repeated will depend on whether these tests were already beyond the 35 days 
from the original screening date. Subjects who are being considered for rescreening by the 
Investigator must be discussed with the Sponsor to identify the subject-specific rescreening 
safety assessments required. Rescreening may be permitted in the case of a temporary condition 
that is expected to resolve.
In the event that repeat safety screening assessments are needed during the screening phase (e.g., 
for misplaced ECG leads or hemolyzed blood sample) that lead to >35 days in the screening 
period (e.g., due to scheduling difficulties), this must be discussed with the sponsor to determine 
subject eligibility to continue in screening. In these scenarios, it will not be considered a protocol 
deviation if the Sponsor and Investigator, following a documented medical review, accept safety 
data that exceeds the 35-day screening window.
9.4.
Subject Eligibility Review
The site will review and document eligibility for the subject in the source document. The site 
will review medical history, prior/concomitant medications, all laboratory tests, pregnancy tests, 
ECGs, and drug test results against inclusion/exclusion criteria. 
9.5.
Sponsor Screening Verification Process
The site will complete a pre-randomization form for subjects who meet the screening 
requirements. This form, along with other pertinent information as part of the eligibility 
assessment, will be submitted to the Sponsor’s Medical Monitor for review and confirmation of 
certain inclusion/exclusion criteria prior to randomization. Randomization may not proceed 
without Sponsor approval.
9.6.
Randomization 
Subjects will be randomized after all screening assessments and placebo lead-in have been 
completed and after the Investigator and the Sponsor have verified that the subjects are eligible 
per criteria in Sections 8.1 and 8.2.
Randomization will be performed using IRT. Randomization will be stratified by region. 
Subjects will be randomized in a 1:1:1 ratio to receive one of the following:

BIIB104 0.15 mg

BIIB104 0.5 mg 

placebo
Refer to the Study Reference Manual for additional details on randomization. 


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9.7.
Blinding Procedures
All study staff will be blinded to the subject treatment assignments. To maintain the study blind, 
it is imperative that subject treatment assignments are not shared with the subjects, their families, 
or any member of the study team, either at the study site or at Biogen, except designated Biogen 
personnel.
At the end of the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, Biogen will provide the randomization codes to 
Investigators, who then can inform their subjects about the treatment received. 


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10.
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
A subject must permanently discontinue study treatment for any of the following reasons:

The subject becomes pregnant. Study treatment must be discontinued immediately, and 
the pregnancy must be reported according to the instructions in Section 15.4.1.

Any seizure event. If a seizure event is suspected, the subject must discontinue study 
treatment and be referred to a neurologist for appropriate follow-up (see Section 7.3). An 
effort should be made to collect a 
 as soon as possible after the event.

The subject withdraws consent.

The subject experiences a medical emergency that necessitates permanent discontinuation 
of study treatment or unblinding of the subject’s treatment assignment.

The subject experiences an AE requiring continued treatment that meets exclusionary 
criteria.

The subject has confirmed ALT or AST >5 ×ULN, or confirmed ALT or AST >3 × ULN 
and bilirubin >2 × ULN.

Depending on the specifics of the subject’s C-SSRS as assessed by the Investigator, 
subjects must have their suicidality managed appropriately by clinicians and must 
discontinue from the treatment.

At the discretion of the Investigator, for medical reasons.

At the discretion of the Investigator or the Sponsor, for noncompliance with the terms of 
the protocol.

The primary reason for discontinuation of study treatment must be recorded in the 
subject’s case report form (CRF).
All subjects who discontinue study treatment prematurely will be asked to remain in the study 
and continue all protocol-specified visits and procedures. At a minimum, these visits should 
include assessment of AEs/SAEs and concomitant medications and key clinical assessments. 
Subjects who discontinue study treatment prematurely will also be asked to return to the study 
site for an SFU Visit 14 days after receiving the last dose of study treatment.


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10.2.
Subject Early Termination/Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.
Subjects must be withdrawn from the study for any one of the following reasons:

At the discretion of the Investigator for medical reasons.

The subject withdraws consent. 

The subject enrolls into another interventional clinical study in which an investigational 
treatment or approved therapy for investigational use is administered.

The subject is unwilling or unable to comply with the protocol.
The primary reason for the subject’s withdrawal from the study must be recorded in the subject’s 
CRF. 
Subjects who withdraw from the study will not be replaced.
10.3.
Lost to Follow-Up
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All reasonable efforts must be made to locate subjects to determine and report their 
ongoing status. This includes follow-up with persons authorized by the subject (e.g., the 
subject’s informant). Lost to follow-up is defined as the inability to reach the subject after a 
minimum of 2 documented phone calls, faxes, or e-mails as well as lack of response by the 
subject to 1 registered mail letter. All attempts should be documented in the subject’s medical 
records. If it is determined that the subject has died, the site will use permissible local methods to 
obtain the date and cause of death. In any circumstance, every effort should be made to 
document subject outcome, if possible. The Investigator should inquire about the reason for 
withdrawal, request that the subject return all unused study treatment, request that the subject 
return for a final visit, if applicable, and follow up with the subject regarding any unresolved 
AEs.


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11.
STUDY TREATMENT USE
11.1.
Regimen
Refer to and follow the Directions for Handling and Administration (DHA). 
Randomized, blinded study treatment will be self-administered orally by the subject BID for the 
duration of the treatment phase. Duration of treatment will be approximately 85 days, for a total 
of approximately 169 doses (assuming only 1 dose on Day 85). 
Subjects will be randomized in a 1:1:1 ratio to receive one of the following treatment regimens:

BIIB104 0.15 mg BID orally for 12 weeks

BIIB104 0.5 mg BID orally for 12 weeks

Placebo BID orally for 12 weeks
Subjects will take 1 capsule in the morning and 1 capsule in the evening, approximately 12 hours 
apart. Subjects are to swallow the capsules whole and not manipulate or chew the capsules prior 
to swallowing. Study site personnel will supervise subjects taking the first dose on Day 1 at the 
investigative site. At subsequent visits, study treatment will be dispensed after all study 
procedures have been completed for the respective visit or as directed on 
. 
11.2.
Modification of Dose and/or Treatment Schedule
If a subject misses a scheduled morning dose, subjects should be instructed that the dose should 
be taken as soon as possible, but no later than 6 hours after the scheduled time of dosing. If it is 
more than 6 hours after the scheduled time of dosing, the subject should be instructed to skip that 
dose and resume dosing at the next regularly scheduled time. 
11.3.
Compliance
Dosing compliance is documented in the drug accountability logs, electronic Case Report Form 
(eCRF) and by the medication compliance platform. Study treatment will be dispensed in blister 
cards. Subjects should make every attempt to self-administer the treatment daily as instructed. 
The subject will bring the blister cards back to the clinic at each visit. At each visit, a capsule 
count will be done by the research staff, and the subject will be questioned about any missed or 
extra doses taken. Based on blister card review and/or capsule count, any subject who is 
noted not to have taken at least 80% or has taken more than 100% of required doses at any 
scheduled visit during the study will be considered out of compliance. See Study Reference 
Manual for additional information. 


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If a subject is out of compliance, the Investigator will need to discuss the subject's continuation 
in the study with the Sponsor’s Medical Monitor. Based upon the assessment of the Investigator 
and Sponsor’s Medical Monitor, an out-of-compliance subject may be withdrawn from the study. 
All dispensed investigational product blister cards will be kept available for routine study checks 
by the Sponsor’s Study Monitor. The time of subject dosing will be reviewed by the Study 
Monitor from the medication compliance application.
A smart phone-based medication compliance application will be used to assist the subject with 
medication compliance. See Section 9.2 for a brief description of the application. See the Study 
Reference Manual for further description and detailed instructions on the training and use of the 
monitoring platform.
11.4.
Concomitant Therapy and Procedures
11.4.1.
Concomitant Therapy
Note that discontinuation of prohibited concomitant treatments for the sole purpose of 
enabling the subject to qualify for participation in Study 263CS201 should only occur after 
the subject and their informant have signed their respective Informed Consent Documents.
Concomitant therapy guidelines will be provided in the Study Reference Manual.

As defined in the inclusion criteria, subjects must be receiving ongoing maintenance 
atypical antipsychotic therapy other than clozapine (oral or depot) on a stable treatment 
regimen for ≥8 weeks prior to Baseline/Day 1, including concomitant psychiatric 
medications. Doses of background atypical antipsychotics should be within the 
recommended dose range listed in the approved product labeling of the country where the 
study is being conducted. Doses exceeding the recommended dose range are not 
permitted and doses below the recommended dose range should be discussed with the 
Sponsor's Medical Monitor. Subjects should be taking no more than 2 background 
antipsychotics. 

Treatment regimen stability is defined as maintaining the same dosage of treatment 
except for minor adjustments (≤25%) to manage medication-specific tolerability issues. 
Note that hypnotics are an exception to this stability requirement; prohibited hypnotics 
may be substituted with allowed hypnotics administered as described below.

Stable concomitant treatment with a second atypical antipsychotic at doses that do not 
exceed the range listed in the approved product labeling of the country where the study is 
being conducted is permissible if used for a targeted symptom (e.g., insomnia) or an 
adverse effect from the primary maintenance antipsychotic treatment, but not if it is used 
for refractory psychotic symptoms. Subjects should be taking no more than 2 background 
antipsychotics.

Compliance with background antipsychotic medication regimen will be monitored during 
the study.


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All concomitant treatments taken during the study must be recorded with indication, daily dose, 
and start and stop dates of administration. All subjects will be questioned about concomitant 
treatment at each clinic visit.
Prohibited treatments must be washed out for a minimum of 5 half-lives of the treatment prior to 
randomization. Allowable exceptions to this rule include the following:

The as-needed treatment of anxiety or agitation with up to 2 mg/day lorazepam (or the 
equivalent dose of another short-acting benzodiazepine) with the following restrictions:
o
Not used within 8 hours of neurological assessments (e.g., neurological 
examination, SARA) or within 12 hours of scheduled efficacy assessments (e.g., 
MCCB, SCI-PANSS, UPSA-Bi, SCoRS).

The as-needed treatment of insomnia with nonbenzodiazepine hypnotics (e.g., zolpidem 
up to 10 mg/day, zaleplon up to 20 mg/day, eszopiclone up to 3 mg/day) are permitted 
within their respective recommended dose ranges with the following restriction:
o
Not to be used within 12 hours of scheduled efficacy assessments. 

Minor adjustment (≤25% of the baseline dose) of the dosage of background atypical 
antipsychotics or psychiatric medications for tolerability. This option should be used only 
if required to support a subject’s continued participation in the study. All efforts should 
be made to maintain background pharmacotherapy at consistent doses throughout the 
treatment phase of the study. Recognizing that physicians outside of the study may be 
managing the subject’s background atypical antipsychotic and other psychiatric 
medications, changes in background medication dosing that exceed this limit should be 
discussed with the Sponsor’s Medical Monitor to determine subject disposition.

As-needed treatment with any other nonprohibited treatment with potential psychotropic 
effects (e.g., centrally acting antihistamines) should not occur within 12 hours of 
scheduled efficacy assessments.

Acetaminophen and nonsteroidal anti-inflammatory medications may be used 
intermittently throughout the study.

The chronic use of certain medications (some hormones, antihypertensives, diuretics, and 
oral hypoglycemics) is allowed if the subject was prescribed these treatments at least 
8 weeks prior to study entry, the treated condition is stable, and the dosage is stabilized 
prior to the first dose of study treatment. Potential exceptions to the 8-week requirement 
may be allowed on an individual basis in consultation with the Sponsor’s Medical 
Monitor to determine whether it is appropriate to include the subject in the study. If 
changes are required to chronic treatments during study participation, these should be 
discussed with the Sponsor’s Medical Monitor to determine appropriateness for the 
subject’s continued participation.

Nicotine therapy (including patches), varenicline, or similar therapeutic agents to support 
smoking cessation are permitted if they have been introduced as treatment prior to the 
Screening Visit.


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The following drugs, classes of drugs, foods, and other nonpharmacological treatments are 
prohibited as concomitant treatments after the Screening Visit (see the Study Reference 
Manual for additional information):

Medications that may lower seizure threshold, including but not limited to 
aminophylline, theophylline, chlorpromazine, clozapine, cyclosporine, pethidine, 
bupropion, clomipramine, maprotiline, and amantadine. The Investigator should discuss 
the use of any concomitant treatment associated with lowering seizure threshold with the 
Sponsor’s Medical Monitor prior to randomizing a subject. 

Medications or foods/food products that are strong inhibitors of CYP3A4, including but 
not limited to: grapefruit juice, boceprevir, cobicistat, conivaptan, danoprevir, 
elvitegravir, indinavir, ketoconazole (topical use is permitted), lopinavir, paritaprevir, 
posaconazole, ritonavir, saquinavir, telaprevir, tipranavir, troleandomycin, voriconazole.

Medications or supplements that significantly induce CYP3A4, including but not limited 
to: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort.

Anorectics and stimulants

Opioids

Treatments with anticholinergic activity, including but not limited to hydroxyzine, 
hyoscyamine, methscopolamine, scopolamine, amitriptyline, imipramine, doxepin, 
diphenhydramine, atropine, cyclobenzaprine hydrochloride, orphenadrine citrate, 
benztropine mesylate, and trihexyphenidyl. The Investigator should discuss the use of 
any concomitant treatment associated with anticholinergics with the study Medical 
Monitor prior to randomizing a subject. (Note: Treatment with anticholinergics for 
extrapyramidal motor symptoms is permitted at no more than the equivalent of 1 mg 
benztropine BID.)

Typical antipsychotic treatments, including but not limited to prochlorperazine, 
haloperidol, loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine, 
trifluoperazine, chlorpromazine, and perphenazine. The Investigator should discuss the 
use of any concomitant treatment associated with typical antipsychotic treatments with 
the study Medical Monitor prior to randomizing a subject.

Vitamin K antagonists, including but not limited to warfarin. 

Antiepileptics, including but not limited to valproate, carbamazepine, phenytoin, 
oxcarbazepine, and phenobarbital. The Investigator should discuss the use of any 
concomitant antiepileptic treatment with the Sponsor’s Medical Monitor prior to 
randomizing a subject. Some antiepileptics are permitted if not being used as antiseizure 
treatments; these include but are not limited to pregabalin, gabapentin, and lamotrigine.

Anti-emetics with dopamine antagonist action (e.g., metaclopramide, prochlorperazine).

Herbal supplements (must be discontinued at least 28 days before the first dose of trial 
treatment)

Lithium

Cognitive remediation therapy and electroconvulsive therapy 


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Note that treatments taken within 28 days before the first dose of study treatment will be 
documented as a prior treatment. Treatments taken after the first dose of study treatment will be 
documented as concomitant treatments.
11.4.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and last study visit.
All subjects will be asked about concomitant procedures at each clinic visit, and all procedures 
reported by subjects will be documented.


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12.
STUDY TREATMENT MANAGEMENT
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment. The DHA supersedes all other references 
(e.g., protocol).
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff. Study 
treatment is to be dispensed only to subjects enrolled in this study. 
12.1.
BIIB104 Study Treatment
BIIB104 and its matched placebo will be provided as capsules (Size 1) for oral administration. 
The BIIB104 0.15 mg and 0.5 mg capsules and their matched placebos will be supplied in 
separate blister cards and labeled in accordance with all applicable regulatory requirements. At a 
minimum, the label will include a study reference code, study treatment identifier, quantity of 
dosage units, lot number, and other pertinent information in accordance with local law. The 
expiry or use-by date is stored in the IRT system, and printable assignment reports are available 
to site staff. Study treatment should not be used after the expiration, expiry, or use-by date.
12.1.1.
BIIB104 Preparation and Dispensing
The study treatment will be dispensed using the IRT drug management system. A qualified staff 
member will dispense the treatment via unique container numbers in the blister cards provided, 
in quantities appropriate for the study visit schedule. The subject and informant should be 
instructed to maintain the product in the blister cards provided throughout the course of dosing 
and return the blister cards to the site at the next study visit.
12.1.2.
BIIB104 Storage
The Investigator, or an approved representative (e.g., pharmacist) will ensure that all study 
treatments are stored in a secured area with controlled access under required storage conditions 
and in accordance with applicable regulatory requirements.
Study treatment should be stored in its original container and in accordance with the label. The 
label is the primary source of information for storage conditions and will supersede any other 
document references to storage conditions.
Site systems must at a minimum be capable of measuring and documenting (e.g., via a log) daily 
minimum and maximum temperatures for all site storage locations (including frozen, 
refrigerated, and/or room temperature products, as applicable). This should be captured from the 
time of receipt of study treatment throughout the study. Even for continuous monitoring systems, 
a log or site procedure that ensures active daily evaluation for excursions should be available. As 


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applicable, the operation of the temperature monitoring device and storage unit (e.g., 
refrigerator) should be regularly inspected to ensure it is maintained in working order. 
Any deviations from the product label storage conditions should be documented upon discovery. 
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible. Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Sponsor. Once a deviation 
is identified, the study treatment must be quarantined and not used until the Sponsor provides 
documentation of permission to resume use. It will not be considered a protocol deviation if the 
Sponsor approves the use of the study treatment after the temperature deviation. Use of the 
treatment in question prior to Sponsor approval will be considered a protocol deviation. 
Specific details regarding information the site should report for any deviation will be provided 
separately to the site in the Study Reference Manual.
Site staff will instruct subjects on the proper storage requirements for take-home study treatment.
12.1.3.
BIIB104 Handling and Disposal
The Investigator must return all used and unused packages of BIIB104 study treatment name as 
instructed by the Sponsor unless approved for onsite destruction.
If any BIIB104 supplies are to be destroyed at the study site, the institution or appropriate site 
staff must obtain prior approval from the Sponsor, by providing, in writing, the destruction 
policy or details of the method of destruction. After such destruction, the Sponsor must be 
notified, in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, 
quantities), the date of destruction, and proof of destruction.
12.1.4.
BIIB104 Accountability
Accountability for study treatment is the responsibility of the Investigator. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost. 
Unless otherwise notified, all blister cards, both used and unused, must be saved for study 
treatment accountability. By the end of the study, reconciliation must be made between the 
amount of BIIB104 supplied, dispensed, and subsequently destroyed, lost, or returned to the 
Sponsor. A written explanation must be provided for any discrepancies.
Subjects should make every effort to return all unused study treatment and all blister cards to the 
site at each visit. Unused study treatment and unused or used study treatment materials must be 
kept in a secure location for final accountability and reconciliation.


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12.2.
Placebo
Subjects will receive a matched placebo for oral administration using a dosing regimen identical 
to that of the active BIIB104 treatment groups for the study treatment periods as well as for the 
placebo lead-in assessment.
Excipients for the manufacturing of the placebo drug product are the same excipients used in the 
active drug product strengths, minus the BIIB104 active ingredient. The placebo is encapsulated 
in a #1 LiCap hard gelatin, white opaque capsule.
Placebo is to be stored under the same conditions as BIIB104.














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14.
SAFETY ASSESSMENTS
See Section 5 for the timing of all safety assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BIIB104.
14.1.1.
Physical Examinations
Physical examinations may be conducted by a physician, trained physician’s assistant, or nurse 
practitioner as acceptable according to local regulation.
The full physical examination will include head, ears, eyes, nose, mouth, skin, heart and lung, 
lymph nodes, and gastrointestinal, musculoskeletal, and neurological systems. The brief physical 
examination will be focused on general appearance and respiratory and cardiovascular systems, 
as well as on subject-reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be placed 
on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight.
14.1.2.
Neurological Examinations
The full neurological examination includes observation for cerebellar (intention) tremor and 
noncerebellar (e.g., resting or positional) tremor, nose-finger, heel-shin, Romberg, tandem walk, 
normal walk/gait, positional nystagmus, gaze-evoked nystagmus, reflexes, muscle strength, 
cranial nerves, and sensory function of the upper and lower extremities. The neurological 
examination will be performed by a physician or the equivalent.
The brief neurological examination will include an assessment of motor and sensory function, 
cranial nerves, reflexes, noncerebellar tremors (e.g., resting or positional), and cerebellar 
function. The assessment of cerebellar function will be complemented by the SARA. The brief 
neurological examinations will be conducted by a physician or the equivalent.
14.1.3.
Scale for the Assessment and Rating of Ataxia
The SARA will be conducted by a physician or the equivalent with experience in neurological 
assessment.
The SARA is a clinical scale that is based on a semiquantitative assessment of cerebellar ataxia 
on an impairment level and will complement the brief neurological examination. The SARA has 
8 items that are related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast 
alternating movements, and heel-shin test [Schmitz-Hübsch 2006].


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14.1.4.
Columbia-Suicide Severity Rating Scale
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior. Versions are available for Screening, Baseline, and follow-up visits.
The C-SSRS should be collected at the times specified in Schedules of Activities (Section 5) by 
an appropriately trained site staff member. The C-SSRS can also be administered at any time in 
the study at the discretion of the Investigator based on any reasonable concern.
The following subjects will be excluded from study participation:

Subjects who have attempted suicide within the last 2 years.

Subjects who, in the Investigator’s judgment, pose a significant suicide risk. 

Subjects who have suicidal ideation associated with actual intent and a method or 
plan in the past 6 months (i.e., “Yes” answers on item 4 or 5 of the C-SSRS).
At each suicidality assessment following the Screening Visit, subjects believed to have 
significant suicidal ideation with actual plan and intent or with suicidal behavior must be 
evaluated by a licensed and qualified mental health professional (MHP) [e.g., a psychiatrist or 
licensed PhD level clinical psychologist] skilled in the evaluation of suicidality by virtue of 
training or experience who will determine whether it is safe for the subject to continue in the 
trial. Specific criteria that indicate a need for such an assessment include the following:

Suicidal ideation associated with actual plan and/or intent since last visit; (Yes answer 
to C-SSRS question 4 [some intent to act without specific plan] or 5 [specific plan 
and intent]).

In the Investigator’s judgment, a risk assessment or exclusion is warranted.
Suicidality AEs or other clinical observations, based on the judgment of the Investigator and/or 
clinician/MHP, may also trigger a risk assessment and a narrative using information from the 
C-SSRS, and other available information including psychiatric/medical history.
Subjects who respond “Yes” to item 4 or 5 or to any behavioral question of the C-SSRS at any 
time after the baseline visit will be assessed by the clinician/MHP to determine whether an AE 
has occurred and whether it is safe for the subject to continue in the trial.
Subjects who respond “Yes” to item 4 or 5 or to any behavioral question of the C-SSRS on more 
than one occasion during the study must have their suicidality managed appropriately by the 
Investigator together with clinician/MHP (or the Investigator alone if they are a qualified mental 
health professional). Depending on the specific circumstances as assessed by the Investigator 
and/or clinician/MHP, the subject may be withdrawn from the study.


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14.1.5.
Blood Pressure and Pulse Rate
Supine blood pressure will be measured with the subject’s arm (preferably the dominant arm) 
supported at the level of the heart and recorded to the nearest measurement (mmHg) after 
approximately 5 minutes of rest. The same arm should be used throughout the study. 
The same properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time. The use of an automated device for measuring blood pressure and pulse rate 
is acceptable; when done manually, pulse rate will be measured in the brachial/radial artery for at 
least 30 seconds. When the timing of these measurements coincides with a blood collection, 
blood pressure and pulse rate should be obtained prior to the nominal time of the blood 
collection.
14.1.6.
Electrocardiogram
Triplicate and single ECGs will be collected as specified in the Schedules of Activities 
(Section 5). Samples obtained outside the proposed sampling timepoints specified in will not be 
captured as a protocol deviation, as long as the exact time of the assessment is noted on the 
source document and data collection tool (e.g., CRF).
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. Triplicate 12-lead ECGs will be obtained approximately 2 to 
4 minutes apart; the average of the triplicate ECG measurements collected before dosing on 
Day 1 will serve the subject’s baseline QTc value. When the timing of these measurements 
coincides with a blood collection, the ECG should be obtained prior to the nominal time of the 
blood collection, blood pressure, and pulse rate.
To ensure safety of the subjects, a qualified individual at the study site will make comparisons to 
baseline measurements. If the QTc interval is increased by ≥45 msec from the baseline, or an 
absolute QTc value is ≥500 msec for any scheduled ECG, then 2 additional ECGs will be 
collected (approximately 2 to 4 minutes apart) to confirm the original measurement. If either of 
the QTc values from these repeated ECGs remains above the threshold value (≥45 msec above 
the baseline) or is ≥500 msec, then a single ECG must be repeated at least hourly until QTc 
values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.
If QTc values are >500 msec (or ≥45 msec above the baseline) for more than 4 hours (or sooner 
at the discretion of the Investigator), or if QTc intervals get progressively longer, the subject 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTc intervals 
do not return to <500 msec (or to <45 msec above the baseline) after 8 hours of monitoring (or 
sooner at the discretion of the Investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a qualified 
physician’s interpretation determines that the QTc values are in the acceptable range.


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14.2.
Laboratory Safety Assessments
The following parameters will be analyzed from samples collected from subjects at the times 
specified in Section 5. Samples will be analyzed using Good Laboratory Practice-validated 
assays.

Complete blood count including: red blood cell count, white blood cell count with 
differentials (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), 
hemoglobin, hematocrit, platelets, mean corpuscular volume, mean corpuscular 
hemoglobin, and mean corpuscular hemoglobin concentration.

Serum chemistry, including albumin, alkaline phosphatase, ALT, AST, BUN, 
bicarbonate, calcium, chloride, creatinine, creatine kinase, direct bilirubin, 
gamma-glutamyl transferase, glucose, lactate dehydrogenase, magnesium, 
phosphorus, potassium, sodium, total bilirubin, total cholesterol, high-density 
lipoproteins, low-density lipoproteins, triglycerides, total protein, and uric acid.

Urinalysis, including urine protein, glucose, ketones, occult blood, and white blood 
cells by dipstick, with microscopic examination if indicated.

Urine drug and alcohol testing (refer to the Study Reference Manual for complete list
of drugs tested).

At Screening Visit only: testing for human immunodeficiency virus (HIV) (to be 
performed based upon Investigator assessment of HIV risk factors; may be omitted if 
not permitted by local regulations); HbA1c, HBsAg, anti-HBc, anti-HBs, and 
hepatitis C antibody; and follicle-stimulating hormone (postmenopausal women 
only).
14.2.1.
Pregnancy Testing
For female subjects of childbearing potential, a serum and urine pregnancy test with sensitivity 
of at least 25 mIU/mL, will be performed at times defined in Section 5. Urine pregnancy tests 
will be performed at the site; serum pregnancy tests will be performed at the central laboratory. 
A negative pregnancy result is required before the subject may receive the study treatment. 
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected), and will be repeated at 
times defined in Section 5 to confirm the subject has not become pregnant during the study. 
Pregnancy tests may also be repeated as per request of IRBs/ethics committees (ECs) or if 
required by local regulations. 
Qualitative urine pregnancy tests must be sensitive to at least 25 mIU/mL. Qualitative 
point-of-service urine pregnancy tests will be conducted with the test kit provided by the central 
laboratory in accordance with instructions provided in its package insert. Subjects who have 
missed a menstrual period or who show an indeterminate or positive result on the qualitative 
point-of-service urine test may not proceed further in the study until pregnancy is ruled out using 


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further diagnostic testing (e.g., a negative quantitative serum pregnancy test conducted at a 
certified laboratory).
In the case of a positive confirmed pregnancy, the subject will discontinue study treatment and 
be withdrawn from the study.
14.2.2.
Antipsychotic Medication Monitoring
Background antipsychotic medication blood levels will be tested at the times specified in 
Section 5 and analyzed using a validated analytical method at a College of American 
Pathologists/Clinical Laboratory Improvement Act certified laboratory. For all visits, the time of 
the sample collection will be documented as well as the time, date, and dosage of the 2 most 
recent doses of primary background antipsychotic medication prior to collection of the 
antipsychotic blood level sample. Details regarding the collection, processing, storage, and 
shipping of the blood samples will be in the laboratory manual that is provided to the 
investigative site prior to the initiation of the study.
14.3.
Japan-Specific Safety Assessment on Day 8
All subjects enrolled at sites in Japan will undergo a review of their safety data following the 
Day 8 Visit. For this review, the Investigator will assess the available blinded safety data for the 
subject for the initial 8 days of dosing (Days 1 through 8), including, but not limited to: all 
available AEs, SAEs, vital signs, ECGs, and clinical assessments. The Investigator will 
communicate any abnormal findings to the Biogen Medical Director and Medical Safety Officer 
(refer to the Study Reference Manual for communication process). The Biogen Medical Director 
and Medical Safety Officer will then decide whether it is safe for a subject to continue in the
study by confirming, at a minimum, that the discontinuation of study treatment rules (see 
Section 10.1) and the study stopping rules criteria (see Section 7.3) have not been met and that 
there are no additional safety concerns. If additional clinically relevant data become available 
(e.g., laboratory results), the Investigator will inform the Biogen Medical Director and Medical 
Safety Officer. This review of safety data will be documented.


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15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If 
an AE occurs, the first concern should be for the safety of the subject. If necessary, appropriate 
medical intervention should be provided.
At the signing of the ICF, each subject and/or main caregiver must be given the names and 
telephone numbers of site staff for reporting AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
Determination of whether an abnormal laboratory value, vital sign result, and/or ECG result 
meets the definition of an AE will be made by the Investigator. Abnormal results are not 
considered AEs unless one or more of the following criteria are met:

The result meets the criteria for an SAE

The result requires the subject to receive specific corrective therapy

The result is considered by the Investigator to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization


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
Results in persistent or significant disability/incapacity

Results in a congenital anomaly/birth defect

Is a medically important event 
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above. (Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization.)
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.
o
If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless 
one of the requirements in Section 15.1.2 is met.
15.2.
Safety Classifications
15.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.2.

The relationship of the event to study treatment as defined in Section 15.2.2.

The severity of the event as defined in Section 15.2.3.




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Investigator will assess the subject for AEs and will record any new AEs or updates to previously 
reported AEs on the CRF.
AEs that are ongoing when the subject completes or discontinues the study will be followed by 
the Investigator until the event has resolved, stabilized, or returned to baseline status. AE 
outcome will be recorded on the CRF, as applicable.
15.3.2.
Adverse Events of Special Interest
An AE of special interest is an AE of scientific and medical concern specific to this study, for 
which ongoing monitoring and reporting are required.
For this protocol, any event of seizure should be considered as medically significant and be 
reported as an SAE.
15.3.3.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and the subject’s 
final clinic visit (including the SFU Visit) is to be recorded on an SAE form, regardless of the 
severity of the event or its relationship to study treatment. SAEs must be reported to Biogen 
within 24 hours as described in Section 15.3.4. Follow-up information regarding an SAE also 
must be reported within 24 hours. 
Subjects will be followed for all SAEs until the subject’s final clinic visit (including the SFU 
Visit). Thereafter, the event should be reported to Biogen only if the Investigator considers the 
SAE to be related to study treatment.
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status.
15.3.4.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify the Sponsor within 24 hours of the site staff becoming aware of the SAE. It is the 
Investigator’s responsibility to ensure that the SAE reporting information and procedures are 
used and followed appropriately.




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Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol. Overdoses are not considered 
AEs and should not be recorded as an AE on the CRF; however, all overdoses must be recorded 
on an Overdose form and transmitted to the Sponsor within 24 hours of the site becoming aware 
of the overdose. An overdose must be reported to Biogen even if the overdose does not result in 
an AE. If an overdose results in an AE, the AE must be recorded. If an overdose results in an 
SAE, both the SAE and Overdose forms must be completed and transmitted to the Sponsor. All 
study treatment-related dosing information must be recorded on the dosing CRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, site staff will apply appropriate medical 
intervention, according to current standards of care. The Investigator (or designee) should 
contact the Sponsor’s Medical Monitor. Refer to the Study Reference Manual for contact 
information. 
15.4.3.1.
Unblinding for Medical Emergency
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator may access the subject’s treatment assignment by 
IRT. The Investigator must document the reasons for unblinding in the subject’s source 
documents. 
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 
individual not directly involved in managing the medical emergency, or to personnel involved 
with the analysis and conduct of the study. The Investigator can contact the Sponsor to discuss 
such situations but such a discussion should not delay management of the medical emergency.
15.5.
Contraception Requirements
All women of childbearing potential and all men must practice highly effective contraception 
during the study and for at least 30 days after their last dose of study treatment. In addition, 
subjects should not donate sperm or eggs for the duration of the study and for at least 3 months 
after their last dose of study treatment.
For the purposes of this study, women who do not meet one of the following criteria listed below 
are considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential:


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
Postmenopausal
o
12 months of natural (spontaneous) amenorrhea without an alternative medical 
cause and a serum follicle-stimulating hormone level >40 mIU/mL
o
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)
For the purposes of the study, highly effective contraception is defined as use of 1 of the 
following:
For females:

Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal methods of contraception associated with the inhibition of 
ovulation.

Established use of oral, injected, or implanted hormonal methods of contraception that 
contain progestogen alone associated with the inhibition of ovulation. 

Placement of an intrauterine device or intrauterine system.

Barrier methods of contraception with use of a spermicide: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository. 
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide.

Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate).
For males:

The use of condoms with spermicide.

Sex with a woman who uses the methods described for females if she is of childbearing 
potential.

Male surgical sterilization (with the appropriate postvasectomy documentation of the 
absence of sperm in the ejaculate).
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
considered acceptable methods of contraception.
Pregnancy reporting is described in Section 15.4.1.


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15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, on the CRF regardless of the severity or 
relationship to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies in female subjects and follow up on the outcome 
of all pregnancies.

Complete an SAE form for each SAE and fax or email it to the Sponsor within 
24 hours of the site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently. Follow-up information 
must be reported to the Sponsor within 24 hours of the site staff becoming aware of 
new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. Record AE follow-up information, including resolution, on the CRF, as 
applicable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
The Sponsor
The Sponsor’s responsibilities include the following:

Before a site can enroll any subjects, the Medical Monitor is responsible for 
reviewing with site staff the definitions of AE and SAE, as well as the instructions for 
monitoring, recording, and reporting AEs and SAEs.

The Sponsor is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
16.1.
Efficacy
16.1.1.
Analysis Population
Analysis of efficacy endpoints will be based on the intent-to-treat (ITT) population. 
The ITT population is defined as all randomized subjects who received at least 1 dose of study 
treatment. Subjects will be analyzed according to the study treatment to which they were 
randomized. Analysis of other nonsafety endpoints (e.g., demographics) will also be based on the 
ITT population, unless otherwise specified in the statistical analysis plan (SAP). Other analysis 
populations will be defined in the SAP. 
16.1.2.
Methods of Analysis
Continuous variables will be summarized using descriptive statistics (number of subjects [n], 
mean, standard deviation [SD], median, minimum, and maximum) by treatment group, and 
categorical variables will be presented using frequency distributions by timepoint and treatment 
group. Point estimates and 90% CIs will be provided where applicable.
16.1.2.1.
Analysis of the Primary Endpoint
The primary endpoint is the change of MCCB Working Memory Domain score from baseline to 
Week 12. An MMRM model will be used as the primary analysis to analyze change from 
baseline in Working Memory Domain score using fixed effects of treatment, visit, treatment by 
visit interaction, baseline Working Memory Domain score, baseline Working Memory Domain 
score by visit interaction, and region.
In the analysis of the primary endpoint, missing data will be assumed to be missing at random 
(MAR). An unstructured variance-covariance structure will be used to model the within patient 
measurements variability. If this analysis fails to converge, other structures will be tested such as 
heterogeneous autoregressive, heterogeneous compound symmetry, or heterogeneous Toeplitz. 
The variance-covariance structure that results in the smallest Akaike information criterion will be 
used. The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. Sensitivity analyses will be carried out to assess the robustness of primary analysis to 
deviation from the MAR assumption. Details of sensitivity analyses and assumptions for 
different missing patterns will be described in the SAP.




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16.4.2.
Methods of Analysis
All AEs, laboratory data, vital signs, SARA, and C-SSRS will be evaluated for safety.
16.4.2.1.
Adverse Events
AEs will be coded using the available, current version of the Medical Dictionary for Regulatory 
Activities (MedDRA). A treatment-emergent adverse event (TEAE) will be defined as any AE 
that started or worsened in severity after initial dose of study treatment through the follow-up 
phase; hereafter, TEAEs will be referred to simply as AEs. AEs will be grouped by system organ 
class, preferred term, and overall, and then summarized. The incidence, severity, and relationship 
to study treatment will be summarized, separately for all AEs, treatment-related AEs, and SAEs.
16.4.2.2.
Clinical Laboratory Results
Clinical laboratory evaluations will include hematology, blood chemistry, and urinalysis. 
Laboratory data will be summarized using shift tables. Shifts from baseline to high/low status for 
hematology and blood chemistry parameters, and shifts from baseline to high/positive status for 
urinalysis will be presented. In addition, the shift from baseline to the maximum postbaseline 
value and the shift from baseline to the minimum postbaseline status will be presented for each 
laboratory test by treatment group. Also, summaries of laboratory values categorized based on 
common toxicity criteria grade will be created. Summary statistics for actual values and change 
from baseline will also be presented for quantitative laboratory data.
16.4.2.3.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities. The number of subjects 
evaluated and the number and percentage of subjects with clinically relevant postbaseline 
abnormalities will be presented by treatment group.
16.4.2.4.
C-SSRS
C-SSRS data will be summarized by each treatment group.
16.5.
Interim Analyses
An interim analysis for futility of the primary endpoint may be performed after approximately 
50% of the subjects have had an opportunity to complete the Week 12 Visit. No test for 
superiority will be performed at the interim analysis; therefore, no alpha spending will be 
incurred. 
In order to maintain the treatment blind, a separate unblinded team will be formed to perform the 
interim analysis. All other study personnel who are involved in the conduct of the study will
remain blinded. Details will be specified in the unblinding plan.
The details of the futility criteria are included in the SAP.


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16.6.
Sample Size Considerations
Fifty-one subjects per treatment group will have approximately 80% power to detect a true mean 
difference of 3.5 in change from baseline MCCB Working Memory Domain score to Week 12 
between the treatment and placebo groups. With the assumed drop-out rate of 30%, 73 subjects 
are required from each group to maintain the 80% power. This power calculation is based on a 
2-sided t-test assuming equal variance with a final significance level of 0.1, and an SD of 7. The 
statistical software EAST 6.3® is used for sample size calculation. The sample size may be 
re-estimated based on blinded data review and evolving development of this study. 


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17.
ETHICAL REQUIREMENTS
The Sponsor, all vendors and CROs, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol and applicable International Council for 
Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines and conduct the study 
according to local regulations.
The Investigator is responsible for endorsing all data on completed CRFs electronically, prior to 
any interim lock or database lock.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines. The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study. The Sponsor will submit documents will submit 
documents on behalf of the study sites worldwide in compliance with local regulations.  
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
the Sponsor. After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
The Sponsor must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study. Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the study site must submit a close-out letter to the 
ethics committee and the Sponsor.




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treatment. It is unknown whether the effects of the study treatment are influenced by race or 
ethnicity.
Video recordings will be made and may be transmitted in order to confirm dosing compliance. 
Audio or video recordings may be made of some clinical assessments in order to allow for 
central review for standardization of test administration, where allowable by country and/or local 
authorities. All audio and video recordings of clinical assessments will be sent to each respective 
site per subject at the end of the study, kept by the vendor 1 year from last subject’s last visit, 
then subsequently destroyed, and not sent to Biogen for archiving purposes.
Study reports will be used for research purposes only. The subject will not be identified by name 
in CRFs, study-related forms, study reports, or any related publications. Biogen, its partners and 
designees, ethics committees, and various government health agencies may inspect the records of 
this study. Every effort will be made to keep the subject’s personal medical data confidential.
17.5.
Compensation for Injury
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
The Sponsor will register the study and post-study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by the Sponsor. This initiation visit will include a detailed review of the protocol and 
study procedures.
18.2.
Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. The Investigator is responsible for endorsing 
all CRF data prior to any interim or final database lock.
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections. The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail). The 
Investigator should maintain a record of the location(s) of essential documents.
The Clinical Monitors will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate. A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of review. It also will provide the monitoring strategy, 
with emphasis on subject safety, data integrity, and critical data and processes.
During these visits, CRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved. Documentation of 
results will be provided to the Sponsor in a timely fashion to allow follow-up and verification of 
compliance with the monitoring plan. Remote evaluation of data (centralized monitoring) may 
also be conducted and reported as defined in the monitoring plan.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.


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18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study. All financial details are provided in 
the separate contracts between the institution, Investigator, and the Sponsor. 
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
External Contract Organizations
The Sponsor will be responsible for all administrative aspects of this study including but not 
limited to study initiation, monitoring, management of AEs, and data management.
The Sponsor will ensure oversight of any study-related duties and functions carried out on its 
behalf and will specify in writing all duties and functions that are transferred. 
19.1.1.
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study, including but not limited to 
study initiation, monitoring, and management of SAE reports and data management. Before 
subjects are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other site staff, as appropriate.
19.1.2.
Interactive Response Technology
IRT will be used in this study. Before subjects are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
19.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool configured by the Sponsor and hosted by the electronic 
data capture vendor.
Clinical Outcome Assessments (COAs) will be administered electronically and/or via paper 
depending on the scale selected, as outlined in the Study Reference Manual. If data are entered 
electronically, the subject, caregiver/informant, rater, and/or site staff will enter the values into 
the electronic tablet per the tablet scale instructions. If entered via paper administration, the 
subject, caregiver/informant, rater, and/or site staff will enter the values in the provided paper 
form per the instructions in the Study Reference Manual. Site staff will monitor the data via a 
secure Web-based portal developed and supported by the electronic COA vendor.
19.1.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by the Sponsor to analyze all hematology, blood 
chemistry, and urine samples collected for this study. 
 will be analyzed at a 
laboratory selected by the Sponsor.


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19.1.5.
Central Facility for Other Assessments
An independent central vendor has been selected by the Sponsor to review and confirm 
diagnostic screening criteria.
A central facility has been selected by the Sponsor to read and interpret all ECG test results for 
this study.
19.2.
Study Committees
19.2.1.
Independent Data Monitoring Committee 
An IDMC will monitor the progress of the study, review interim safety data, and oversee the 
safety of subjects participating in this study. The IDMC will meet periodically during the study 
to review AE listings and laboratory results for all enrolled subjects. In addition to the periodic 
meetings, the IDMC may meet on an ad hoc basis to address any issues of concern. An IDMC 
charter will be written and will contain additional details about the composition of the IDMC, as 
well as IDMC procedures and meetings. 
19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law. Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study. If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject. In this case, the appropriate regulatory authorities will be notified subsequent 
to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 17).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify Biogen 
in writing and receive written authorization from Biogen to destroy study records. In addition, 


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the Investigator must notify Biogen of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site.
19.6.
Study Report Signatory
The Sponsor will designate one of the participating Investigators as a signatory for the study 
report. This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by the Sponsor.






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Kremen WS, Seidman LJ, Faraone SV, et al. The paradox of normal neuropsychological 
function in schizophrenia. J Abnorm Psychol. 2000;109(4):743-52.
Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA 
antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine 
responses. Arch Gen Psychiatry. 1994;51(3):199-214.
Lynch G, Granger R, Ambros-Ingerson J, et al. Evidence that a positive modulator of AMPA-
type glutamate receptors improves delayed recall in aged humans. Exp Neurol. 1997;145(1):89-
92.
Lynch G, Kessler M, Rogers G, et al. Psychological effects of a drug that facilitates brain AMPA 
receptors. Int Clin Psychopharmacol. 1996;11(1):13-9.
Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev 
Neurosci. 2002;25:103-26. Epub 2002/03/04.
Mansouri B, Henne WM, Oomman SK, et al. Involvement of calpain in AMPA-induced toxicity 
to rat cerebellar Purkinje neurons. Eur J Pharmacol. 2007;557(2-3):106-14. Epub 2006/11/22.
Meador-Woodruff JH, Healy DJ. Glutamate receptor expression in schizophrenic brain. Brain 
Res Brain Res Rev. 2000;31(2-3):288-94.
Mohn AR, Gainetdinov RR, Caron MG, et al. Mice with reduced NMDA receptor expression 
display behaviors related to schizophrenia. Cell. 1999;98(4):427-36.
Partin KM, Fleck MW, Mayer ML. AMPA receptor flip/flop mutants affecting deactivation, 
desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate. J Neurosci. 
1996;16(21):6634-47.
Pláteník J, Kuramoto N, Yoneda Y. Molecular mechanisms associated with long-term 
consolidation of the NMDA signals. Life Sci. 2000;67(4):335-64.
Ranganathan M, DeMartinis N, Huguenel B, et al. Attenuation of ketamine-induced impairment 
in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-
04958242. Mol Psychiatry. 2017;22(11):1633-1640. Epub 2017/02/28.
Roberts BM, Holden DE, Shaffer CL, et al. Prevention of ketamine-induced working memory 
impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction. 
Behav Brain Res. 2010;212(1):41-8. Epub 2010/03/27.
Rosi S, Giovannini MG, Lestage PJ, et al. S 18986, a positive modulator of AMPA receptors 
with cognition-enhancing properties, increases ACh release in the hippocampus of young and
aged rat. Neuroscience letters. 2004;361(1-3):120-3.


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Rund BR, Melle I, Friis S, et al. Neurocognitive dysfunction in first-episode psychosis: 
correlates with symptoms, premorbid adjustment, and duration of untreated psychosis. Am J 
Psychiatry. 2004;161(3):466-72.
Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: 
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2007;32(6):1272-83. Epub 2006/11/22.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Phase 2, Randomized, Double-Blind, Multiple-Dose, 
Placebo-Controlled Study to Evaluate the Safety and Efficacy of BIIB104 in Subjects With 
Cognitive Impairment Associated With Schizophrenia (CIAS),” and agree to conduct the study 
according to the protocol and the applicable ICH guidelines and GCP regulations, and to inform 
all who assist me in the conduct of this study of their responsibilities and obligations.
_______________________________________________________________
Investigator’s Signature
Date (DD MMM YYYY)
_______________________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


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Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 263CS201
A Phase 2, Randomized, Double-Blind, Multiple-Dose, Placebo-Controlled Study to Evaluate 
the Safety and Efficacy of BIIB104 in Subjects With Cognitive Impairment Associated With 
Schizophrenia (CIAS)
Version 3
Date:  12 June 2019
EUDRA CT NUMBER:  2018-003825-27
IND NUMBER:  106,053
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2.


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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 263CS201 is to expand the number of study 
sites from approximately 40 to approximately 80 and to allow the inclusion of subjects in Japan 
and possibly other countries.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7, Study Design
Now reads:
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the safety, tolerability, and efficacy of BIIB104 in subjects with CIAS. Approximately 219 male 
and female subjects with stable schizophrenia from age 18 to 50 years, inclusive, will be 
recruited. Dosing with BIIB104 0.15 mg BID and 0.5 mg BID versus placebo will be evaluated 
over a treatment phase of 12 weeks. The study will be conducted at approximately 4080 sites 
globally
Section 8.1, Inclusion Criteria
Now reads:
9.  Must be a native English speaker of the local language and be able to read at least at a 6th 
grade level (or equivalent local 11- to 12-year-old age-appropriate reading level) as 
confirmed by the Wide Range Assessment Test 4 – Reading (WRAT4 R) test at Screening. by 
a validated reading assessment test for the local language used in the study (please refer 
to Study Reference Manual for appropriate local reading test).  
Rationale: These changes were made to allow additional sites from Japan and other countries to 
enroll subjects.
These changes also affect:

Section 3, Sponsor Information

Section 5, Schedules of Activities

Section 8, Selection of Subjects

Section 9.1.1.1, Validated Reading Test

Section 11.4.1, Concomitant Therapy




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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 5, Schedules of Activities, Table 3
Change:  A window of up to 3 days is now allowed between completion of the Placebo Lead-In 
evaluation and start of dosing (Baseline/Day 1).
Now reads:
14 The 7-day Placebo Lead-In evaluation may begin any time after eligibility has been established 
based on Screening assessments, provided that the Placebo Lead-In is completed no earlier than 3 
days prior to the Baseline/Day 1 Visit.
Rationale:  The 3-day window was added to allow flexibility in scheduling for subjects and sites 
and is not considered to affect the validity of the Lead-In evaluation results.
This change also affects:

Section 7, Study Design (including Figure 1, Study 263CS201 Schematic)

Section 9.2, Placebo Lead-In
Section 5, Schedules of Activities, Table 4 and Table 5
Change:  Additional 
and safety assessments were added for subjects at 
study sites in Japan.
Now Reads (Table 4 footnotes):
10 For Japanese study sites only (items designated with Footnote 10 are for Japanese sites only 
unless otherwise specified):

On Day 1, in addition to baseline assessments, a 
 will be collected (see Table 5 for 
timing) and additional safety evaluations (AE recording, 12-lead ECG, brief neurological 
examination, and SARA) will be performed 2-hours postdose. Should any abnormal 
findings arise during these evaluations, an additional 
 will be collected. Dosing 
will be performed under medical supervision and observation may be extended at the 
Investigator’s discretion prior to discharge from the site, if necessary, including an 
overnight stay.

 and additional safety 
assessments 2-hours postdose (AE recording, 12-lead ECG, brief neurological exam, and 
SARA) will be performed.








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and written and signed documentation will be provided by the site for each rater’s certification. 
In return, each site will be provided written and signed documentation outlining each rater’s 
certification for specific study assessments. Recertification may be required at periodic intervals 
during the study. The raters who administer specific study assessments will be documented in a 
centralized location, and all site staff who administer ratings will be verified in the site study 
documentation during the conduct of the study.It is recommended that, whenever possible, 
subjects and informants be interviewed and assessed throughout the study by the same rater. 
Reasons for changes in certified raters should be documented in the source. The Study Reference 
Manual provides a detailed description of specific study assessment information.
Rationale: Details that describe the process of selecting, ensuring qualifications, training,
certification, recertification, and documentation of training and certification in study site records 
were removed from the description of rater qualifications since similar instructions are included 
in the Study Reference Manual.  
Section 7.3, Study Stopping Rules
Change: The Diagnostic Interview for Seizure Identification form was specified as an 
assessment to be provided to the independent panel of neurologists in the event of suspected 
seizure.
Now Reads:

All available information regarding the seizure event, including a Diagnostic 
Interview for Seizure Identification form, will be provided to an independent 
panel of neurologists for review and adjudication as to the diagnosis and the 
possible relationship to the blinded study treatment.
Rationale:  This change makes explicit that the use of this form in the evaluation of possible 
seizures is required.
Section 8.1, Inclusion Criteria (Criterion 5)
Change: The criterion was edited to:

make instructions for allowable antipsychotic medication dose ranges applicable to all 
countries and provide more detailed explanation of allowable dose ranges;

change the allowable minor adjustments in maintenance antipsychotic therapy dose from 
less than 25% adjustment to less than or equal to 25% adjustment;

change the term “psychotropic medications” to “psychiatric medications.” 
Now Reads:
5. Subjects must be in ongoing maintenance atypical antipsychotic therapy (except 
clozapine), on a stable treatment regimen for ≥2 months8 weeks prior to Baseline/Day 1, 
including concomitant psychotropic treatments.psychiatric medications. Doses of 


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background atypical antipsychotics should be within the recommended dose range listed 
in the approved product labeling in the USof the country where the study is being 
conducted. Doses exceeding the recommended dose range are not permitted and 
doses below the recommended dose range should be discussed with the Sponsor's 
Medical Monitor (see theSection 11.4.1).

Treatment regimen stability is defined as maintaining the same dosage of 
treatments except for minor adjustments (<(≤25%) to manage medication-specific 
tolerability issues. Recognizing that physicians outside of the study may be 
managing the subject’s background antipsychotic and other 
psychotropicpsychiatric medications, changes in background antipsychotic and 
psychotropicpsychiatric medications should be discussed with the Sponsor’s 
Medical Monitor.

Stable concomitant treatment with a second atypical antipsychotic, at doses that 
do not exceed the range listed in the approved product labeling in the USof the 
country where the study is being conducted, is permissible if used for a 
targeted symptom (e.g., insomnia) or an adverse effect from the primary 
maintenance antipsychotic treatment, but not if it is used for refractory psychotic 
symptoms. Treatment regimen stability as defined above applies to the second 
antipsychotic. Subjects should be taking no more than 2 background 
antipsychotics.
Rationale:  The criterion was edited to accommodate the inclusion of subjects in countries 
outside of the United States (e.g., Japan) and to provide more specificity and greater accuracy to 
the language describing background antipsychotic medication and other concomitant psychiatric 
medication usage.
These changes also affect:

Section 11.4.1, Concomitant Therapy
Section 8.1, Inclusion Criteria (Criterion 7)
Changes:

The specific name of the informant interview tool for PANSS was added.

It was specified that the in-person informant interview does not need to be conducted 
at the study site.
Now Reads:
7. Must have an identified informant (e.g., family member, social worker, caseworker, or 
nurse that spends ≥4 hours per week with the subject) who should, whenever possible, be 
consistent throughout the study and considered reliable by the Investigator. The 


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9
informant will provide input for completing the PANSSInformant Questionnaire for
Positive and Negative Syndrome Scale and SCoRS assessments. The informant needs 
to be able and willing to provide written informed consent and participate in at least one 
in-person interview (during the Screening VisitPeriod; however, the interview does not 
need to be conducted at the study site) and be able to provide input in person or via the 
phone (for all other study visits that include PANSSInformant Questionnaire for
Positive and Negative Syndrome Scale and/or SCoRS assessments). Evidence of 
adequacy of the identified informant should be documented in source documentation. As 
long as both the subject visit and informant visit are within the study visit window, it is 
not necessary that they occur on the same day.
Rationale:

The questionnaire name was spelled out to differentiate the Informant Questionnaire from 
the Structure Clinical Interview.

The clarification on the interview timing is to allow the sites and informants greater 
flexibility for scheduling and conducting the informant interview.
These changes also affect:

Section 5, Schedule of Activities (Table 3, Footnote 2; Table 4, Footnote 16)
Section 8.1, Inclusion Criteria (Criterion 12)
Change: The minimum numeric score was added for the moderate severity rating on the 
positive formal thought disorder item of the SCI-PANSS assessment.
Now Reads:
1. SCI-PANSS: No more than moderate-severe rating (score ≤5) on hallucinations, 
delusions, and hostility; PANSS positive symptom items (P1, P3, P5, P6, P7), or unusual 
thought content (G9); and no more than a moderate severity rating (score ≤4) on positive 
formal thought disorder (P2). 
Rationale: A specific score ensures that standardization of scoring occurs at all study sites.
Section 8.2, Exclusion Criteria (Criterion 3)
Change: The criterion was changed to exclude subjects who participated in any trial that used 
specific assessments within 6 months prior to screening.
Now Reads:


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3. Participation in a CIAStrial that uses any component or version of MCCB or UCSD 
Performance-Based Skills Assessment test within the previous 6 months. 
Rationale:  The change was made to narrow the scope of the exclusion to the specific tests that 
would affect performance in the present study.
Section 8.2, Exclusion Criteria (Criterion 5)
Change: An exclusion for subjects receiving cognitive behavioral therapy was added.
Now Reads:
5. Participation in ongoing cognitive behavioral therapy that was initiated <8 weeks 
prior to Baseline/Day1.
Rationale:  Recent treatment with cognitive behavioral therapy may have an impact on efficacy 
response.
Section 8.2, Exclusion Criteria (Criterion 14)
Change: A numeric value for HbA1c was added to the description of exclusion for type 2 
diabetes. A statement was added to clarify that type 1 diabetes is exclusionary. Some 
explanatory text and the reference to the study reference manual were deleted.
Now Reads:
14. Evidence or history of current clinically significant hematological, renal, endocrine 
(excluding adequately controlled hypothyroidism or hyperthyroidism), pulmonary 
(excluding chronic bronchitis, mild emphysema or chronic obstructive pulmonary 
disease), gastrointestinal (including conditions that can affect drug absorption, e.g., 
gastrectomy), oncological, dermatological, immunological disease, as determined by the 
Investigator in discussion with the Sponsor. Medical conditions not specifically 
addressed in this section may be discussed with the Sponsor’s Medical Monitor to 
determine subject eligibility. Note that controlled type 2 diabetes (as determined by 
current HbA1C guidelines per American Diabetes Association [ADA] criteria (HbA1c 
≤7%) will not be considered a significant medical illness and will not exclude subjects 
from the study; see the Study Reference Manual for details of ADA criteriatype 1 
diabetes is exclusionary.
Rationale:  This paragraph now clearly defines the definition of controlled type 2 diabetes by 
providing an exact numeric cutoff for HbA1c. It also highlights that type 1 diabetes is always 
exclusionary.
Section 8.2, Exclusion Criteria (Criterion 24)
Change:  Replace “psychotropic” with “psychiatric” and provide additional detail about 
discontinuation of psychiatric medications prior to study entry.


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Now Reads:
15. Use of prohibited treatments (see Section 11.4.1) and inability to discontinue these 
concomitant treatments after the Screening Visit. These treatments must be discontinued 
(or tapered if medically indicated) for a minimum of 5 half-lives prior to randomization at 
the Baseline/Day 1 Visit. Note that psychotropic treatments other thanpsychiatric 
medications (excluding psychiatric medications prescribed for non-psychiatric 
conditions and hypnotics) cannot be discontinued to address this criterion due to the 
treatment regimen stability requirements listed in inclusion criterion 5, above.
Rationale:  This change clarifies that psychiatric medications used for non-psychiatric 
conditions may be discontinued in order to meet study entry requirements.
Section 8.2, Exclusion Criteria (Criterion 25)
Change:  An example of a type of concomitant medication that can impair cognition was added.
Now Reads:
25. Use of concomitant treatment that can impair cognition, (e.g., centrally acting 
antihistamines) as determined by the Investigator in consultation with the Sponsor.
Rationale:  The example provides additional information about exclusionary concomitant 
medications.
Section 8.2, Exclusion Criteria (Criterion 31)
Change:  Additional detail was added to the description of exclusion for hepatitis C infection. 
Now Reads:
31. Current, acute hepatitis C infection. Subjects with(defined as positive hepatitis C virus 
[HCV] antibody and normal liver functions tests can be includeddetectable HCV 
ribonucleic acid [RNA]). Subjects with positive HCV antibody and undetectable 
HCV RNA are eligible to participate in the study (United States Centers for Disease 
Control and Prevention).
Rationale:  This criterion was updated for consistency with the current Biogen standard for 
hepatitis C exclusion.
Section 8.2, Exclusion Criteria (Criterion 37)
Change: Exclusion for previous suicide attempts was reduced from 5 years to 2 years.
Now Reads:


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37. Suicide attempt within the last 52 years. Subjects who, in the Investigator’s judgment, 
pose a significant suicide risk, or who have suicidal ideation associated with actual intent 
and a method or plan in the past 6 months (i.e., “Yes” answers on items 4 or 5 of the C-
SSRS) will be excluded from the study.
Rationale:  2 years without suicide attempt is considered clinically acceptable and is consistent 
with other clinical studies of CIAS.
This change also affects:

Section 14.1.4, Columbia Suicide Severity Rating Scale
Section 9.1, Screening
Change: The option for a subject’s legally authorized representative to sign the informed consent 
was removed.
Now reads:
Subjects or their legally authorized representative must provide informed consent before any 
screening tests are performed (see Section 17.3). Participating study sites are required to 
document all screened candidates initially considered for inclusion in the study. 
Rationale:  Only the subject may sign the informed consent.
This change also affects:

Section 15, Safety Definitions, Recording, Reporting, and Responsibilities

Section 17.3, Subject Information and Consent
Section 9.6, Randomization
Change:  Subjects will be stratified by region.
Now reads:
Randomization will be performed using IRT. Randomization will be stratified by region.
Subjects will be randomized in a 1:1:1 ratio to receive one of the following:

BIIB104 0.15 mg

BIIB104 0.5 mg 

placebo   


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Refer to the Study Reference Manual for additional details on randomization.
Rationale:  This change will enable Biogen to investigate whether BIIB104 results in any 
regional differences in the primary and secondary endpoints.
This change also affects:

Section 7, Study Design

Section 16.1.2.1, Analysis of the Primary Endpoint

Section 16.1.2.2, Analysis of the Secondary Endpoints
Section 14.2, Laboratory Safety Assessments
Changes:  

HbA1c will be performed only at Screening

Testing for alcohol was added to the urine drug screen

Editorial changes to terminology and abbreviations (no other changes in sample 
collection or testing)
Now reads:
The following parameters will be analyzed from blood samples collected from subjects at the 
times specified in Section 5. Samples will be analyzed using Good Laboratory Practice-validated 
assays.

Complete blood count (CBC) including:  red blood cell count, white blood cell count 
(WBCs) with differentials (neutrophils, lymphocytes, monocytes, 
eosiniophilseosinophils, and basophils), hemoglobin, hematocrit, platelets, mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular 
hemoglobin concentration.

Serum chemistry, including albumin, alkaline phosphatase, ALT, AST, BUN, 
bicarbonate, calcium, chloride, carbon dioxide, creatinine, creatine kinase, direct 
bilirubin, gamma-glutamyl transferase, glucose, HbA1c, lactate dehydrogenase, 
magnesium, phosphorus, potassium, sodium, total bilirubin, total cholesterol, high-
density lipoproteins, low-density lipoproteins, triglycerides, total protein, and uric 
acid.

Urinalysis, including urine protein, glucose, ketones, occult blood, and WBCswhite 
blood cells by dipstick, with microscopic examination if indicated.


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
Urine drug and alcohol testing (refer to the Study Reference Manual for 
complete list of drugs tested)
At Screening Visit only: testing for human immunodeficiency virus (HIV) [to be performed 
based upon Investigator assessment of HIV risk factors; may be omitted if not permitted by local 
regulations], glycosylated hemoglobin, hepatitis B surface antigen, hepatitis B core 
antibodyHbA1c, HBsAg, anti-HBc, and hepatitis C antibody; alcohol/drug screen;and follicle-
stimulating hormone (postmenopausal women only).
Rationales:

HbA1c collection was decreased to Screening only to assess for diabetes; additional 
testing was considered unnecessary.

Urine alcohol testing was added onto the urine drug screen panel to clarify and 
standardize the method of alcohol testing.
The addition of alcohol testing to urine drug screen affects:

Section 5, Schedules of Activities (Table 3 and Table 4)

Section 8.3.2, Alcohol, Caffeine, and Tobacco

Section 14.2, Laboratory Safety Assessments
Section 17.4, Subject Data Protection
Change: A paragraph providing information about the use and disposition of audio and video 
recordings of clinical assessments was added to the section.
Now Reads:
Audio or video recordings may be made of some clinical assessments in order to allow for 
central review for standardization of test administration, where allowable by country 
and/or local authorities. All audio and video recordings of clinical assessments will be sent 
to each respective site per subject at the end of the study, kept by the vendor 1 year from 
last subject’s last visit, then subsequently destroyed, and not sent to Biogen for archiving 
purposes.
Rationale:  This paragraph explicitly states the use and disposition of audio and video 
recordings of subjects during the study.
This change also affects:

Section 13.1, Clinical Efficacy Assessments

Section 17.3, Subject Information and Consent






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Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
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Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 263CS201
A Phase 2, Randomized, Double-Blind, Multiple-Dose, Placebo-Controlled Study to Evaluate the
Safety and Efficacy of BIIB104 in Subjects With Cognitive Impairment Associated With 
Schizophrenia (CIAS)
Version 2
Date:  10 August 2018
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1.


Protocol 263CS201, Version 2
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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 263CS201 is to decrease the duration of the 
study treatment period from 24 weeks to 12 weeks.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7, Study Design
Now reads:
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the safety, tolerability, and efficacy of BIIB104 in subjects with CIAS. Approximately 219 male 
and female subjects with stable schizophrenia from age 18 to 50 years, inclusive, will be 
recruited. Dosing with BIIB104 0.15 mg BID and 0.5 mg BID versus placebo will be evaluated 
over a treatment phase of up to 2412 weeks. The study will be conducted at approximately 40 
sites in the United States globally. 
The study includes a screening phase, a placebo lead-in phase, a randomized treatment phase 
(with 2 treatment periods), and a safety follow-up (SFU) phase to begin after the last dose of 
study treatment. The primary analysis will be conducted after 12 weeks of placebo-controlled 
treatment(Treatment Period 1). Some subjects will enter the SFU phase after Treatment Period 1
and then conclude their participation in the study. It is planned that most subjects will continue 
placebo controlled treatment for 12 more weeks (Treatment Period 2). Subjects who continue 
into Treatment Period 2 will receive an additional 12 weeks of dosing with study treatment as 
originally randomized (i.e., 24 weeks of continuous dosing for Treatment Periods 1 and 2 
combined), with the SFU phase to occur after the last dose of study treatment.  
To ensure the safety of study subjects, Treatment Period 2 of the study will not begin until 
24-week data from a nonclinical toxicology study, along with any available safety data from 
Treatment Period 1 of the current study, have been reviewed by an Independent Data Monitoring 
Committee (IDMC) and it is determined that dosing up to 24 weeks has an acceptable risk
benefit profile. At the time the decision to continue with Treatment Period 2 is reached, all 
subjects currently in Treatment Period 1 and all subjects enrolled in the study thereafter will 
receive 24 weeks of continuous dosing. The 28 day follow up phase will begin after the last 
dose. Note that subjects who complete the first 12 weeks of treatment (i.e., Treatment Period 1) 
before the determination is made by the IDMC to proceed with 24 week dosing will not 
participate in Treatment Period 2.   
Screening evaluation will occur between 35 days and 8 days prior to randomization. In the 7 days 
prior to randomization, a placebo lead-in assessment will be conducted to evaluate the subject’s 
ability to comply with dosing requirements. After Sponsor confirmation of eligibility and 
completion of baseline measurements at the Baseline/Day 1 Visit, subjects will be randomized in 
a 1:1:1 ratio to receive BIIB104 0.5 mg, BIIB104 0.15 mg, or placebo (planned for 73 subjects 
per treatment group). Subjects will be dosed at approximately 12-hour intervals for 
approximately 12 weeks (Treatment Period 1 only) or approximately 24 weeks (Treatment 


Protocol 263CS201, Version 2
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3
Periods 1 and 2). Total duration of subject participation will be up to approximately 2119 weeks
(Treatment Period 1 only) or approximately 33 weeks (Treatment Periods 1 and 2) from 
screening to final follow-up visit.
See Figure 1 for a schematic presentation of the study design.
Rationale:  Per regulatory agency advisement, current nonclinical data does not support the 24-
week treatment period planned in Version 1 of this protocol. Therefore, the second 12 weeks of 
treatment (referred to as Treatment Period 2 in the original protocol) are removed from
Version 2.
This change also affects:

Section 1, Synopsis

Section 4.4, Study Rationale

Section 5, Schedules of Activities

Section 6, Study Objectives and Endpoints

Figure 1, Study 263CS201 Schematic

Section 7.1, Study Duration for Subjects

Section 8.3.1, Meals and Dietary

Section 11.1, Regimen


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 7.1, Study Duration for Subjects
Change:  In addition to the overall change in study treatment duration, as described in the 
Primary Reason for Amendment section, the duration of the safety follow-up phase was reduced 
from 4 weeks to 2 weeks.Now reads:
The maximum total duration of study participation for each subject will be up to approximately 
33 approximately 19 weeks including a screening phase of approximately 5 weeks, a 
treatment phase of approximately 12 weeks, and a safety follow-up phase of approximately 
2 weeks.
The duration of the Screening phase will be approximately 5 weeks, including a 4 week 
screening period and a 1 week placebo lead in period. 
The duration of Treatment Period 1 will be approximately 16 weeks including a 12 week 
placebo controlled treatment phase and a 4 week SFU phase (SFU only for subjects who do not 
participate in Treatment Period 2). Therefore, for subjects who do not continue into Treatment 
Period 2, total study duration will be approximately 21 weeks.
For subjects who continue into Treatment Period 2, placebo-controlled treatment will continue 
for approximately 12 weeks with no pause in dosing after Treatment Period 1 (for a total of 
approximately 24 weeks of continuous treatment during the study). The 4 week SFU phase will 
begin after the last dose. Therefore, for subjects who participate in Treatment Period 2, total 
study duration will be approximately 33 weeks, including a 4 week screening phase, a 1 week 
placebo lead in phase, a 24 week treatment phase, and a 4 week SFU phase.
The end of study date for a subject may be the last study visit, last follow-up telephone 
conversation, or last protocol-specified assessment.  If the subject has ongoing AEs that are being 
followed, the end of study date may be the date of AE resolution.
Rationale:  Based on evaluation of current clinical and nonclinical safety data, as well as the 
pharmacological profile of BIIB104, a 14-day safety follow-up period is considered to be an 
adequate post-treatment duration to assess the safety of BIIB104 following the 12-week treatment
period.
This change also affects:


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
Section 1, Synopsis

Section 5, Schedules of Activities

Section 7, Study Design

Figure 1, Study 263CS201 Schematic

Section 10.1, Discontinuation of Study Treatment


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

Typographical errors and formatting irregularities were corrected.

In Section 7, Study Design, the location of the study was changed from “the United 
States” to “globally.” 

A statement was added to Section 9.1.1, Screening Assessments, and Section 13.1, 
Clinical Efficacy Assessments, as follows: “Some [“screening” specified in 9.1.1] 
assessments may be recorded (see Study Reference Manual for further details).” 

In Section 8.2, exclusion criterion 22 was modified to state that marijuana use is 
prohibited at any time during the study.

In Section 11.4.1, Concomitant Therapy, cognitive remediation therapy and 
electroconvulsive therapy were added to the list of prohibited therapies during the 
study (these were already listed as exclusion criteria in Section 8.2).

In Section 14.2, Laboratory Safety Assessments, the text describing blood sample 
collection for the complete blood count was edited to specify white blood cell count 
differentials (neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

SAP_001.pdf: 


2
VERSION HISTORY
SAP Version
Date
Primary Reasons for 
Amendment
V1.0
11-JAN-2021
V2.0
30-MAR-2022
Additional analyses and 
clarifications made as a 
result of Interim Analysis, 
Dry Run review and 
Advisory Board comments


3
1. TABLE OF CONTENTS
VERSION HISTORY ................................................................................................................2
1.
TABLE OF CONTENTS....................................................................................................3
LIST OF ABBREVIATIONS ....................................................................................................5
1.  DESCRIPTION OF OBJECTIVES AND ENDPOINTS .....................................................8
1.1
Primary Objective and Endpoints ................................................................................8
1.2
Secondary Objectives and Endpoints...........................................................................8
9
9
9
2.
STUDY DESIGN..............................................................................................................10
2.1
Study Overview..........................................................................................................10
2.2
Study Schematic.........................................................................................................11
2.3
Schedule of Events.....................................................................................................11
3.
SAMPLE SIZE JUSTIFICATION ...................................................................................11
4.
STATISTICAL ANALYSIS METHODS ........................................................................12
4.1
General Considerations ..............................................................................................12
4.1.1
Analysis Population ..........................................................................................13
4.2
Imputation of Partial Dates for Adverse Events and Concomitant Medication.........13
4.3
Background Characteristics........................................................................................14
4.3.1
Accounting of Subjects.....................................................................................14
4.3.2
Demographics and Baseline Characteristics.....................................................15
4.3.3
Concomitant Medications and Antipsychotic Treatment .................................15
4.3.4
Protocol Deviations...........................................................................................16
4.3.5
Study Drug Exposure and Study Drug Compliance .........................................16
4.4
Efficacy Analysis .......................................................................................................17
4.4.1
General Considerations.....................................................................................17
4.4.2
Primary Efficacy Endpoint ...............................................................................20
4.4.3
Secondary Efficacy Endpoints..........................................................................20
21
22
4.5
Safety Analysis...........................................................................................................23
4.5.1
General considerations......................................................................................23
4.5.2
Adverse Events .................................................................................................23
4.5.3
Clinical Laboratory Data ..................................................................................25
4.5.4
Vital Signs.........................................................................................................28


4
4.5.5
C-SSRS data .....................................................................................................29
4.5.6
Physical and Neurological Exams ....................................................................30
4.5.7
SARA................................................................................................................31
4.5.8
Electrocardiogram (ECG).................................................................................31
4.5.9
COVID-19 Related Analyses............................................................................32
32
32
33
33
33
5.
INTERIM ANALYSIS .....................................................................................................33
6.
REFERENCES..................................................................................................................35
 


5
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine transaminase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
AMPAR
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
AST
aspartate transaminase
AUC
area under the plasma drug concentration-time curve
AUC2 
area under the plasma drug concentration-time curve from 0 to 2 hours
AUC4 
area under the plasma drug concentration-time curve from 0 to 4 hours
AUC24 
area under the plasma drug concentration-time curve from 0 to 24 hours
AUCinf 
area under the plasma drug concentration-time curve from 0 to infinity
AUClast
area under the plasma drug concentration-time curve from 0 to the time of last 
measurement
AUCtau
area under the concentration-time curve within a dosing interval
BID
twice daily
Cb,u
unbound brain drug concentration
Ceff
efficacious plasma drug concentration
BUN
blood urea nitrogen
 
 
CGI-I
Global Clinical Impression – Improvement
CGI-S
Global Clinical Impression – Severity
CIAS
cognitive impairment associated with schizophrenia
Cmax
maximum observed plasma concentration
Cmin
minimum plasma drug concentration
CNS
central nervous system
CRF
case report form
eCRF
electronic case report form
CSF
cerebrospinal fluid
Css,av
average steady-state drug plasma concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
CYP
cytochrome P450 
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
EC
ethics committee
ECG
electrocardiogram
EDCMS
electronic data capture and management system
EQ-VAS
Euroqol-Visual Analog Scale


6
ERP
Event-related potential
ET
early termination
EU
European Union
FDG
2-deoxy-2-[18F]fluoro-D-glucose
fMRI
functional magnetic resonance imaging
HIV
human immunodeficiency virus
 
 
IA
Interim analysis
ICH
International Council for Harmonisation
ID
identification
IDMC
independent data monitoring committee
IQ
intelligence quotient
IRB
institutional review board
IRT
interactive response technology
ITT
intent to treat
LNS
letter number sequencing
MAD
multiple ascending dose
MAR
missing at random
MATRICS
Measurement and Treatment Research to Improve Cognition in Schizophrenia
MCCB
MATRICS Consensus Cognitive Battery
MGH
Massachusetts General Hospital
MHP
mental health professional
MINI
Mini-International Neuropsychiatric Interview for Psychotic Disorders
MMRM
mixed model repeated measures 
MTD
maximum tolerated dose
NMDA
N-methyl-D-aspartate
NMDAR
N-methyl-D-aspartate receptor
NOAEL
no observable adverse effect level
NOEL
no observable effect level
NPI
Neuropsychiatric Inventory
PANSS
Positive and Negative Syndrome Scale
PD
pharmacodynamics
QD
once daily
QTcF
QT interval corrected for heart rate using Fridericia’s correction
RNA
ribonucleic acid
SAE
serious adverse event
SAFER 
(criteria)
State versus trait, Accessibility, Face validity, Ecological validity, Rule of 3 Ps 
(pervasive, persistent, and pathological)
SAP
statistical analysis plan


7
SARA
Scale for the Assessment and Rating of Ataxia
SCI-
PANSS
Structured Clinical Interview for Positive and Negative Syndrome Scale
SCID
Structured Clinical Interview for DSM disorders
SCoRS
Schizophrenia Cognition Rating Scale
SD
standard deviation
SM
safety margin
TID
3 times daily
UCSD
University of California, San Diego
ULN
upper limit of normal
US
United States
UPSA-Bi
UCSD Performance-Based Skills Assessment – Brief, international version
WRAT4-R
Wide Range Achievement Test 4 – Reading


8
1.  DESCRIPTION OF OBJECTIVES AND ENDPOINTS 
1.1
Primary Objective and Endpoints
The primary objective of the study is to evaluate the efficacy of BIIB104 in subjects with 
cognitive impairment associated with schizophrenia (CIAS), using the Working Memory Domain 
of the MATRICS Consensus Cognitive Battery (MCCB). 
The primary endpoint that relates to this objective is the change from baseline in MCCB Working 
Memory Domain score to Week 12. 
1.2
Secondary Objectives and Endpoints
The secondary objectives are:
•
To evaluate the safety and tolerability of BIIB104 in subjects with CIAS.
•
To evaluate the efficacy of BIIB104 in subjects with CIAS on measures of cognition,
functioning, and psychiatric symptomology, as measured by:
o
University of California, San Diego Performance Based Skills Assessment–Brief,
     international version (UPSA-Bi)
o
Schizophrenia Cognition Rating Scale (SCoRS)
o
MCCB
o
Positive and Negative Syndrome Scale (PANSS)
o
Clinical Global Impression–Severity (CGI-S) and Clinical Global Impression
     Improvement (CGI-I).
The secondary endpoints are:
•
Incidence of adverse events (AEs) and serious adverse events (SAEs) reported during the
study, Scale for the Assessment and Rating of Ataxia (SARA), Columbia–Suicide Severity 
Rating Scale (C-SSRS)
•
Change from baseline in UPSA-Bi assessment to Week 12
•
Change from baseline in SCoRS assessment to Week 12
•
Change from baseline in MCCB Composite and Individual Domain scores (excluding
    Working Memory Domain) to Week 12
•
Change from baseline in PANSS total score, and subscale scores to Week 12
•
Change from baseline in CGI-S to Week 12 
•
CGI-I at Week 12


9
•
•
•
   
•
•
•
     
 
•
    
•
•
 
 
•
          
•
•
•


10
2.
STUDY DESIGN
2.1
Study Overview
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the safety, tolerability, and efficacy of BIIB104 in subjects with CIAS. Approximately 219 male 
and female subjects with stable schizophrenia from age 18 to 55 years, inclusive, will be 
recruited. Dosing with BIIB104 0.15 mg BID and 0.5 mg BID versus placebo BID will be 
evaluated over a treatment phase of 12 weeks. The study will be conducted at approximately 80 
sites globally including non-English speaking countries.
The study includes a screening phase, a placebo lead-in phase, a randomized treatment phase,
and a safety follow-up (SFU) phase to begin after the last dose of study treatment. 
Screening evaluation will occur up to 35 days prior to randomization. Once eligibility has been 
established, a 7-day Placebo Lead-In evaluation will be conducted to assess the
subject’s ability to comply with dosing requirements. After Sponsor confirmation of eligibility
and completion of baseline measurements at the Baseline/Day 1 Visit, subjects will be
randomized in a 1:1:1 ratio to receive BIIB104 0.5 mg, BIIB104 0.15 mg, or placebo. Subjects 
will be dosed at approximately 12-hour intervals for 12 weeks. Total duration of subject 
participation will be approximately 19 weeks from screening to final follow-up visit.
There are 3 treatment groups and subjects are randomized in a 1:1:1 ratio into 1 of 3 treatment 
groups. The randomization will be stratified by region. 
Table1: Treatment groups
Treatment Groups
Description
Placebo group 
Up to 73 subjects to receive oral dosing BID
with placebo for 12 weeks.
BIIB104 0.15 mg group
Up to 73 subjects to receive oral
dosing BID with BIIB104 0.15 mg for 12 weeks
BIIB104 0.5 mg group
Up to 73 subjects to receive oral
dosing BID with BIIB104 0.5 mg for 12 weeks


11
2.2
Study Schematic
Figure 1: study design
2.3
Schedule of Events
See protocol section 5. 
3.
SAMPLE SIZE JUSTIFICATION
The protocol states that:
Fifty-one subjects per treatment group will have approximately 80% power to detect a true mean 
difference of 3.5 in change from baseline MCCB Working Memory Domain score to Week 12 
between the treatment and placebo groups.  With the assumed drop-out rate of 30%, 73 subjects 
are required from each group to maintain the 80% power. This power calculation is based on a 2-


12
sided t-test assuming equal variance with a final significance level of 0.1, and a standard deviation 
of 7. The statistical software EAST 6.3® is used for sample size calculation. The sample size may 
be re-estimated based on blinded data review and evolving development of the study.
4.
STATISTICAL ANALYSIS METHODS
4.1
General Considerations
This statistical analysis plan (SAP) describes the planned analyses for this phase 2 study 
evaluating the primary, secondary 
 objectives. This SAP also covers the planned 
interim and final analyses, and therefore there is no separate SAP for the interim analysis. 
Data listings will be provided by treatment group, visit, and subject, if applicable. Summary 
statistics and statistical analyses will only be presented for data where detailed in this SAP. For 
continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation (SD), median, minimum (Min), maximum (Max) and n; for log-normal data the 
geometric mean and geometric coefficient of variation (CV) will also be presented. For 
categorical data, frequency count and percentages will be presented. Data listings will be provided 
for all subjects up to the point of withdrawal, with any subjects excluded from the relevant 
population highlighted. Summary statistics and statistical analyses will generally only be 
performed for subjects included in the relevant analysis population.
Data will be summarized and presented by treatment group, defined in Table 1. Data will be listed 
by treatment group. Exposure to study medication will be tabulated by treatment group. 
Unless stated otherwise, baseline data are defined as the data collected prior to the time and/or on 
the day of the first dose, which is usually the same day as the Day1/Baseline visit. If data are not 
available on Day 1 for safety assessment, the measurements recorded up to 3 days prior to first 
dose (i.e. Day -3) will be used as baseline. For efficacy assessments, the Day1/Baseline visit may 
be performed over 2 days, i.e., on Day 1 and Day 2. Therefore, an assessment performed on the 
second day of visit Day1/Baseline (i.e., Day 2), will be used as baseline if not already performed 
on the first day of visit Day1/Baseline (i.e., Day 1). If there is more than one value on/before the 
day of the first dose, the non-missing value closest to and prior to the first dose will be used as the 
baseline value 
Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level of 
0.10. 
The statistical software, SAS 9.4®, will be used for all summaries and statistical analyses. 


13
4.1.1
Analysis Population
•
Intent-to-treat (ITT) population: 
The ITT population is defined as all randomized subjects who received at least one dose of study 
treatment (BIIB104 or placebo). Subjects will be in the treatment group to which they were 
randomized in statistical analyses based on the ITT population.
•
Per-protocol (PP) population: 
The PP population is defined as all subjects in the ITT population who do not have major protocol 
deviation(s) that impact efficacy. Exclusion of subjects from the PP population will be determined 
by the SMT members including but not limited to medical director, clinical pharmacologist and 
biostatistician. The main reasons for exclusion will be documented.  
•
Safety population: 
The safety population is defined as all randomized subjects who received at least 1 dose of study 
treatment (BIIB104 or placebo). Subjects will be in the treatment group they received in statistical 
analyses based on the safety population.
•
 
 
 
4.2
Imputation of Partial Dates for Adverse Events and Concomitant 
Medication
Partial start dates (of intervention or event): 
•
Case 1, day is missing (only month and year are present):
o
If year and month are same as treatment period start date, then assign the day of 
treatment period start date to the partial date. [worst case scenario (WCS)] 
▪
However, if end date of event or intervention is clearly before treatment 
period start date, assign day ‘01’ to partial start date. [Max Duration]
o
Otherwise, assign day of ‘01’ to partial start date. [Max Duration]
•
Case 2, only year is present:
o
If year is same as treatment period start date, then assign the month and day of the 
treatment period start date to the partial date. [WCS]
▪
However, if end date of event or intervention is clearly before treatment 
period start date, assign ‘Jan. 01’ to partial start date. [Max Duration]
o
Otherwise, assign the month and day of ‘Jan. 01’ to partial start date. [Max 
Duration]
•
Case 3, completely missing date, no imputation is performed.


14
Partial end dates (of intervention or event): 
•
Case 1, day is missing (only month and year are present): 
o
If year and month are same as study end date, then assign the day of the study end 
date to the partial date. [Do not exceed study end]
o
Otherwise, assign day of last day of the month (28, 29, 30 or 31) to the partial end 
date [Max Duration]
•
Case 2, only year is present: 
o
If year is same as study end date, then assign the month and day of the study end 
date to the partial date.  [Do not exceed study end]
o
Otherwise, assign ‘Dec. 31’ to the partial end date. [Max Duration]
•
Case 3, completely missing date, no imputation is performed.
If any partial dates have missing month, with day present, then day is ignored and considered 
missing.  The year-only scenario is considered for imputation purposes.
Also, if the study is ongoing (e.g., interim analysis) and study end date is not available then the 
cut-off date will be used in the place of study end date.  If both a cut-off date and study end date 
are present for a patient, then the minimum of the two dates will be used as the study (or 
reference) end date.
4.3
Background Characteristics
The summaries in this section will be based on the ITT population. Unless otherwise specified, 
summary tables will be presented by treatment group (BIIB104 0.15mg, BIIB104 0.5mg, and 
placebo). All the listing will be presented by treatment group. 
4.3.1
Accounting of Subjects
Accounting of subjects will include number (%) of subjects randomized and dosed, number (%) of 
subjects who completed the treatment/study, number (%) of subjects who discontinued treatment, and 
number (%) of subjects who withdrew from study. For subjects who discontinued treatment, the 
reasons for treatment discontinuation and the number of days on treatment will be summarized. For 
subjects who withdrew from the study, the reasons for withdrawal and the number of days on the 
study will be summarized. Time to treatment discontinuation and time to study withdrawal will be 
displayed by Kaplan-Meier plots. 
Accounting of subjects will be also summarized in each analysis population. 


15
4.3.2
Demographics and Baseline Characteristics
The demographic information of age, gender, ethnicity, race, height, weight, smoking status, and body 
mass index (BMI) will be summarized by treatment group. By-subject listings of such information 
will be provided.
The categorization of regions is determined from geography, language and culture from each 
country. The region category will be used as a covariate in statistical models and in subgroup 
analyses as appropriate.
Baseline clinical assessment variables include baseline MCCB domains, MCCB overall 
composite score, MCCB neurocognitive composite score, UPSA-Bi, SCoRS, PANSS total score, 
PANSS Positive Scale, PANSS Negative Scale, PANSS General Psychopathology Scale, SARA, 
C-SSRS, and CGI-S.  Number of years since first episode of schizophrenia, age of first treatment 
of schizophrenia, number of previous episodes or exacerbations of schizophrenia in the last 24 
months, and number of past psychiatric hospitalizations will also be summarized. 
Medical history will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). The number (%) of subjects with history (including both ongoing and not 
ongoing medical conditions) will be summarized by system organ class and preferred term. A listing 
of medical history will be generated.
4.3.3
Concomitant Medications and Antipsychotic Treatment
Concomitant medications will be coded using the latest version of the World Health Organization 
(WHO) medication dictionary. Concomitant non-drug treatments will be coded using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA). A concomitant 
medication could be taken on or after the day of the first dose of study drug. This includes 
concomitant medications that start prior to the initiation of the first dose if their use continues or 
after the date of first dose. An antipsychotic treatment is any treatment for CIAS that is ongoing at 
the time of trial entry.
To define concomitant use for therapies or antipsychotic treatments with missing start or stop 
dates, the following additional criteria will be used:
•
If both the start and stop dates of a therapy are missing, then the therapy will be 
considered concomitant;
•
If the start date of a therapy is missing and the stop date of that therapy falls on/after the 
first dose date, the therapy will be considered concomitant;


16
•
If the start date of a therapy is prior to the date of the first dose and the stop date of the 
therapy is missing and the therapy is listed as ongoing, that therapy will be considered 
concomitant;
•
If the start date of a therapy is prior to the date of first dose and the stop date of that 
therapy is missing and the therapy is not listed as ongoing, the therapy will be considered 
non-concomitant.
•
If start date of a therapy is after the last dose date but before the end of study date, the 
therapy will be considered concomitant. 
The number and percent of subjects taking concomitant medication, non-drug treatments and 
antipsychotic treatment will be summarized by treatment group. 
4.3.4
Protocol Deviations
Protocol deviations identified during site monitoring will be captured in a protocol deviation log 
and categorized as major or minor deviations. The major protocol deviations will be summarized 
by treatment groups. Listings will be generated for the major and minor protocol deviations. 
4.3.5
Study Drug Exposure and Study Drug Compliance
A summary table of study drug exposure and compliance will be provided.  Number of weeks on 
study treatment (BIIB104 or placebo), will be calculated as (date of last dose – date of first dose 
+1) /7. The cumulative duration of weeks on study treatment will be displayed (≥ 1,  ≥ 2,  ≥ 4, ≥ 
6, ≥ 8, ≥ 12 weeks). Descriptive statistics will be presented for days on study treatment. 
Compliance, which is the percentage of study treatment taken up to the last dose, calculated as 
(the actual number of dose taken / by the number of doses a subject is expected to take until the 
date of last dose) *100, will be summarized both as a continuous variable and a categorical 
variable (i.e., < 80, 80 to < 90, 90 to <=100, and >100%).  
Time on study (in weeks) will be summarized both as a continuous variable and a categorical 
variable. The categorical variable will be grouped as ≤ 2, 2 - ≤ 4, 4 - ≤ 6, 6 - ≤ 8, 8 - ≤ 10, 10 - ≤ 
12, and >12 weeks. 
A listing of study drug administration records for placebo subjects who received any dose of 
active treatment will be provided. 


17
4.4
Efficacy Analysis
4.4.1
General Considerations
For efficacy endpoints, the following treatment groups of BIIB104 (per randomization) will be 
evaluated and compared with placebo: 
•
High dose (0.5 mg BID) 
•
Low dose (0.15 mg BID) 
 
All efficacy analyses will be performed on the ITT population. In addition, the per-protocol 
population will also be used in the analyses of primary and key secondary efficacy endpoints 
including MCCB Working Memory, MCCB Neurocognitive Composite, UPSA-Bi, SCoRS. 
Primary analysis for continuous endpoints
The primary analysis is the mean difference of the change from baseline to Week 12 between 
treatment and control group in the ITT population. Data will be censored when a subject prematurely 
discontinues the study treatment. The estimate of this analysis reflects the treatment effect of BIIB104 
if the drug were taken as directed. This is considered [de jure] efficacy estimand [ICH E9 (R1) 
Addendum 2014, 2017].
The change from baseline will be summarized by treatment group at each post-baseline visit. A mixed 
model repeated measures (MMRM) model will be used as the primary analysis to analyze change 
from baseline of the endpoint of interest, using fixed effects of treatment group, study visit, study 
visit-by-treatment interaction, baseline value of the endpoint, and baseline-by-visit interaction. Region 
(stratification factor for randomization) will be included as a fixed effect but may be omitted in the 
case that the model fails to converge. An unstructured covariance matrix will be used to model the 
within-patient variance-covariance errors. If the unstructured covariance matrix results in a lack of 
convergence, the following structures will be used in order: heterogeneous Toeplitz (TOEPH), 
heterogeneous compound symmetry (CSH), antedependence (ANTE1), heterogeneous autoregressive 
(ARH1), autoregressive (AR1) and compound symmetry (CS). The first covariance structure yielding 
convergence will be used. If a structured covariance is used, the empirical “sandwich” estimator of the 
standard error (SE) of the fixed effects parameters will be used to deal with possible model 
misspecification of the covariance matrix. The Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom. The primary treatment comparison is BIIB104 treatment group 
versus placebo at the end of Week 12. In the primary analysis, missing data are assumed to be missing 
at random (MAR) [Rubin 1976]. To account for the interim analysis at the time of the final analysis, 
the median unbiased estimate of the primary treatment effect will be calculated as a supporting 
analysis.


18
However, for UPSA-Bi and SCoRS, which only have assessments at baseline and at Week 12, the 
primary analysis will be based on subjects who have both baseline and Week 12 assessments. An 
analysis of covariance (ANCOVA) model will be applied adjusting for treatment group and baseline 
value of the endpoint (UPSA-Bi or SCoRS, respectively). 
Sensitivity analysis: Reference-based multiple imputation approach
The following sensitivity analysis will be performed to assess the robustness of the primary analysis 
with respect to deviation from the MAR assumption. All sensitivity analyses will be conducted for the 
ITT population.
Intermittent (non-monotonic) missing data will be imputed based on the MAR assumption and with a 
multiple imputation model using Markov chain Monte Carlo (MCMC) method within each treatment 
group. The imputation models will include baseline value and the values at each post-baseline week 
for the endpoint of interest. The MCMC method in the PROC MI procedure in SAS will be used with 
a single chain, with a burn-in of 1000, and a thinning of 100 and non-informative priors for all 
parameters.
Reference-based multiple imputation (MI) approach will be used to impute missingness post treatment 
discontinuation and consider a missing not at random (MNAR) mechanism for monotonic missing 
data. Imputed values in the reference group (placebo) will assume MAR. Imputed values in the 
BIIB104 treatment groups will be based on data from the placebo group using sequential regression 
MI model. Each sequential regression model (i.e., for imputation of values at a given week) will 
include visits of endpoint. This approach assumes no sustained benefit of BIIB104 after 
discontinuation of study treatment and limits post-discontinuation effects to that of placebo. 
Two hundred imputations will be performed and from each of the imputed datasets, least square (LS) 
mean differences from placebo and their standard errors will be combined using Rubin’s method 
[Rubin 1987]. PROC MIANALYZE procedure is used to produce a pooled LS mean estimate of 
treatment difference at Week 12, its 95% CI, and a pooled p-value. 
Complementary Analysis: include data after intercurrent events 
This is a complementary analysis to the primary and sensitivity analyses (efficacy estimand) for the 
ITT population. All observed data including those collected after intercurrent events [ICH E9 (R1) 
Addendum 2017], i.e. premature discontinuation of the study treatment, will be included. The estimate 
of this analysis reflects the treatment effect of BIIB104 seen as actually taken. This is considered [de 
facto] effectiveness estimand. When all data after intercurrent events are included, the same MMRM 
model as the primary analysis will be applied. In this complementary analysis, missing data are 
assumed to be missing at random [Rubin 1976]. 
The per-protocol analysis will be done using the same model as the primary analysis and applying 
in the per-protocol population. 


19
Responder Analysis: threshold determined using distribution-based method 
This is a supplementary analysis to assess the effect of individual treatment response in the ITT 
population only. The threshold, defined as the minimal clinically important difference (MCID), 
will be estimated based on the distribution-based approach and will use 1/2 pooled standard 
deviation at baseline calculated from subjects in the ITT population. A subject will be classified 
as a responder if their change from baseline (in terms of improvement) is greater or equal to the 
threshold, otherwise they will be classified as a non-responder. All subjects with missing data at 
Week 12 will be classified as non-responders.
The number of responders and non-responders will be modelled using a logistic regression with 
treatment group and baseline included as covariates.  Region will also be included but may be 
omitted in the case the model fails to converge.  
Visit windows for mapping efficacy endpoints
For efficacy data that are summarized by visit, data collected on all scheduled visits and all 
unscheduled visits will be mapped to an appropriate analysis visit using the windowing scheme 
shown in the following few tables. If there are 2 or more assessments available in the same 
analysis window for a subject, the assessment closest to the target visit day will be used for 
analysis. If there are 2 or more assessments in the same analysis window with the same distance 
from the target visit day, the later assessment will be used.
Table 2: Visit Windows for Efficacy Endpoints: MCCB, 
 
, and PANSS
Analysis visit 
Target visit day Analysis visit window
Baseline
1
Prior to the time of, or within one day after, the first treatment dose
Week 2
15
[2, 28]
Week 6
43
[29, 70]
Week 12
85
[71, 91]
* If subject terminate the treatment before Day 71, their visits will be mapped to corresponding analysis visit 
based on the analysis day (ADY). 
Table 3: Visit Windows for efficacy endpoints: UPSA-Bi, SCoRS, 
Analysis visit 
Target visit day Analysis visit window
Baseline
1
Prior to the time of, or within one day after, the first treatment dose
Week 12 
85
[71, 91] 
Early Termination
N/A
[2, 70]
* If subject terminate the treatment early before Day 71, their visits will be mapped to nominal visit of “early 
termination”. 


20
Table 4: Visit Windows for Efficacy Endpoints: CGI-S/CGI-I
Analysis visit 
Target visit day 
Analysis visit window
Baseline
1
Prior to the time of, or within one day after, the first treatment dose
Week 6
43
[2, 70]
Week 12
85
[71, 91]
* CGI-I does not have baseline collected and therefore its visits are applied to Week 6 and 12. 
* If subject terminate the treatment early before Day 71, their visits will be mapped to corresponding analysis 
visit based on the analysis day (ADY). 
Considerations for multiple comparison adjustments 
There will be no multiple comparison adjustments for primary, secondary efficacy 
 
endpoints, nor the subgroup analyses.
4.4.2
Primary Efficacy Endpoint
4.4.2.1
Primary Analysis
The primary endpoint is the change from baseline in MCCB Working Memory Domain
score to Week 12. The MMRM model will be applied to the primary endpoint and it is described 
in Section 4.4.1. The same model will also be applied to per-protocol population. 
4.4.2.2
Sensitivity Analysis
Reference-based multiple imputation approach will be performed on the primary endpoints using 
the methods as described in Section 4.4.1.
4.4.2.3
Complementary Analysis 
All observed data including those collected after intercurrent events will be applied by MMRM 
model to the primary endpoint. 
4.4.2.4
Responder Analysis 
The number of responders and response rate in MCCB Working Memory at Week 12 will be 
summarised and modelled using the methods as described in Section 4.4.1. 
4.4.3
Secondary Efficacy Endpoints
Three key secondary endpoints including changes from baseline to Week 12 in MCCB 
neurocognitive and overall composite scores, UPSA-Bi, and SCoRS will be applied by the 
primary analysis, sensitivity analysis, and complementary analysis described in Section 4.4.1. A 
responder analysis for MCCB neurocognitive, UPSA-Bi Total score, and SCoRS Interviewer 
Rating Subtotal score only will also be applied as described in Section 4.4.1.


21
Other secondary efficacy endpoints including MCCB individual domain (except working memory 
domain), PANSS total score, PANSS positive syndrome, PANSS negative syndrome, CGI-S will 
be applied by MMRM model of the primary analysis only, which is described in Section 4.4.1. 
The summaries of CGI-I at Week 12 will be displayed. 
 
 
 
The analysis methods used for primary, secondary, 
 endpoints are listed in table 5: 
Table 5: Analysis for Efficacy Endpoints:
Endpoints
Analysis
Analysis 
Population
Assumption 
for Missing 
Data
Primary (for MCCB Working 
Memory, and Neurocognitive 
Composite): analysis of 
change from baseline to Week 
12 (MMRM)
ITT and per-
protocol 
population
Missing at 
Random 
(MAR) 
Primary (for UPSA-Bi and 
SCoRS): analysis of change 
from baseline to Week 12 
(ANCOVA)
ITT and per-
protocol 
population
N/A
Sensitivity: multiple 
imputation using MCMC 
(MAR) for intermittent 
missing data; reference-
based multiple imputation 
missing data post treatment 
discontinuation
ITT
Missing at 
Random 
(MAR) for 
intermittent 
missing data 
and Missing 
Not at Random 
(MNAR) for 
missing data 
post treatment 
discontinuation
Primary endpoint and 
key secondary 
endpoints: 
MCCB Working 
Memory, MCCB 
Neurocognitive 
Composite, UPSA-Bi, 
SCoRS
Complementary: include data 
after intercurrent events 
ITT
Missing at 
Random 
(MAR)




23
4.5
Safety Analysis
4.5.1
General considerations
Analysis population
Safety population will be used for safety analyses of adverse events, clinical laboratory data, 
Columbia Suicide Severity Rating Scale (C-SSRS) data, ECG data and vital signs data.  
Safety treatment groups 
Different from efficacy analysis, for safety treatment group if a subject who was randomized to a 
placebo group accidentally received one or more doses of the active treatment during the study, he 
or she will be classed to low or high dose group based on the dose group of the active treatment 
received. A listing of these subjects will be provided. Safety treatment groups will be the same as 
the randomization treatment groups for other subjects (subjects randomized to active treatment 
groups, and subjects randomized to placebo without any accidental active dose). Safety treatment 
groups will be used for all the safety analyses unless otherwise specified. 
Incidence and incidence proportion
Incidence and incidence proportion will be provided in incidence tables. Incidence is defined as 
the number of subjects who experienced an event. Incidence proportion is defined as the number 
of subjects who experienced an event divided by total number of subjects in the analysis 
population, i.e., percentage. Each subject will be counted only once within each category. 
4.5.2
Adverse Events
All AEs will be analysed based on the principle of treatment emergence. A TEAE is defined as an 
AE that started or worsened between the time of first dose  of study treatment and the end of 
study date (EOS/ET Visit) recorded on the eCRF.  


24
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used:
•
if both the start and stop dates for an AE are missing, then this AE is considered treatment 
emergent;
•
if the start date for an AE is missing and the stop date falls after the first dose date, then this 
AE is considered treatment emergent;
•
if the start date for an AE was the same as the first dose date, then that event is considered 
treatment emergent.
4.5.2.1
Summary of adverse events 
Overall TEAE summary table will include the number of subjects with any TEAE, with any 
TEAE by maximum severity, the number of subjects with any related TEAE, the number of 
subjects with SAE, the number of subjects with related SAE, the number of subjects with TEAE 
leading to study drug discontinuation, the number of subjects with TEAE leading to study 
withdrawal, and the number of deaths. 
A subject is counted only once within each category in each table. A subject with more than one 
TEAE for a preferred term will be counted only once in preferred term.  Similarly, a subject who 
experienced more than one TEAE for a system organ class (SOC) will be counted only once in 
that SOC category. 
The sorting order for AE incidence tables, unless otherwise specified, will be by decreasing 
frequency order of BIIB104 total column within each category. A subject is counted only once 
within each category in each table. For the table of TEAEs by system organ class and preferred 
terms sorted by decreasing frequency presented by treatment group, system organ class will be 
presented in decreasing frequency order of BIIB104 total column, and within each system organ 
class, preferred terms will be presented in decreasing frequency order of total column. A subject 
is counted only once within each system organ class and preferred term.
The following TEAE incidence tables will be presented by treatment group:
•
Overall summary of adverse events
•
TEAEs by system organ class and preferred term sorted by decreasing frequency
•
TEAEs by system organ class and preferred term sorted by alphabetical order
•
TEAEs with at least 5% higher in incidence for either low or high dose compared to  
    placebo, by SOC and preferred term
•
TEAEs by preferred term with an incidence rate of 5% or more in any treatment group 
•
SAEs by system organ class and preferred term by decreasing frequency
•
SAEs by preferred term


25
•
TEAE by maximum severity by system organ class and preferred term
•
TEAEs by maximum severity by preferred term 
•
Related TEAEs by system organ class and preferred term 
•
TEAEs that led to discontinuation of study treatment by system organ class and preferred 
   term
•
TEAEs that led to withdrawal from study by system organ class and preferred term 
The following listings will be provided:
•
A listing of subjects experiencing seizure event
•
A listing of subjects experiencing TEAEs
•
A listing of subjects experiencing SAEs 
•
A listing of subjects experiencing TEAEs leading to discontinuation of study treatment
•
A listing of subjects experiencing TEAEs leading to withdrawal from study
•
A listing of deaths 
4.5.3
Clinical Laboratory Data
The following laboratory safety assessments will be conducted:
•
Hematology: complete blood count (CBC) including red blood cell count (RBCs), white blood 
cell counts (WBCs) with differentials (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).
•
Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen (BUN), calcium, chloride, carbon dioxide, 
creatinine, creatine kinase, direct bilirubin, gamma-glutamyl transpeptidase (GGT), glucose, 
HbA1c, lactate dehydrogenase (LDH), magnesium, phosphorus, potassium, sodium, total 
cholesterol, total bilirubin, high-density lipoproteins, low-density lipoproteins, triglycerides, 
total protein, and uric acid 
•
Urinalysis: including determination of the presence of urine protein, glucose, ketones, occult 
blood, and WBCs by dipstick, with microscopic examination if indicated 
4.5.3.1
Quantitative Analyses 
Hematology, serum chemistry, and urinalysis will be summarized by treatment group and visit. 
Descriptive statistics will be presented at each visit by treatment group, including number of 
subjects, mean, standard deviation, median, 25%, 75% quartiles, minimum, and maximum values. 


26
Changes from baseline in quantitative laboratory values will be summarized using descriptive 
statistics by treatment group and visit. Plots of mean values by visits will presented for numeric 
laboratory parameters, except for mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), and mean corpuscular hemoglobin concentration (MCHC). 
Individual subject listings of clinical laboratory parameters at each visit will be provided. Values 
for hematology, serum chemistry, and urinalysis values outside the central laboratory reference 
ranges will be flagged on the individual subject data listings.
Visit windows for by visit summaries
For laboratory by visit summaries, the analysis visit is defined by visit windows in the table 
below. If there is more than 1 value in the same analysis visit window for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If there 
are 2 values in the same analysis visit window with the same distance from the target visit day for 
a certain parameter for a subject, then the record with the later date will be used for the by visit 
analysis.  If there are 2 values on the same day for a certain parameter for a subject, then the 
record with the later time will be used for the by visit analysis.
Table 6: Visit Windows for Laboratory 
Analysis visit 
Target visit day 
Analysis visit window
Baseline
1
Most recent non-missing pre-dose value
Week 1
8
[2, 10]
Week 2
15
[11, 21]
Week 4
29
[22, 42]
Week 8
57
[43, 70]
Week 12
85
[71, one day before start of safety follow-up]
Safety follow-up
Safety follow-up
[start of safety follow up, the end of study]
4.5.3.2
Qualitative analysis
Clinically significant laboratories
Clinically significant laboratory data will be summarized using shift tables where appropriate.  
For each subject, the lab values in hematology, blood chemistry and urinalysis will be flagged as 
“low”, “normal”, or “high” relative to the normal ranges of the central laboratory, or as 
“unknown” if no result is available. The categorical value in urinalysis will be flagged as 
“positive” (or “high”), “negative” (or “normal”), or “unknown”. 


27
For blood chemistry and serum chemistry, shifts tables from baseline to low/high post-baseline 
will be presented. Shift to low includes normal to low, high to low, and unknown to low. Shift to 
high includes normal to high, low to high, and unknown to high. For a subject if a lab is collected 
multiple times at post baseline, as long as one lab value is low this subject is regarded to have 
“low” post-baseline for this lab parameter. Similarly, if at least one post-baseline lab value is 
“high” this subject is regarded to have “high” post-baseline for this lab parameter. 
For urinalysis, shifts tables from baseline to high/positive post-baseline will be presented.  Shift to 
high/positive includes low to high/positive, normal/negative to high/positive, or unknown to 
high/positive. 
Markedly abnormal laboratory
Markedly abnormal indicate clinically significant laboratory abnormalities determined by Biogen. 
For hematology and blood chemistry the number and percentage of subjects with markedly 
abnormal laboratory post-baseline will be summarized by treatment group from the criteria in 
Table 7. Shifts tables from baseline to markedly abnormal post-baseline will also be summarized. 
For a subject if a lab is collected multiple times at post baseline, as long as one lab value is 
markedly abnormal this subject is counted to be markedly abnormal for this lab parameter. 
Subject’s listings will also be presented for all subjects with any markedly abnormal laboratory. 
In the listings, each subject’s complete history from screening to last study visit for that specific 
laboratory test meeting the criteria will be listed.
Table 7: Criteria for markedly abnormal laboratory
Parameter name 
Unit
Low
High
Hematology
White blood cells 
x109 cells/L
<3.0  
>16 
Lymphocytes 
x109 cells/L
<0.8 
>12  
Neutrophils 
x109 cells/L
<1.5 
>13.5 
Monocytes 
x109 cells/L
N/A 
>2.5 
Eosinophils 
x109 cells/L
N/A 
>1.6 
Basophils 
x109 cells/L
N/A 
>1.6 
Red blood cells (RBC)
x1012 cells/L
≤ 3.5 
≥ 6.4 
≤ 95 
≥ 175 
Hemoglobin - Females
                     - Males
g/L
≤ 115 
≥ 190
≤ 32
≥ 54
Hematocrit - Females 
                   - Males 
%
≤ 37 
≥ 60
Platelet count 
x109 cells/L
≤ 75
≥ 700
Blood Chemistry
Alanine aminotransferase 
(ALT) 
N/A 
> 3 x ULN 


28
Parameter name 
Unit
Low
High
Aspartate aminotransferase 
(AST) 
N/A 
> 3 x ULN 
Alkaline phosphatase (ALP)
N/A 
>3 x ULN 
Total bilirubin 
N/A 
>2 x ULN 
Blood urea nitrogen (BUN) 
N/A 
≥10.7 mmol/L 
Creatinine 
N/A 
≥176.8 umol/L 
Sodium 
mmol/L
≤ 126 
≥ 156
Potassium 
mmol/L
≤ 3
≥ 6 
Chloride 
mmol/L
≤ 90  
≥ 118 
Bicarbonate 
mmol/L
≤ 16 
≥ 35 
Glucose (non-fasting)
mmol/L
≤ 2.2 
≥ 9.7  
HbA1C
%
N/A
≥ 6.5%
Calcium 
mmol/L
≤ 2 
≥ 3 
Phosphorus 
mmol/L
≤ 0.5491 
≥ 1.7119 
Albumin 
g/L
≤ 25 
≥ 100
Total protein 
g/L
≤ 45 
≥ 100 
Liver Function Abnormalities
The number and percentage of subjects with the following potentially clinically significant liver 
function laboratory abnormalities:
•
post-baseline ALT ≥3x ULN or ≥5x ULN
•
post-baseline AST ≥3x ULN or ≥5x ULN
•
post-baseline total bilirubin >1.5x or ≥2x ULN 
•
post-baseline AST or ALT ≥3x ULN accompanied by concurrently elevated total 
bilirubin ≥2x ULN, where concurrent is defined as on the same day.
4.5.4
Vital Signs
Vital sign parameters include temperature, systolic blood pressure, diastolic blood pressure, pulse 
rate, respiration rate and weight.  The descriptive statistics for actual values and change from 
baseline will be summarized at each visit. 
The analysis of vital signs will also focus on the incidence of clinically relevant outliers based on 
the following criteria. The incidence and percentage of clinically relevant outliers determined by 
each criterion will be summarized. A listing of subjects with clinically relevant vital signs will be 
provided.


29
Table 8: Criteria to determine clinically relevant abnormalities in vital signs
Variable
Low
High
Systolic Blood Pressure
<90 mmHg or > 15 mmHg 
decrease from baseline 
>180 mmHg or > 20 mmHg 
increase from baseline
Diastolic Blood Pressure
< 50 mmHg or > 15 mmHg 
decrease from baseline
>105 mmHg or > 15 mmHg 
increase from baseline
Pulse*
< 50 bpm post-baseline or >  20  
bpm decrease from baseline
>120 bpm post-baseline or > 30  
bpm increase from baseline
Temperature
>38˚C or > 1˚C increase from baseline
Respiration Rate
≤10 breaths/min post-baseline 
and >10 breaths/min at baseline
≥20 breaths/min post-baseline 
and <20 breaths/min at baseline 
* bpm = beats per minute
Visit windows for by visit summaries
For vital sign by visit summaries, the analysis visit should be defined using window in the table 
below. If there is more than 1 value in the same analysis visit window for a certain parameter for a 
subject, the closest record to the target visit day will be used for the by visit analysis.  If there are 
2 values in the same analysis visit window with the same distance from the target visit day for a 
certain parameter for a subject, then the record with the later date will be used for the by visit 
analysis.  
Table 9: Visit windows for vital sign 
Analysis visit
Target visit day Analysis visit window
Baseline
1
Most recent non-missing pre-dose value
Week 1
8         
[2, 10]
Week 2
15
[11, 21]
Week 4
29
[22, 35]
Week 6
43
[36, 49]
Week 8
57
[50, 63]
Week 10
71
[64, 77]
Week 12
85
[78, EOS]
4.5.5
C-SSRS data 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an assessment that evaluates suicidal 
ideation and behavior. 


30
There are 5 “Yes/No” questions from suicidal ideation section with the following increasing severity 
order: (1) Wish to be dead, (2) Non-specific active suicidal thoughts, (3) Active suicidal ideation with 
any methods (not plan) without intent to act, (4) Active suicidal ideation with some intent to act, 
without specific plan, (5) Active suicidal ideation with specific plan and intent. 
From suicidal behavior section, there are 6 “Yes/No” questions with the following order: (1) Actual 
attempt, (2) Has subject engaged in non-suicidal self-injurious behavior? (3) Interrupted attempt (4) 
Aborted Attempt (5) Preparatory Acts or Behavior (6) Suicidal behavior was present during the 
assessment period?  
The summary table for C-SSRS will include the number of subjects who answered “Yes” to one of the 
5 questions in suicidal ideation section, or answer “Yes” to one of the 6 questions in suicidal 
behaviour section. A listing of subjects with any suicidal ideation or suicidal behaviour at baseline or 
post-baseline will be provided.
4.5.6
Physical and Neurological Exams
The full physical examination will include head, ears, eyes, nose, mouth, skin, heart and lung, lymph 
nodes, and gastrointestinal, musculoskeletal, and neurological systems. The brief physical examination 
will be focused on general appearance and respiratory and cardiovascular systems, as well as on subject-
reported symptoms.
The full neurological examination includes observation for cerebellar (intention) tremor and 
noncerebellar (e.g., resting or positional) tremor, nose-finger, heel-shin, Romberg, tandem walk, 
normal walk/gait, positional nystagmus, gaze-evoked nystagmus, reflexes, muscle strength, cranial 
nerves, and sensory function of the upper and lower extremities. The neurological examination will be 
performed by a physician or the equivalent.
The brief neurological examination will include an assessment of motor and sensory function, cranial 
nerves, reflexes, noncerebellar tremors (e.g., resting or positional), and cerebellar function. The 
assessment of cerebellar function will be complemented by the SARA. The brief neurological 
examinations will be conducted by a physician or the equivalent.
The summary table for Physical and Neurological Exams will include number of subjects who are 
assessed as Normal, Abnormal (Not clinically significant), Abnormal (clinically significant), and Not 
done/Missing for each function. 
Table 10: Visit windows for Brief Physical and Neurological Examination
Analysis visit
Target visit day Analysis visit window
Baseline
1
Most recent non-missing pre-dose value
Week 1
8
[2, 10]
Week 2
15
 [11, 28]
Week 6
43
 [29, 63]
Safety follow-up
Safety follow-up
[64, the end of study] 


31
4.5.7
SARA
Descriptive statistics will be used to summarize SARA measurements at each visit for each 
treatment group. Individual subject listings of SARA at each timepoint will also be provided by 
treatment group.
Table 11: Visit windows for SARA
Analysis visit
Target visit day Analysis visit window
Baseline
1
Most recent non-missing pre-dose value
Week 1
8
[2, 10]
Week 2
15
 [11, 28]
Week 6
43
 [29, 63]
Week 12
85
[64, one day before start day of safety follow-up]
Safety follow-up
Safety follow-up
[Start day of safety follow-up, the end of study] 
4.5.8
Electrocardiogram (ECG)
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the PR 
interval, QTcB interval, QTcF interval, QRS duration, and pulse rate. The ECG data will be listed 
by subject. Descriptive statistics will be used to summarize ECG measurements at each visit for 
each treatment group. In addition, a shift table of ECG interpretation results will be presented at 
each visit by treatment group. Individual subject listings of ECG parameters at each timepoint 
will also be provided by treatment group. Plots of mean QTcB and mean QTcF over time will be 
also presented. 
Visit windows for by visit summaries
For ECG by visit summaries, the analysis visit should be defined using window in the table 
below. If there is more than 1 value in the same analysis visit window for a certain parameter for a 
subject, the closest record to the target visit day will be used for the by visit analysis.  If there are 
2 values in the same analysis visit window with the same distance from the target visit day for a 
certain parameter for a subject, then the record with the later date will be used for the by visit 
analysis.  
Table 12: Visit windows for ECG 
Analysis visit
Target visit day Analysis visit window
Baseline
1
Most recent non-missing pre-dose value
Week 2
15
[2, 21]
Week 4
29
[22, 35]
Week 6
43
[36, 49]
Week 8
57
[50, 70]
Week 12
85
[71, EOS]


32
4.5.9
COVID-19 Related Analyses
Any impacts to the study or study data due to COVID-19 will be summarised and/or listed.  These 
include:
•
Participant accountability of participants who discontinued due to COVID-19.
•
COVID-19 adverse events.
•
Concomitant non-drug treatment related to COVID-19.
•
Protocol deviations due to COVID-19.
•
Participants with protocol alternations due to COVID-19 (as reported on the COVID-19 Impact 
Log).
 
  
 
 
 
 
 
 
 
 
 


33
 
 
 
 
 
 
 
5.
INTERIM ANALYSIS 
An interim analysis (IA) for futility of the primary endpoint will be performed after 
approximately 50% of the subjects have completed the Week 12 Visit. This is to allow early 
termination of the study if it is evident that the efficacy of BIIB104 is unlikely to be achieved. 


34
The futility criteria will be based on conditional power, which is the probability that the primary 
efficacy endpoint analysis will be statistically significant in favour of the treatment at the planned 
final analysis, given the data at the IA. 
The conditional power will be calculated using PROC SEQTEST which allows for calculation 
under different hypothesised treatment effects and assumed variance. The treatment effects and 
variance to be used for calculating the conditional power will be determined as follows: 
•
The treatment effects will be assumed to be equal to the observed values at the IA, i.e. the 
maximum likelihood estimate (MLE).
•
Prior to unblinding at the interim analysis, the pooled variance will be assessed to project the 
likely amount of statistical information at the final analysis. If the pooled variance is less than 
the value assumed in the study design the pooled variance will be used to calculate the 
assumed quantity of information at the final analysis. If the pooled variance is greater than the 
value assumed in the study design the value assumed in the study design will be used to 
calculate the assumed quantity of information at the final analysis. This approach ensures the 
futility analysis is conservative for falsely declaring futility.
•
For additional context, conditional power under other hypotheses may be calculated. 
No test for superiority will be performed at the IA, while the LS mean differences and 
corresponding standard errors will be derived from the primary analysis model.
The interim analysis results will be reviewed by a Biogen internal unblinded team. Given the 
insufficient knowledge of BIIB104’s potential effects on various cognitive and functional 
endpoints at this clinical stage, selected analyses on key efficacy endpoints in addition to the pre-
specified futility criteria will also be considered for the decision to stop one or both BIIB104 dose 
arms. Details of these analyses and criteria for futility are documented separately. 


35
6.
REFERENCES
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. J Biopharm 
Stat. 2013;23(6):1352-71.
ICH E9 (R1): Addendum to statistical principles for clinical trials on choosing appropriate estimands 
and defining sensitivity analyses in clinical trials. Endorsed by the ICH Steering Committee. 2014.
 
ICH E9 (R1): Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline 
on Statistical Principles for Clinical Trials. European Medicines Agency. 2017.
Rubin, D. B. (1976) “Inference and missing data.” Biometrika, 63(3), 581-592.


Signature Page
Document Name: BIIB104 263CS201 SAP v2.0 Final
Document Title: A Phase 2, Randomized, Double-Blind, Multiple-Dose, Placebo-
Controlled Study to Evaluate the Safety and Efficacy of BIIB104 in Subjects with
Cognitive Impairment Associated with Schizophrenia (CIAS)
Signed by
Role
Date / Time (UTC)
Signing as Author
04-Apr-2022 15:46:05
Signing as Approver
05-Apr-2022 11:57:08
Signing as Approver
04-Apr-2022 18:29:41
Signing as Approver
04-Apr-2022 16:12:31