Clinical trial NCT02342548
Conditions: Huntington's Disease
Keywords: Huntington; chorea; total motor score; CAG repeat: total functional capacity; motor cognitive and behavioral symptoms
Sponsor: Pfizer
Start date: 2015-02-25; Completion date: 2017-02-06
Enrollment: 188 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a 12 month open label extension study of PF-02545920 20 mg dosed BID following study A8241021 in subjects with HD. Primary endpoints will be to assess long-term safety and tolerability of 20 mg BID of PF-02545920. Secondary endpoints will be the change from baseline in the Total Motor Score (TMS)assessment, and/ior the Total maximum Chorea (TMC) assessment of the Unified Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment, and Clinical Global Impression-Improvement score after 6 and 12 months of treatment. Subjects, who were assigned to the 20 mg PF-02545920 dose group in the preceding A8241021 study, will receive 20 mg PF-02545920 without any titration. All other subjects will be titrated to the 20 mg BID dose as follows: 5 mg BID for 7 days, 10 mg BID for 7 days, 15 mg BID for 7 days, then 20 mg BID for the remainder of the treatment phase. Up to 260 subjects may take part in this open label extension

Detailed description:

Arms: arm 1: Subjects who received 20 mg BID in completed study A8241021 will continue to receive 20 mg BID PF-02545920 arm 2: Subjects who received either Placebo or 5mg BID of PF-02545920 in completed study A8241021 will be titrated up to 20 mg with 5mg increment per week, over 4 weeks (5mg increment/wk)
Interventions: intervention 1: 20 mg BID of PF-02545920
Intervention descriptions: intervention 1: All subject who completed A8241021 will receive 20 mg BID (with or without titration)

Protocol documents:
Prot_001.pdf: 
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CLINICAL PROTOCOL
AN OPEN LABEL EXTENSION STUDY TO INVESTIGATE THE LONG TERM 
SAFETY, TOLERABILITY AND EFFICACY OF PF-02545920 IN SUBJECTS WITH 
HUNTINGTON’S DISEASE WHO PREVIOUSLY COMPLETED STUDY A8241021 
Compound:
PF-02545920
Compound Name:
N/A
United States (US) Investigational New 
Drug (IND) Number:
118,646
European Clinical Trials Database 
(EudraCT) Number:
2014-001291-56
Universal Trial Number:
U1111-1162-4293
Protocol Number:
A8241022
Phase:
Phase 2a
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes
Original protocol
23 October 2014
Not Applicable


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Table 1.
Abbreviations
This is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ACE
angiotensin converting enzyme
AE
adverse event
ALT
alanine transaminase
ANC
absolute neutrophil count
AST
aspartate transaminase
BACHD
transgenic mouse and rat model of Huntington’s disease using a 
bacterial artificial chromosome
BID
twice a day (bis in die)
BP
blood pressure
BPM
beats per minute
CAG 
cytosine adenine guanine codon for glutamine
CGI
clinical global impression
CHDI
Cure Huntington’s Disease Initiative
CNS
central nervous system
CRF
case report form
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSSRS
Columbia suicide severity rating scale
CTA
clinical trial application
DAI
dosage and administration instructions
DBS
Deep brain stimulation
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
Electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EHDN
European Huntington’s Disease Network
ET
early termination
EudraCT
European Clinical Trials Database
FAS
full analysis set
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FSH
follicle-stimulating hormone
FU
follow-up
GCP
good clinical practice
HD
Huntington’s disease
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HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HR
hour
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICD
informed consent form
ID
Identification
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
LFT
liver function test
LSLV
last subject last visit 
MAOI
monoamino oxydase inhibitor
MDMA
methylenedioxy methylamphetamine (ecstasy)
MHP
medical health practitioner
N/A
not applicable
NSAID
nonsteroidal anti-inflammatory drug
PANSS
positive and negative syndrome scale
 
PCD
primary completion date
PDE10A
phosphodiesterase 10A 
PET
positron emission tomography
PI
principle investigator
POC
proof of concept
PT
prothrombin time
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SIB
suicidal ideation and behavior
SRSD
single reference safety document
TCA
tricyclic antidepressants
TMS
total motor score
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UHDRS
unified Huntington’s disease rating scale
ULN
upper limit of normal
US
United States
UTN
Universal Trial Number
WBC
white blood cell


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PROTOCOL SUMMARY
INDICATION
PF-02545920 is a highly selective phosphodiesterase 10A (PDE10A) inhibitor that is being 
developed for the symptomatic treatment of Huntington’s disease (HD).
BACKGROUND AND RATIONALE
The Disease:
HD is an autosomal dominant neurodegenerative disease that targets the corticostriatal 
system and results in (1) progressive movement disorder, initially manifesting as chorea; 
(2) progressive cognitive disturbance culminating in dementia; and (3) various behavioral 
disturbances that often precede diagnosis and can vary depending on the state of disease.  
The mean age of onset is 35-44 years and the median survival time is 15-18 years after onset.
HD is caused by an expansion of a translated trinucleotide cytosine adenine guanine codon or 
CAG, coding for a glutamine repeat in the 5′- region of the Htt gene on the short arm of 
chromosome 4, resulting in widespread corticostriatal pathology.
The diagnosis of HD relies on characteristic clinical findings and the detection of an 
expansion of CAG equal to or greater than 36 repeats in the Htt gene, which is often 
associated with a positive family history. 
The neuropathological hallmark of HD is the accumulation of aggregates of mutated 
huntingtin protein and progressive loss of medium spiny neurons (MSNs), beginning in the 
dorsal medial head of the caudate with subsequent progression to the ventrolateral striatum 
with significant, if less pronounced, neuronal loss in other subcortical and cortical structures. 
The Compound:
PF-02545920 is a highly selective PDE10A inhibitor.  PDE10A is an enzyme which is highly 
enriched in the MSNs of the striatum and has an important role in the regulation of cAMP 
and cGMP levels.  PF-02545920 is a selective inhibitor of PDE10A in in vitro systems.  
Reduced PDE10A mRNA and protein levels have been found in homogenates from the
striatum of HD subjects.  Results from a recent pilot positron emission tomography (PET) 
imaging study with the PDE10A ligand [18F]MNI-659 showed decreased PDE10A binding 
sites in HD stage I/II patients as expected, consistent with the degeneration of MSNs in HD.  
A cross-sectional study on quantification of PDE10A levels in pre-manifest, early and 
mid-stage disease HD subjects and healthy volunteers is currently ongoing at the Karolinska 
Institute.  Preliminary results from this study confirmed previous reports suggesting that 
PDE10A enzyme expression in HD brain is compatible with further clinical development of 
PF-02545920 for the symptomatic treatment of HD.  Preclinical HD models have 
demonstrated that PDE10A enzyme levels 20% of normal can elicit robust biochemical 
signatures by increasing cyclic nucleotide signaling in response to PDE10A inhibition.


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In vivo PF-02545920 administration results in increased striatal levels of cGMP and cAMP 
and in the putative activation of a number of downstream signaling molecules regulated by 
cyclic nucleotide cascades in MSNs, leading to overall increased striatal activation and 
decreased locomotor hyperactivity.
The Mechanism:
Preclinical studies conducted in collaboration with the Cure Huntington’s Disease Initiative 
(CHDI) Foundation, Inc. demonstrated that PDE10A inhibition is effective in reversing 
multiple parameters of aberrant excitability of MSNs, and in improving elements of 
corticostriatal connectivity in brain slices derived from symptomatic R6/2 and Q175 
knock-in mice.  Chronic (4 months) dosing of Q175 HD transgenic mice with PF-02545920 
significantly improves dysfunction of the corticostriatal circuits, which develops with disease 
progression. 
Moreover, recent studies in two additional transgenic models of HD using a bacterial 
artificial chromosome, BACHD mice and BACHD rats, showed that both acute and chronic 
(2 weeks) administration of PF-02545920 results in functional improvement of indirect 
pathway activity.  Most importantly, in vivo functional improvement measured as a reversal 
of the impaired subthalamic nucleus firing rate was demonstrated in the full length mHtt 
transgenic BACHD rat following acute treatment with PF-02545920. 
In summary, these preclinical observations suggest that treatment with PF-02545920 
preferentially improves activity of the indirect pathway of the basal ganglia, which is 
primarily impaired in the earlier stages of HD, and thus it may lead to functional 
normalization of affected corticostriatal brain circuitry and alleviate motor symptoms, and 
potentially behavioral and cognitive symptoms in individuals with HD.
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator Brochure.
Safety:
To date, evaluation of PF-02545920 has been completed in 7 clinical studies included in the 
2014 Investigator Brochure. 
Interpretation of the study results and the possible risks associated with the administration of 
PF-02545920 are summarized in Section 7 of the Investigator's Brochure (IB 2014 version).
Dose Rationale:
Based on the previous pre-clinical efficacy data and clinical safety data, a dose of 20 mg is 
estimated to produce the most robust PDE10A inhibition while still being well tolerated.  
Therefore, the present study with 20 mg BID PF-02545920 will continue to evaluate safety 
and tolerability in subjects with HD.  A double blind titration scheme will be used to mitigate 
the potential risk of dystonia for subjects who did not receive 20 mg in the preceding study 
(A8241021).  The incidence rate of dystonia for the titrated 15 mg BID dose group in study 
A8241012 was substantially lower than the rate observed in a similar study (A8241006) 
population with a non-titrated 15 mg BID dosing regimen.


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STUDY OBJECTIVES
Primary Objective:

To assess long-term safety and tolerability of 20 mg BID of PF-02545920 in subjects 
with HD.
Secondary Objectives:

To assess motor function after 6 and 12 month oral dosing with 20 mg BID of 
PF-02545920 in subjects with HD. 

To assess the efficacy of 6 and 12 month oral dosing with 20 mg BID of
PF-02545920 on chorea severity in subjects with HD.

To assess whether 6 and 12 month oral dosing with 20 mg BID of PF-02545920 can 
improve the overall clinical impression in subjects with HD.
:

 

 

 

 

 

 

STUDY ENDPOINTS
Primary Endpoint:

Adverse events, weight, vital signs (pulse, blood pressure and body temperature), 
physical examination, neurological examination, electrocardiogram (ECG) and 
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clinical laboratory findings (hematology, biochemistry and urinalysis).  The endpoints 
are:

The number and proportion of subjects with adverse events.

Assessment of clinical laboratory parameters.

Assessment of vital signs.

Assessment of ECG parameters.

White blood count (WBC) and absolute neutrophil count (ANC) at each visit.

Abnormal laboratory findings from baseline.

Frequency and severity of adverse events related to extrapyramidal symptoms 
(EPS) including dystonia and akathisia, as assessed by the investigator.

C-SSRS (suicide severity assessment).
Secondary Endpoints:

Change from baseline in the Total Motor Score (TMS) assessment of the Unified 
Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment.

Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS 
after 6 and 12 months of treatment.

Clinical Global Impression-Improvement score after 6 and 12 months of treatment. 
:
:

 
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: 
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
 
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
 
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STUDY DESIGN 
This study is a 12 month open label extension study, following study A8421021, with a 
single dose of 20 mg PF-02545920 BID for the treatment of motor impairment of subjects 
with HD.  Subjects, who received 20 mg BID of PF-02545920 in the preceding study 
A8241021, will receive 20 mg BID of PF-02545920 in this study without any titration.  A 
double blind titration scheme will be used to mitigate the potential risk of dystonia for those 
subjects who did not receive 20 mg in the first study (A8241021).
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
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.
Visit Window
Day (3 days)1
Day (7 days)1
Visit Identifier
Screening2
Baseline3
Week 2
Week 4
Month 3
Month 6
Month 9
Month 12 
/ET4
Follow 
up5
Visit Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
Study Day
Day 1
Day 14
Day 28
Day 91
Day 182
Day 273
Day 365
Day 
372 to 
379
Informed Consent
X
File Record of Signed and Dated 
Pre-screening Checklist A6
X
Complete Screening Checklist B for 
review of study A8241021 data6
X
Review Inclusion/Exclusion Criteria
X
X
CAG profile documentation
(X)7
Demography
(X)7
Review Medical History and 
Prior/Concomitant Medications
X 
Review Adverse Events (AE) & Changes 
since last visit (medical history, 
procedures, con. meds)
X
X
X
X
X
X
X
Height
(X)7
Weight
(X)8
X
X
Brief Physical Examination
(X)8
X
X
X
Brief Neurological Examination
(X)8
X
X
X
Electrocardiogram (ECG)9
(X)8
X
X
X
X
Supine and Standing Blood Pressure and 
Pulse (orthostatic vitals); Body 
Temperature10
(X)8
X
X
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Visit Window
Day (3 days)1
Day (7 days)1
Visit Identifier
Screening2
Baseline3
Week 2
Week 4
Month 3
Month 6
Month 9
Month 12 
/ET4
Follow 
up5
Visit Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
Study Day
Day 1
Day 14
Day 28
Day 91
Day 182
Day 273
Day 365
Day 
372 to 
379
Sitting Blood Pressure and Pulse; Body 
Temperature (standard vital signs)10
X
X
X
X
X
Contraception Check
(X)8
X
X
X
X
X
X
Laboratory tests:11
    Hematology12
(X)8
X12
X12
X
X
X
X
X12
Blood Chemistry
(X)8
X
X
Serum Pregnancy Test
(X)8
X
X
X
X
Urine Pregnancy Test
X
X
Serum FSH13
X
Urinalysis
(X)8
X
X
Urine drug screen14
X
 
Assessments:
C-SSRS Since Last Visit
(X)8
X
X
X
X
X
X
X
8
 
 
          
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Visit Window
Day (3 days)1
Day (7 days)1
Visit Identifier
Screening2
Baseline3
Week 2
Week 4
Month 3
Month 6
Month 9
Month 12 
/ET4
Follow 
up5
Visit Number
V1
V2
V3
V4
V5
V6
V7
V8
V9
Study Day
Day 1
Day 14
Day 28
Day 91
Day 182
Day 273
Day 365
Day 
372 to 
379
 
ANC and WBC Review17
X
(X)8
X
X
X
X
X
X
X
Site Eligibility Review6
X
X
Sponsor Eligibility Verification18 and 
Documentation of Confirmation
X
Randomization19
X
20
     
      
      
      
      
Dispense dosing diary
X 
Dispense study drug for outpatient dosing
X 
X
X
X
X
X
Subject instruction on outpatient dosing 
from blister packs/bottles, dosing diary use 
and reporting AEs and SAEs.
X
Assess compliance based on observation 
of blister packs, pill counts, review dosing 
diary
X
X
X
X
X
X
Collect dosing diary
X
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Footnotes:
1.
All visits windows are relative to the V2 Baseline Day 1 visit date.
2.
Screening visit will take place during the Week 19 Visit for study A8241021. 
3.
Baseline Day 1 activities will take place during Week 26 Visit for Study A8241021. 
4.
In case of Early Termination between Baseline and Day 14 (exclusive), only safety assessments will be performed (See STUDY PROCEDURES).  If Early 
Termination occurs after Day 14 (inclusive), as many Month 12/ET assessments as possible should be completed.
5.
Follow-up visit is to take place 7 to 14 days after the last dose on Month 12 (V8).
6.
Site eligibility review: the site will review all laboratory test results, pregnancy test, ANC and WBC, drug test results, against I/E criteria. Checklists A and 
B will be provided to the site by the sponsor.
7.
Data collected at Screening for Study A841021 will be used.
8.
Assessment results collected at Week 26 for Study A8241021 will be used for Baseline Day 1 (V2).
9.
Single 12-lead ECG will be recorded at Baseline Day 1 (V2) and collected at Month 3 (V5), Month 6 (V6), Month 9 (V7) and Month 12/ET (V8).
10. Vital signs to include blood pressure, pulse and oral or tympanic body temperature.
11. Samples for laboratory can be obtained without regard to fasting status. 
12. Hematology samples will be collected only for ANC and WBC safety monitoring at Week 2 (V3), Week 4 (V4) and Follow-up (V9).
13. Serum FSH may be performed to confirm postmenopausal status for females who have been amenorrheic for at least 12 consecutive months. 
14. Urine Drug screen may be performed at Baseline Day 1 (V2) and any time at the discretion of the investigator. 
15.
 
. 
16. CGI-S will be administered once at Baseline Day 1 (V2); CGI-I will be administered at Month 6 (V6) and Month 12 (V8) or Early Termination.
17. The site will perform and document ANC and WBC review at all visits for neutropenia safety monitoring.  A source document worksheet will be provided 
by the sponsor to ensure this is documented and monitored carefully throughout the course of the study. 
18. Sponsor Eligibility Verification process: The Sponsor will verify key elements of the study inclusion/exclusion criteria prior to randomization of each 
subject.  All information related to subject eligibility, including, but not limited to, HD diagnosis and screening safety laboratory data, electrocardiograms, 
and Vital Sign results from study A8241021, should be entered in the subject eCRF and available for sponsor review.  Investigators will be trained on the 
Screening Verification process, as part of the protocol training prior to study start.
19. Randomization code can be obtained by the clinical sites as soon as the sponsor has verified that the subject is eligible (2 business days reserved at the end of 
the Screening period). 
20.
 
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Abbreviations: AE = adverse event; ANC = absolute neutrophil cell count; BP = blood pressure; CAG = cytosine adenine guanine 
codon for glutamine; 
= 
; CGI-S = Clinical Global Impression Severity Scale; CGI-I = Clinical 
Global Impression Improvement scale; C-SSRS = Columbia Suicide Severity Rating Scale; 
: 
; 
ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone; FU = follow-up; 
 = 
 
 
 = 
;  
 = 
; 
 = 
; 
= 
; 
 = 
;
 = 
 
; 
 = 
; TMS = Total Motor Score; SAE =  serious adverse event; 
 = 
 
; 
 = 
; 
 = 
; 
=
; 
 = 
; WBC = white blood cell
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................22
LIST OF FIGURES .................................................................................................................22
APPENDICES .........................................................................................................................22
1. INTRODUCTION ...............................................................................................................23
1.1. Mechanism of Action/Indication.............................................................................23
1.2. Background and Rationale ......................................................................................23
1.2.1. Drug Development and Study Rationale:...................................................23
1.2.2. Safety and Clinical Data.............................................................................25
1.2.3. Pharmacokinetics........................................................................................29
1.2.4. Dose Selection Rationale............................................................................30
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................30
2.1. Objectives................................................................................................................30
2.2. Endpoints.................................................................................................................31
3. STUDY DESIGN.................................................................................................................33
3.1. Stopping Criteria .....................................................................................................34
3.1.1. Subject Stopping Criteria............................................................................35
3.1.2. Study Stopping Criteria ..............................................................................35
4. SUBJECT SELECTION......................................................................................................35
4.1. Inclusion Criteria.....................................................................................................35
4.2. Exclusion Criteria....................................................................................................36
4.3. Randomization Criteria ...........................................................................................40
4.4. Lifestyle Guidelines ................................................................................................40
4.4.1. Activity .......................................................................................................40
4.4.2. Contraception..............................................................................................40
4.4.3. Meals and Dietary Restrictions...................................................................41
4.5. Sponsor’s Qualified Medical Personnel..................................................................41
4.6. Rater Qualifications.................................................................................................42
5. STUDY TREATMENTS.....................................................................................................42
5.1. Allocation to Treatment ..........................................................................................43
5.2. Breaking the Blind ..................................................................................................44
5.3. Subject Compliance.................................................................................................44


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5.4. Drug Supplies..........................................................................................................45
5.4.1. Dosage Form(s) and Packaging..................................................................45
5.4.2. Preparation and Dispensing........................................................................45
5.5. Administration.........................................................................................................45
5.6. Drug Storage ...........................................................................................................46
5.7. Drug Accountability................................................................................................47
5.8. Concomitant Treatment(s).......................................................................................47
5.9. Rescue Medication ..................................................................................................48
5.9.1. Rescue Medications for Anxiety/agitation .................................................48
5.9.2. Rescue Medication for Insomnia................................................................48
5.9.3. Rescue Medications for the Management of Extrapyramidal 
Symptoms (akathisia, dystonia, tardive dyskinesia)........................................49
6. STUDY PROCEDURES .....................................................................................................49
6.1. Screening.................................................................................................................49
6.2. Study Period ............................................................................................................50
6.2.1. Visit 2 - Baseline Day 1 (Randomization)..................................................50
6.2.2. Visit 3 – Week 2/Day 14 (3 days) ............................................................52
6.2.3. Visit 4 – Week 4/Day 28 (3 days) ............................................................53
6.2.4. Visit 5 – Month 3/Day 91 (7 days)...........................................................54
6.2.5. Visit 6 –Month 6/ Day 182 (7 days).........................................................54
6.2.6. Visit 7 – Month 9/Day 273 (7 days).........................................................56
6.2.7. Visit 8 – Month 12/Day 365 (7 days).......................................................57
6.2.8. Early Termination Visit..............................................................................59
6.2.9. Unscheduled Visit.......................................................................................59
6.3. Follow-up Visit (V9)...............................................................................................60
6.4. Subject Withdrawal.................................................................................................60
7. ASSESSMENTS..................................................................................................................61
7.1. Review of Inclusion/Exclusion Criteria ..................................................................62
7.2. CAG Profiling Documentation................................................................................62
7.3. Medical History/Prior Medications/Procedures......................................................62
7.4. Site Eligibility Review ............................................................................................62
7.5. Sponsor Eligibility Verification Process.................................................................63


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7.6. Blood Volume .........................................................................................................63
7.7. Safety Assessments .................................................................................................63
7.7.1. Brief Physical Examination........................................................................63
7.7.2. Vital signs...................................................................................................64
7.7.3. Brief Neurological Examination.................................................................65
7.7.4. Laboratory Tests .........................................................................................65
7.7.5. Pregnancy Testing ......................................................................................67
7.7.6. Assessment of Suicidal Ideation and Behavior (SIB).................................67
7.7.6.1. Columbia Suicide Severity Rating Scale ..................................67
7.7.6.2. Suicidality Risk Assessment .....................................................68
7.7.7. Electrocardiogram (ECG)...........................................................................68
7.8. Special Safety Assessment......................................................................................69
7.8.1. ANC and WBC Monitoring........................................................................69
7.8.2. Neutropenia Assessment.............................................................................69
7.9. Other Assessments ..................................................................................................70
7.9.1. Unified Huntington’s Disease Assessment Scale (UHDRS) – TMS, 
, 
...................70
7.9.2. The 
hort 
(
) .................................................................................71
7.9.3. 
 (
)........................................................71
7.9.4. 
.......................................................................72
7.9.4.1. 
...........................................................................72
7.9.4.2.
.........................................................72
7.9.4.3. 
 (
).....................................................72
7.9.4.4. 
 (
) ....................................73
7.9.4.5. 
 (
)....................................73
7.9.4.6. 
 (
) .......................................73
7.9.5. 
.................................................................................74
7.9.5.1. 
 (
).................75
7.9.5.2.
(
 
) ............................................................................................75
7.9.5.3. 
 (
 
) ...............................................................................75
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7.9.5.4.
...........................................................................75
7.9.6. Clinical Global Impression of Severity/Improvement (CGI-S/CGI-I).......76
7.9.7. 
..............................................................................76
7.9.8. 
 (
) .........................................................77
7.9.9. 
 (
) 
...................................................................................................78
7.10. 
..................................................................................................78
7.10.1.
 (
)......78
7.10.2. 
....................................................79
8. ADVERSE EVENT REPORTING......................................................................................79
8.1. Adverse Events........................................................................................................79
8.2. Reporting Period .....................................................................................................80
8.3. Definition of an Adverse Event...............................................................................80
8.4. Medication Errors....................................................................................................81
8.5. Abnormal Test Findings..........................................................................................81
8.6. Serious Adverse Events...........................................................................................82
8.6.1. Protocol-Specified Serious Adverse Events...............................................82
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................82
8.7. Hospitalization ........................................................................................................83
8.8. Severity Assessment................................................................................................85
8.9. Causality Assessment..............................................................................................85
8.10. Exposure During Pregnancy..................................................................................85
8.11. Occupational Exposure .........................................................................................87
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal)...............................................................................................................87
8.13. Eliciting Adverse Event Information ....................................................................87
8.14. Reporting Requirements........................................................................................87
8.14.1. Serious Adverse Event Reporting Requirements .....................................87
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................88
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities...................88
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................88
9.1. Sample Size Determination.....................................................................................88
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9.2. Efficacy Analysis ....................................................................................................88
9.2.1. Analysis of Primary Endpoint ....................................................................89
9.2.2. Analysis of Secondary Endpoints...............................................................89
9.3. 
...................................................................................90
9.4. 
.......................................................................................90
9.5. Safety Analysis........................................................................................................91
9.5.1. Electrocardiogram (ECG) Analysis............................................................91
9.6. Interim Analysis ......................................................................................................92
9.7. Data Monitoring Committee ...................................................................................92
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................93
11. DATA HANDLING AND RECORD KEEPING .............................................................93
11.1. Case Report Forms/Electronic Data Record .........................................................93
11.2. Record Retention...................................................................................................94
12. ETHICS..............................................................................................................................94
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................94
12.2. Ethical Conduct of the Study ................................................................................94
12.3. Subject Information and Consent..........................................................................95
12.4. Subject Recruitment ..............................................................................................95
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................95
13. DEFINITION OF END OF TRIAL...................................................................................96
13.1. End of Trial in a Member State.............................................................................96
13.2. End of Trial in All Other Participating Countries.................................................96
14. SPONSOR DISCONTINUATION CRITERIA ................................................................96
15. PUBLICATION OF STUDY RESULTS..........................................................................96
15.1. Communication of Results by Pfizer ....................................................................96
15.2. Publications by Investigators ................................................................................97
16. REFERENCES ..................................................................................................................99
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LIST OF TABLES
Table 1.
Abbreviations..........................................................................................................3
Table 2.
 
 (
)..................30
Table 3.
Allocation to Study Treatments............................................................................43
Table 4.
Drug Supplies .......................................................................................................45
Table 5.
Blood Volume.......................................................................................................63
Table 6.
Laboratory Tests ...................................................................................................66
Table 7.
Safety QTc............................................................................................................92
LIST OF FIGURES
Figure 1.
Study Design Schematic.......................................................................................34
Figure 2.
Guidance for Clinical Management of EPS........................................................107
APPENDICES
Appendix 1. Guidance on Clinical Management of Subjects with Acute Extrapyramidal 
Symptoms - EPS (reported AE of dystonia, akathisia, tardive dyskinesia)........106
Appendix 2. Drugs and Classes of Drugs Allowed and Prohibited as Concomitant 
Medications.........................................................................................................108
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-02545920 is a highly selective PDE10A inhibitor that is being developed for the 
symptomatic treatment of Huntington’s disease (HD).
1.2. Background and Rationale
1.2.1. Drug Development and Study Rationale:
HD is an autosomal dominant neurodegenerative disease that targets the corticostriatal 
system and results in (1) progressive movement disorder, generally presenting as chorea in 
the early stages of the disease; (2) progressive cognitive disturbance culminating in dementia;
and (3) various behavioral disturbances that may precede the emergence of diagnostic motor 
signs and can vary, depending on the disease state.  The mean age of onset is 35-44 years and 
the median survival time is 15-18 years after onset.1,2,3
HD is caused by an expansion of a CAG trinucleotide in the first exon of the IT15 gene on 
the short arm of chromosome 4,4 which codes for the huntingtin (Htt) protein.  The CAG 
repeats are translated into polyglutamine repeats (polyQ) that confer toxic activity to 
huntingtin and lead to widespread corticostriatal pathology5 and ultimately to neuronal death 
most prominent in the striatum.  Htt gene alleles containing 36 CAG repeats are disease 
causing.3
The diagnosis of HD relies on characteristic clinical findings and the detection of an 
expansion of 36 or more CAG repeats in the Htt gene, often associated with a positive family 
history. 
The neuropathological hallmark of HD is the accumulation of aggregates of mutated Htt in 
neurons and the progressive loss of medium spiny neurons (MSNs), beginning in the tail of 
the caudate nucleus with subsequent progression to the ventromedial striatum2 with 
significant, albeit less pronounced, neuronal loss in other subcortical and cortical structures.6
Depending on the species, MSNs account for approximately 74% (humans) to more than 
90% (rodents) of the striatal neuronal population.7 MSNs are the output system of the 
striatum, and they receive glutamate input from cortical pyramidal cells, which also undergo 
substantial degeneration and loss in HD.8  Although damage occurs in other brain regions, 
corticostriatal circuitry pathology and dysfunction appear to be the primary substrate of the 
cognitive, behavioral and motor abnormalities that characterize HD.8  Impairment in the 
corticostriatal circuitry is also present in transgenic mice and rats expressing mutant Htt as 
demonstrated by electrophysiological studies in corticostriatal brain slices from these 
animals9,10 and by in vivo recordings from basal ganglia structures.11,12,13,14  Aberrant 
frontostriatal connectivity in response to cognitive tasks is present in pre-symptomatic HD 
subjects and worsens as the disease progresses.  There also appears to be an association 
between connectivity strength of frontostriatal circuits and several clinical measures and 
genetic markers, including Unified Huntington's Disease Rating Scale motor score, predicted 
years to manifest symptom onset, as well as CAG repeat length.15


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Phosphodiesterase 10A (PDE10A) is an enzyme that has an important role in the regulation 
of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) 
levels16,17,18 and is highly enriched in the medium-sized spiny neurons of the 
striatum.19,20,21,22  Reduced PDE10A mRNA and protein levels have been found in 
homogenates from the striatum of HD patients.23 Results from a recent pilot PET imaging 
study with the PDE10A ligand [18F] MNI-659, showed decreased PDE10A binding sites in 
HD stage I/II patients, as expected considering the degeneration of MSNs in HD.  A 
cross-sectional study on quantification of PDE10A levels in pre-manifest, early and 
mid-stage disease HD subjects and healthy volunteers is currently ongoing at the Karolinska 
Institute.  Preliminary results from this study confirmed previous reports suggesting that 
PDE10A enzyme expression in the brains of HD subjects is compatible with further clinical 
development of PF-02545920 for the symptomatic treatment of HD.  Preclinical HD models 
have demonstrated that PDE10A enzyme levels 20% of normal can elicit robust 
biochemical signatures by increasing cyclic nucleotide signaling in response to PDE10A 
inhibition.
PF-02545920 is a potent and highly selective inhibitor of PDE10A in in vitro systems being 
developed for symptomatic treatment of both HD and schizophrenia.  In vivo PF-02545920 
administration resulted in increased striatal levels of cGMP and cAMP and in the putative 
activation of a number of downstream signaling molecules regulated by cyclic nucleotide 
cascades in MSNs, leading to overall increased striatal activation and decreased locomotor 
hyperactivity.17-23,24  The presence of mutated huntingtin has been found to impair cAMP 
signaling and cAMP responsive-element binding protein (CREB) mediated transcription of 
genes responsible for neurotransmitter synthesis, release and signaling pathway as well as the 
production of brain derived neurotrophic factor (BDNF).16,25,26  Inhibition of PDE10A has 
been found to modulate striatal signaling towards neuroprotective pathways,16 to decrease 
neurodegenerative changes in the striatum of animal models of HD and to restore cAMP 
dependent CREB signaling.27,28 The accumulated data strongly support targeting of the 
deficient cAMP and cGMP signaling29,30 as a therapeutic strategy to correct 
cortico-striatal-thalamic-cortical circuitry dysfunction and relieve both motor and cognitive 
symptoms of HD. 
Preclinical studies conducted in collaboration with the CHDI Foundation, Inc. demonstrated 
that PDE10A inhibition is effective in reversing multiple parameters of aberrant excitability 
of MSNs, and in improving elements of corticostriatal connectivity in brain slices derived 
from symptomatic R6/2 and Q175 knock-in mice.  Chronic (4 months) dosing of Q175 HD 
transgenic mice with PF-02545920 significantly improved dysfunction of the corticostriatal 
circuits, which develops with disease progression.9,10,31
Moreover, recent studies in two additional transgenic models of HD, BACHD mice and 
BACHD rats showed that both acute and chronic (2 weeks) administration of PF-02545920 
results in functional improvement of indirect pathway activity.  Most importantly, in vivo 
functional improvement measured as a reversal of the impaired subthalamic nucleus firing 
rate, was demonstrated in the full length mHtt transgenic BACHD rat, following acute 
treatment with PF-02545920.13


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In summary, these preclinical observations suggest that treatment with PF-02545920 
preferentially activates the function of the indirect pathway of the basal ganglia which is 
primarily impaired in the earlier stages of HD and thus may lead to functional normalization 
of affected corticostriatal brain circuitry.32 For this reason, the PDE10A inhibitor, 
PF-02545920, may offer HD patients amelioration of motor and cognitive symptoms, and 
potentially slow disease progression.
Summary of Benefit Risk Assessment
To date, PF-02545920 appears to be safe and well tolerated in more than 400 subjects 
(including healthy volunteers, subjects with schizophrenia and subjects with HD) (see Safety 
and Clinical Data) whether as a monotherapy or as an adjunctive treatment with 
antipsychotic medications.  From these studies, the development of neutropenia and 
extrapyramidal symptoms (EPS) have emerged as potential, albeit infrequent, risks for the 
subjects, which have been mitigated by the inclusion of a titration regimen, together with a 
close monitoring plan for WBC/ANC (see Stopping Criteria) and an EPS monitoring and 
rescue plan (see Rescue Medications for the Management of Extrapyramidal Symptoms 
(akathisia, dystonia, tardive dyskinesia). 
1.2.2. Safety and Clinical Data
To date, evaluation of PF-02545920 has been completed in 7 clinical studies, which are 
included in the 2014 Investigator Brochure. 

Protocols A8241001 and A8241008 were Phase 1 studies that evaluated the safety, 
tolerability, and pharmacokinetics of PF-02545920 in a total of 35 healthy subjects. 

Protocol A8241013 was a Phase 1 study that evaluated the effects of a single dose of 
PF-02545920 on regional glucose metabolism (PET) in the striatum and characterized 
the exposure-response relationship for PF-02545920 in 31 healthy subjects. 

Protocol A8241002 was a multiple dose Phase 1b study that further evaluated the 
safety, tolerability and pharmacokinetics of PF-02545920 in 40 subjects with stable 
symptoms of schizophrenia. 

Protocol A8241006 was the first Phase 2a study designed to evaluate the efficacy, 
safety, tolerability and pharmacokinetics of PF-0254920 in 35 subjects with an acute 
exacerbation of schizophrenia. 

Protocol A8241012 was a second Phase 2 study that evaluated the safety and efficacy 
of PF-02545920 in 259 subjects with schizophrenia, who were experiencing an acute 
exacerbation at the time of admission.

Protocol A8241018 was a randomized, double blind, sponsor open, placebo 
controlled, Phase 1b study of the safety, tolerability and pharmacokinetics of 
PF-02545920 in 37 psychiatrically stable subjects with schizophrenia on a stable 
regimen of antipsychotics and other adjunctive psychotropic medications.


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In 2 completed Phase 1 studies (A8241001 and A8241008), single oral doses of 30 mg of 
PF-02545920 were given to healthy subjects.  PF-02545920 10 mg dose was well tolerated.  
Dose-related adverse events included mild sedation at doses of 15 mg and extrapyramidal 
symptoms (EPS) (including tremor and dystonic reactions) at doses 20 mg.  At the 20 mg 
dose level, 1/11 subjects had a moderate episode of dystonia with onset 4 hours post-dose, 
and of approximately 3 hour duration.  At the 30 mg dose level, 1/5 subjects had a moderate 
episode of dystonia with onset within 1 hour post-dose and of approximately 2 minute 
duration.  Both episodes resolved spontaneously without requiring anticholinergic medication 
and did not recur. 
In the completed Phase 1 PET study (A8241013), 31 healthy subjects were divided into two 
cohorts and received single oral doses of PF-02545920 (3 mg, 6 mg, or 15 mg) in two stages.  
In Stage 1, all subjects received a single oral dose of 6 mg PF-02545920 and a single dose of 
placebo in random order.  In Stage 2, all subjects received 3 mg PF-0254920, 15 mg 
PF-02545920 and placebo in random order.  In the first stage of the study, two mild adverse 
events (AEs) of dizziness and fatigue were reported in the 6 mg group.  Most AEs reported 
during the second stage were mild in severity, with 1 moderate case of fatigue (PF-02545920 
3 mg), 1 moderate headache (PF-02545920 3 mg), 1 moderate case of seborrhoeic dermatitis 
(PF-02545920 3 mg), and 1 severe case of somnolence (PF-02545920 15 mg).
In the completed multiple dose Phase 1 study (A8241002), a total of 40 subjects with chronic 
schizophrenia were randomized in the first multiple-dose study that evaluated the safety, 
tolerability, and pharmacokinetic parameters of PF-02545920.  Subjects were randomized to 
1 of 5 cohorts of PF-02545920 (5 to 40 mg Q12H) or placebo for 13 days.  There were no 
deaths or serious adverse events (SAEs) reported during this study.  The most frequently 
occurring treatment-emergent “all causality” AEs following multiple doses of PF-02545920 
were central nervous system (CNS) related, which included sedation, dystonia, and 
dyskinesia.  There were 17 subjects who experienced mild to moderate sedation occurring 
more often in the 20 mg BID dose groups.  There were 8 subjects who experienced an AE 
of mild to severe dystonia, which was dose dependent and more frequent in the 20 mg BID 
dose groups.  There were 6 subjects who experienced dyskinesia (1 in placebo [severe], 4 in 
the 15 mg PF-02545920 [mild], and 1 in the 30 mg PF-02545920 [moderate] treatment 
groups). All adverse events of dyskinesia were attributed to the protocol specified 
withdrawal of prior antipsychotic therapy. 
Protocol A8241006 was the first Phase 2 study that was planned to evaluate the efficacy, 
safety, tolerability and pharmacokinetics of PF-02545920 in a total of 54 subjects with an 
acute exacerbation of schizophrenia.  This was a 3 week, double-blind, parallel-group, 
fixed-dose, placebo-controlled, multi-center, randomized study of PF-02545920 15 mg 
Q12H.  This study was terminated prematurely to further investigate a potential safety 
concern of neutropenia.  Six subjects (3 assigned to PF-02545920 and 3 assigned to placebo) 
had decreases in absolute neutrophil count that met the criteria of potential clinical concern.  
Five cases were classified as neutropenia and one as agranulocytosis.  None of these subjects 
were symptomatic.  The case of agranulocytosis rapidly resolved without sequelae.  There 
have been no additional cases of agranulocytosis in subsequent completed and ongoing 
studies.  After review of the cases an expert panel of hematologists concluded that further 


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studies should not pose an unacceptable risk to subjects with appropriate hematology 
monitoring.  Based on the panel’s recommendations, white blood cell (WBC) and absolute 
neutrophil count (ANC) exclusion criteria, local laboratory WBC and ANC monitoring, and 
WBC and ANC stopping criteria, were incorporated in the design of the next Phase 2 study 
(A8241012).  Changes in white blood cell (WBC) counts were not reported in the single dose 
(A8241001) or multiple dose (A8241002) studies with PF-02545920.  The most frequently 
reported AEs in PF-02545920 treated subjects in protocol A8241006 included dystonia, 
headache, and somnolence.  The study results regarding the efficacy of PF-02545920 (15 mg 
Q12H) were inconclusive. 
Protocol A8241012 was the second Phase 2 study.  The efficacy and safety of PF-02545920 
in subjects with schizophrenia, who were experiencing an acute exacerbation, was evaluated 
in this double-blind, placebo-controlled, randomized multicenter study.  Risperidone was 
used as an active control.  Subjects were randomly assigned to 1 of 4 treatment groups in a 
2:2:2:1 ratio, respectively: 1) PF-02545920 5 mg Q12H; 2) PF-02545920 15 mg Q12H 
(titrated); 3) placebo; and 4) risperidone 3 mg Q12H (titrated).  A total of 258 subjects were 
randomized into the study, of which 74 subjects received PF-02545920 5 mg and 74 subjects 
received PF-02545920 15 mg, 36 subjects received risperidone 3 mg, and 74 subjects 
received placebo. 
Two subjects died post-therapy (1 due to acute myocardial infarction and myocardium 
rupture and the other due to sudden cardiac death); both subjects were in the PF-02545920 
5 mg group.  Both occurred approximately 2.5 weeks after treatment with investigational 
drug was completed, after treatment with currently marketed medication was reinstituted; 
1 subject died during the follow-up period and 1 subject died after completion of study 
participation.  Autopsy reports attributed both deaths to myocardial infarction, and noted that 
both subjects had a history of cardiac disease and other cardiac risk factors.  Per the 
investigators, the events were not related to study drug, concomitant medications, or study 
procedures, and internal medical safety review was in agreement.  The SAEs observed in this 
study were predominately due to exacerbation of psychosis or schizophrenia symptoms, 
which is commonly observed in similar placebo-controlled trials in this study population.  
The most frequently reported treatment-related, treatment-emergent AEs across all treatment 
groups were headache, constipation, akathisia, nausea, sedation, neutropenia, somnolence, 
dizziness, and insomnia.  Neutropenia was reported by subjects in all treatment groups.  
Severe treatment-emergent, treatment-related AEs of oculogyric crisis (PF-02545920 15 mg), 
akathisia (PF-02545920 15 mg), and exacerbation of schizophrenia (placebo) were reported 
by 1 subject each.
There were no trends for differences between treatment groups in absolute values or change 
from baseline of ECG parameters.  No significant differences were observed between 
treatment groups for laboratory abnormalities.
The proportion of subjects triggering the subject stopping criteria for neutropenia did not 
differ substantively between the PF-02545920 5 mg (6 subjects), 15 mg (5 subjects), and 
placebo (5 subjects) treatment groups. 


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The overall dystonia incidence rate (includes dystonia, oromandibular dystonia and 
oculogyric crisis) was 1/74 in the PF-02545920 5 mg, 6/74 in the 15 mg treatment 
groups, 2/74 in the placebo group, and no subjects in the risperidone 3 mg group.  Among the 
6 subjects in the PF-02545920 15 mg group, 5 dystonia events occurred before Day 7, of 
which only 1 was reported as severe (oculogyric crisis).  A single subject discontinued 
treatment in the study due to a dystonia AE.  Dystonia AEs were successfully managed with 
as needed (prn) use of anticholinergic medication only, except in 1 case that required 4 days 
of treatment. 
The 5 mg and 15 mg BID dose groups of PF-02545920 appeared to be generally well 
tolerated, with an overall tolerability profile comparable to risperidone.  In general, there 
were few differences in AE frequency between the treatment groups, and most AEs were 
mild or moderate in severity.  The most commonly occurring AEs with PF-02545920 were 
akathisia in both PF-02545920 groups, and dystonia and sedation/somnolence in the 15 mg 
group.  The incidence rate of dystonia for the titrated 15 mg Q12H dose group in this study 
(8.1%) was substantially lower than the rate observed in a similar study (A8241006) 
population with a non-titrated 15 mg Q12H dose (43%) suggesting that titration reduced the 
risk for dystonia with this compound. 
Although there were 14 SAEs in 12 subjects, all of them were judged to be non-treatment 
related by the investigator and the sponsor. 
At the a priori specified level of significance of 0.1 (1-sided), it can be concluded from the 
primary analysis for the mean change from Baseline in the positive and negative syndrome 
scale (PANSS) total, that neither dose of PF-02545920 was different from placebo.
Study A8241018 showed that overall PF-02545920 was safe and well tolerated in subjects 
with schizophrenia treated with adjunctive PF-02545920 titrated to 15 mg BID via the 
3 approaches to titration.  The most common AEs were somnolence, akathisia, dystonia, 
headache and extrapyramidal disorder.  The majority of reported AEs were mild or moderate.  
Two subjects experienced severe AEs of oromandibular dystonia and myalgia (PF-02545920 
treatment group).  There were no deaths, SAEs, discontinuations, dose reductions, or 
temporary discontinuations of study medication due to AEs. 
In prior studies with PF-02545920 (A8241006, A8241012), the incidence of dystonia was 
reduced by the incorporation of dose titration.  In this study A8241018, dystonia and 
oromandibular dystonia were observed.  The incidence rate of dystonia and oromandibular 
dystonia was lower in PF-02545920 treated subjects in Cohort 3 (14.2%) using the 7 day 
titration interval than in Cohorts 1 and 2 (33.4% in Cohort 1, 25.0% in Cohort 2) that used a 
shorter titration interval.  Dystonia AEs responded well to “as needed” (PRN) use of 
anticholinergic medication treatment and resolved without interruption in study drug 
administration.  No subjects required ongoing prophylactic treatment with anticholinergic 
medications, and no subjects were discontinued due to dystonia. 
There were no notable changes from baseline in blood pressure (BP) or pulse rate in any 
treatment group or between the PF-02545920 and placebo groups.  Two subjects were noted 


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to exhibit non-symptomatic orthostatic hypotension on routine assessments that were 
documented as AEs but not accompanied by lightheadedness and one subject exhibited 
non-symptomatic orthostatic changes in pulse rate that was documented as an AE but not 
accompanied by lightheadedness.  There were no notable changes from baseline in ECG 
parameters or notable differences in mean ECG parameters between the PF-02545920 and 
placebo treatment groups.  No ECG values were considered to be AEs.  There were no 
clinically important trends in laboratory values during the study.  There were no laboratory 
abnormalities reported as AEs.
As of August 2014 there are three active trials with PF-02545920, one in schizophrenia
(A8241019), one in HD subjects (A8241016) and one in healthy volunteers (A8241017).
The proof-of-concept study in subjects with schizophrenia (A8241019) is a 12 week, 
randomized, outpatient, parallel group, double blind comparison of PF-02545920 5 mg, 
PF-02545920 15 mg, and placebo dosed BID in the adjunctive treatment of subjects with 
stable schizophrenia who have demonstrated a suboptimal response to a stable dose of 
antipsychotic monotherapy and other psychotropic medications. 
Study A8241017 is a Phase 1 open-label, single center, single oral dose, serial cohort study in 
healthy volunteers to establish the extent to which PF-02545920 occupies central PDE10A 
enzyme as assessed by in vivo PET scanning using the PDE10A radioligand [18F]MNI-659. 
Study A8241016 is a Phase 2, double-blind, sequential treatment group, fixed dose, 
placebo-controlled, single center, randomized trial in subjects with a diagnosis of early HD.  
This study assesses the safety of PF-02545920 and its efficacy in improving motor, cognitive 
and behavioral deficits after 28 days of treatment.  Subjects are randomized to PF-02545920 
20 mg BID (titrated) or placebo (Cohort A), or to PF-02545920 5 mg BID or placebo 
(Cohort B), and are evaluated with several outcome measures including total motor score 
(TMS), executive function tasks, the Problem Behaviors Assessment for HD short form, and 
the Starkstein apathy scale.
As of August 2014, there have not been reports of new unexpected adverse events from the 
above ongoing studies and the available information suggests that the safety profile of 
PF-02545920 in subjects with HD should not be expected to be different than that observed 
in subjects with schizophrenia or healthy volunteers.
Complete information for PF-02545920 may be found in the SRSD, which for this study is 
the Investigator’s Brochure. 
1.2.3. Pharmacokinetics
Following single and multiple dose administration of PF-02545920, exposure of both parent 
and a pharmacologically active N-desmethyl metabolite (PF-01001252) increased with 
increases in dose in a nearly dose proportional manner.  PF-02545920 absorption was rapid 
with median time to maximum plasma concentration (Tmax) of approximately 1 hour 
post-dose.  The mean terminal half-lives of PF-02545920 and PF-01001252 at steady state 
were approximately 11-13 hours and 8-12 hours, respectively. 


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To date, PF-02545920 has been evaluated in healthy subjects, subjects with chronic 
symptoms of schizophrenia, and subjects with acute exacerbation of schizophrenia.  There 
was no significant difference in exposure across these populations.  Steady state exposures of 
PF-02545920 and PF-01001252 are shown in Table 2.
Table 2.
Steady State Exposures of PF-02545920 and PF-01001252 observed after 
Multiple Dosing in Subjects with Stable Schizophrenia (A8241002)
PF-02545920
PF-01001252
PF-02545920 Dose = 20 mg Q12H for 13 days
Cmax (ng/mL)
327
66.1
AUC12 (ng*hr/mL)
1280
334
The major clearance pathway for PF-02545920 in humans is expected to be cytochrome 
P450 (CYP)-mediated hepatic metabolism, predominantly executed by CYP3A4.  
Additionally, the disposition of PF-02545920 does not appear to be modulated by 
p-glycoprotein (P-gp). 
Both non-clinical data and clinical cerebrospinal fluid (CSF) data suggest equilibrium of 
unbound PF-02545920 concentration in plasma and CNS, therefore free plasma 
PF-02545920 concentration can be used as a surrogate of CNS target exposure with high 
confidence.  Based on preclinical estimates of enzyme occupancy and observed PF-02549520 
Cmax values (Table 2), the 20 mg BID dose is projected to result in approximately 
66% PDE10A occupancy at steady state Cmax (Fu=0.0017).  Similarly, the average enzyme 
occupancy at steady state over a 12 hr period is projected to be approximately 
39% (Fu=0.0017) at 20 mg BID dosing.  The in vitro IC50 for PF-02545920 on PDE10A 
inhibition was 0.18 nM, which corresponds to 42 ng/mL of total plasma PF-02545920 
concentration, adjusted by molecular weight of 392 and free fraction of 0.0017.
1.2.4. Dose Selection Rationale
A single dose of 20 mg PF-02545920 (BID) will be studied to evaluate long-term safety and 
efficacy in subjects with HD.  Based on the previous pre-clinical efficacy data and clinical 
safety data, a dose of 20 mg BID is estimated to produce the most robust PDE10A inhibition 
while still being well tolerated. The 20 mg BID dose is the maximum dose evaluated in the 
double blind Phase 2 Proof-Of-Concept Study (A8241021) in subjects with HD. 
A titration scheme will be used for all subjects who did not receive the 20 mg BID dose in 
the previous study A8241021 in order to mitigate the potential risk of dystonia.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective:

To assess long-term safety and tolerability of 20 mg BID of PF-02545920 in subjects 
with HD.


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Secondary Objectives:

To assess motor function after 6 and 12 month oral dosing with 20 mg BID of 
PF-02545920 in subjects with HD. 

To assess the efficacy of 6 and 12 month oral dosing with 20 mg BID of 
PF-02545920 on chorea severity in subjects with HD.

To assess whether 6 and 12 month oral dosing with 20 mg BID of PF-02545920 can 
improve overall clinical impression in subjects with HD.
:

 

 

 

 

 

 

2.2. Endpoints
Primary Endpoint:

Adverse events, weight, vital signs (pulse, blood pressure and body temperature), 
physical examination, neurological examination, electrocardiogram (ECG) and 
clinical laboratory findings (hematology, biochemistry and urinalysis).  The endpoints 
are:

The number and proportion of subjects with adverse events.

Assessment of clinical laboratory parameters.

Assessment of vital signs.
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
Assessment of ECG parameters.

White blood count (WBC) and absolute neutrophil count (ANC) at each visit.

Abnormal laboratory findings from baseline.

Frequency and severity of adverse events related to extrapyramidal symptoms 
(EPS) including dystonia and akathisia, as assessed by the investigator.

C-SSRS (suicide severity assessment).
Secondary Endpoints:

Change from baseline in the Total Motor Score (TMS) assessment of the Unified 
Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment.

Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS 
after 6 and 12 months of treatment.

Clinical Global Impression-Improvement score after 6 and 12 months of treatment. 
:
:

 
:

 
 

 
: 

 
:

 
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
 

 
:

 

 
 

 

 

 
.
3. STUDY DESIGN
This study is a 12 month open label extension study of PF-02545920 20 mg dosed BID 
following study A8241021. 
The study includes a Screening visit (V1) to assess eligibility followed by a Baseline visit 
(V2) and visits after 2 weeks, 4 weeks, 3 months, 6 months, 9 months, and 12 months of 
treatment.  The final scheduled visit is a Follow-up visit 7-14 days after the last dose.  
Screening visit (V1) and Baseline visit (V2) will coincide with Week 19 and Week 26 Visits 
from study A8241021, respectively.  For the Screening visit (V1) and Baseline visit (V2)
procedures and assessments, the investigator will use data collected during Week 19 and 
Week 26 visits for study A8241021, respectively.  Subjects, who meet study entry criteria,
will be assigned to the 20 mg BID dose.  During the 12-month treatment phase, subjects will 
return for study assessments at Week 2 (V3), Week 4 (V4), Month 3 (V5), Month 6 (V6), 
Month 9 (V7), Month 12 (V8), and for a Follow-up visit (V9). 
Subjects, who were assigned to the 20 mg PF-02545920 dose group in the preceding 
A8241021 study, will continue to receive 20 mg PF-02545920 in this study without any 
titration.  All other subjects will be titrated to the 20 mg BID dose as follows: 5 mg BID for 
7 days, 10 mg BID for 7 days, 15 mg BID for 7 days, then 20 mg BID for the remainder of 
the treatment phase.  Titration is in place to reduce incidence of AEs, frequent monitoring is 
in place for neutropenia, and an option for de-escalation by 5 mg decrements (temporary or 
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permanent) will be available should the investigator consider the AE intolerable (see 
Guidance on clinical management of subjects with acute extrapyramidal symptoms, 
Appendix 1).
Subjects who are discontinued (Early Termination) at or after Day 14 should complete as 
many of the Month 12 (V8) assessments as possible.  Subjects should return to complete the 
Follow-up visit whenever possible. 
Based on the total number of 260 subjects expected to be randomized in study A8241021, up 
to 260 subjects may take part in this open label extension. 
 
(
)
(
).
Figure 1.
Study Design Schematic
3.1. Stopping Criteria
White Blood Count (WBC) and Neutrophil (ANC) Monitoring:
WBC counts and differentials will be reviewed at Screening (V1) and Baseline Day 1 (V2) 
reviewed and performed at the following visits: Week 2 (V3), Week 4 (V4), Month 3 (V5), 
Month 6 (V6), Month 9 (V7), Month 12 (V8)/ET and Follow-up (V9).  In the event that the 
ANC and/or WBC results are abnormal, the investigator (or a delegate) will contact the 
subject to inquire about potential symptoms.  The lab results will be reviewed by the 
investigator (or delegate) as soon as possible once they are available, but no later than 
2 business days after receipt of the lab results.  The investigator must confirm and document 
that the results do not meet WBC/ANC stopping criteria listed below and that the subject can 
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continue to receive study medication.  The Pfizer Medical Monitor and the Pfizer clinician
should be contacted immediately if a subject meets any of the WBC/ANC stopping criteria.  
A separate source document worksheet will be provided to each site to assist in the 
monitoring of these criteria.  See Neutropenia Assessment for a description of the minimal 
safety assessment for evaluating cases of neutropenia meeting any of the study stopping 
criteria described below.
3.1.1. Subject Stopping Criteria

Subjects with WBC 3000 cells/mm3 but 2000 cells/mm3 and/or ANC 
1500 cells/mm3 but 1000 cells/mm3 will have study treatment temporarily 
suspended and have three times per week WBC counts with differential until WBC 
3000 cells/mm3 and ANC 1500 cells/mm3.  Subjects who have at least 
2 consecutive WBC or neutrophil findings meeting this criterion will be evaluated by 
a hematologist to determine the etiology of the adverse event and for medical 
management recommendations.

Subjects will be discontinued from study participation if WBC 2000 cells/mm3
and/or ANC 1000 cells/mm3.  Subjects who are discontinued or permanently 
suspended due to WBC or ANC findings will be evaluated by a hematologist to 
determine the etiology of the adverse event and for medical management 
recommendations.
3.1.2. Study Stopping Criteria

The study will be stopped if any subject develops agranulocytosis, ie, ANC 
500 cells/mm3, which cannot be explained by other disease states or concurrent 
medications after medical assessment, including a hematology consultation.  The data 
generated in the evaluation of events potentially meeting this stopping criterion will 
be reviewed by the independent External Data Monitoring Committee (E-DMC),
which will make the final determination whether this criterion has been met.  See 
Data Monitoring Committee for additional detail on DMC procedures.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:


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1. Evidence of a personally signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
3. Subjects must have completed Study A8241021 and, in the opinion of the investigator 
and sponsor, have been compliant with the STUDY PROCEDURES, Lifestyle 
Guidelines and study treatment. 
4.
 
.
5. Males or females between the age of 30 years and 66 years (inclusive).
6. Diagnosis of HD based on characteristic clinical findings, including presence of chorea, 
and genetic confirmation with the detection of an expansion of 36 CAG trinucleotide 
repeats in the huntingtin gene (Htt).
7. Male and female subjects of childbearing potential and at risk for pregnancy must agree 
to use a highly effective method of contraception throughout the study and for at least 
28 days (90 days for males) after the last dose of assigned treatment. 
Female subjects who are not of childbearing potential (ie, meet at least 1 of the following 
criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed by having a serum follicle stimulating hormone 
(FSH) level within the laboratory’s reference range for postmenopausal women.
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Subjects 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 subjects who are Pfizer employees directly involved in the conduct of the 
study.
2. Participation in study(ies) involving investigational drug(s) (Phases 1-4) other than 
PF-02545920 within the past 9 months before the current study begins and/or during 
study participation.
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3. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
4. Evidence or history of:
a.
Clinically significant neurologic disorder other than Huntington’s disease.  This also 
includes subjects with previous history of epilepsy or seizures (except childhood 
febrile seizures), stroke, head injury with significant neurologic sequelae.
b. Other severe acute psychiatric condition, mania and/or psychosis.
c.
For subjects who score 3 on the suicidal ideation item of the Problem Behaviors 
Assessment or answer “Yes” to the C-SSRS questions 4 or 5, a risk assessment 
should be done by a qualified mental health professional (eg, a psychiatrist or 
licensed PhD level clinical psychologist) to assess whether it is safe for the subject to 
participate in the study (See Suicidality Risk Assessment).  In addition, subjects 
deemed by the investigator to be at significant risk of suicidal or violent behavior 
should be excluded.  Attempted suicide or suicidal ideation with intention or plan, 
which required hospital admission and/or change of level of care within 15 months 
prior to Screening should be discussed with medical monitor or clinician before 
proceeding. 
5. Evidence or history of any clinically significant conditions which affect one of the 
following systems and which were used as exclusion criteria in preceding A8241021 
study:
a.
Renal.
b. Endocrine.
c.
Pulmonary. 
d. Hematological.
e.
Gastrointestinal (including any condition possibly affecting drug absorption, eg, 
gastrectomy, gastric bypass).
f.
Immunological, including positivity for human immunodeficiency virus (HIV) and 
acquired immunodeficiency syndrome (AIDS).
g. Severe allergic diseases (excluding untreated, asymptomatic, seasonal and 
environmental allergies at time of dosing).
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6. Subjects with: 
a.
WBC 3500/mm3 OR ANC 2000/mm3 anytime in study A8241021 which were not 
approved as acceptable for enrollment in study A8241022 by the sponsor study 
clinician or sponsor medical monitor.  These cases should be discussed with the 
sponsor medical monitor or clinician prior to submitting subject for an eligibility 
approval.
b. History of neutropenia, including benign ethnic neutropenia, clozapine induced 
agranulocytosis or granulocytopenia.
c.
History of myeloproliferative disorders (primary myelofibrosis, polycythemia vera, 
essential thrombocythemia, chronic eosinophilic leukemia/hypereosinophilic 
syndrome, systemic mastocytosis).
7. Evidence or history of clinically significant cardiovascular disease, including:
a.
Uncontrolled hypertension (sitting or supine diastolic blood pressure >95 mmHg 
and/or sitting or supine systolic blood pressure >170 mmHg with or without 
treatment).
b. Evidence of orthostatic symptoms (eg, dizziness upon standing) or systolic blood 
pressure (BP) drop 20 mm Hg or diastolic BP drop 10 mmHg from supine to 
standing assessment at screening.
c.
Any 12-lead ECG with repeated demonstration of QTc >450 msec or a QRS interval 
>120 msec.
d. Coronary bypass surgery.
e.
History of myocardial infarction or ischemic heart disease.
f.
Heart failure.
g. Non clinically significant ECG findings including sinus bradycardia and tachycardia 
will not exclude subjects from the study.
8. Subjects with laboratory test results reviewed at screening that deviate from the upper or 
lower limits of the reference range, as assessed by the study-specific laboratory and 
confirmed by a single repeat, if deemed necessary, except for non-clinically significant 
values, as determined by the investigator. 
a.
AST or ALT must be 2 X upper limit of reference range.
b. Total bilirubin must be within 1.5 X of the upper limit of reference range at 
screening; subjects with a history of Gilbert's syndrome may have a direct bilirubin 
measured and would be eligible for this study provided the direct bilirubin is ULN.


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9. Subjects with laboratory abnormality that may increase the risk associated with study 
participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would make the 
subject inappropriate for entry into this study. 
10. Any positive urine drug screen documented during study A8241021 and not explained by 
subject’s medication regimen.
11. Drugs or foods/food products which strongly inhibit CYP3A4 (including but not limited 
to atazanavir, amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, 
fluvoxamine, grapefruit, grapefruit juice, grapefruit-related citrus fruits/juices, indinavir, 
itraconazole, ketoconazole, mibefradil, nefazodone, nelfinavir, ritonavir, troleandomycin, 
and verapamil).
12. Drugs which significantly induce CYP3A4 (including but not limited to rifampin, 
rifapentine, rifabutin, phenytoin, carbamazepine, oxcarbazepine, phenobarbital, St. John’s 
Wort).
13. Any history of deep brain stimulation (DBS).
14. Any history of surgical and experimental procedures aiming at improving HD symptoms 
including:
a.
Neural transplantation.
b. Central nervous system lesions.
c.
Infusion of neurotrophic agents.
15. Any reported change in regular alcohol consumption since Baseline Day 1 (V2) of study 
A8241021, which raises clinical concern.
16. Any subject who is likely to be hospitalized (for any reason) during the study.
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18.
 
19. Unwilling or unable to comply with the Lifestyle guidelines described in this protocol 
(see Lifestyle Guidelines).
20. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male and female subjects of childbearing potential who are unwilling 
or unable to use a highly effective method of contraception as outlined in this protocol for 
the duration of the study and for at least 28 days (90 days for males) after the last dose of 
investigational product.
21. Any drug-related SAE experienced during the Study A8241021 which were not approved 
as acceptable for enrollment in A8241022 study by the sponsor study clinician and 
sponsor medical monitor.  These SAEs should be discussed with the sponsor clinician 
and sponsor medical monitor prior to submitting the subject for an eligibility approval.
4.3. Randomization Criteria
Once subjects have satisfied all selection criteria, they will be assigned a randomization 
number that will determine whether they will undergo blinded titration to 20 mg BID 
(subjects in the placebo and 5 mg BID arm in study A8241021) or continue the same dose 
(subjects already in the 20 mg BID arm in study A8241021) (See STUDY TREATMENTS). 
4.4. Lifestyle Guidelines
4.4.1. Activity
Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, calisthenics, 
aerobics) for 48 hours prior to each blood collection for clinical laboratory tests.
4.4.2. Contraception
All male and female subjects who, in the opinion of the investigator, are biologically capable 
of having children and are sexually active must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days (90 days for males) after the last dose of investigational product.  The 
investigator or his/her designee, in consultation with the subject, will confirm that the subject 
has selected the most appropriate method of contraception for the individual subject and his 
female partner from the permitted list of contraception methods (see below) and instruct the 
subject in its consistent and correct use.  Subjects need to affirm that they meet at least one of 
the selected methods of contraception.  The investigator or his/her designee will discuss with 
the subject the need to use highly effective contraception consistently and correctly according 
to the schedule of activities (SOA) and document such conversation in the subject’s chart.  In 
addition, the investigator or his/her designee will instruct the subject to call immediately if 
the selected contraception method is discontinued or if pregnancy is known or suspected. 
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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, or implanted hormonal methods of 
contraception is allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for 90 days after the last dose.
4.4.3. Meals and Dietary Restrictions
Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus fruits 
(eg, Seville oranges, pomelos) from the Screening visit through the Month 12 Visit (V8).
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located on the team SharePoint site. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a help desk in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The help desk number can also be used by 
investigational staff if they are seeking advice on medical questions or problems; however, it 
should only be used in the event that the established communication pathways between the 
investigational site and the study team are not available. It is therefore intended to augment, 
but not replace, the established communication pathways between the investigational site and 
the study team for advice on medical questions or problems that may arise during the study. 


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The help desk number is not intended for use by the subject directly, and if a subject calls 
that number, he or she will be directed back to the investigational site.
4.6. Rater Qualifications
Raters must demonstrate sufficient assessment experience as well as appropriate educational 
background and indication experience.  Rater qualification will be documented as part of the 
overall rater qualification process. 
Raters performing the following assessments will require certification or training by the 
sponsor designated vendor prior to rating in this study:

UHDRS, 
, clinical global impression (CGI) 
 
(
),
,
and C-SSRS.
Other efficacy and safety/screening scales outlined in the Schedule of Activities may require 
documentation of study specific training on these instruments before rating in the trial is 
permitted.
Vendor(s) designated by the sponsor will conduct rater qualification(s) and will provide 
written and signed documentation(s) about each rater’s certification(s) and/or training(s).  
Recertification may be required and will be provided by the sponsor designated vendor(s) at 
periodic intervals during the study.  A separate guideline will be developed to facilitate rater 
selection at the sites.
If possible, each subject will be interviewed and assessed throughout the study by the same 
rater.  Reasons for rotation of approved raters should be documented in the site source 
documents. 
5. STUDY TREATMENTS
All subjects who consent to participate will undergo screening procedures during the 
screening period.  Informed consent should be obtained by Screening Visit, which is 
Week 19 of the A8241021 study, for subjects to participate in the open-label extension study.  
Subjects who meet enrollment criteria AND have received confirmation by the sponsor will 
be randomized to participate in the 12 month, open label study.
Subjects will be assigned to 20 mg BID dosing of PF-02545920 (with blind titration for 
subjects previously receiving 5 mg BID PF-02545920 or placebo in study A8241021).
Option for temporary or permanent blind de-escalation by 5 mg decrements will be available 
should the investigator consider the AE intolerable (see Guidance on clinical management of 
subjects with acute extrapyramidal symptoms - Appendix 1).  Once AEs have resolved the 
principle investigator (PI) will have the option to resume escalation.
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5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
Investigators will use an Interactive Response Technology (IRT) to assign a unique subject 
identification number to each subject who has signed the informed consent document (ICD).
This identifying number will be retained throughout the duration of the study participation.
Subject eligibility for participation in the study will be determined following the Screening 
assessments (V1). Once the subject is determined to be eligible for treatment, the 
investigator will obtain a randomization number and study medication assignment utilizing 
the IRT.
Subjects, who received PF-02545920 20 mg BID in the preceding A8241021 study, will 
continue to receive PF-02545920 20 mg BID in this study.  Subjects, who previously 
received either PF-02545920 5 mg BID or placebo in the A8241021 study, will be titrated to 
PF-02545920 20 mg.  The titration will start at 5 mg BID and the dose will be increased by 
5 mg BID every 7 days, up to a 20 mg BID to be reached at Day 22, and maintained until 
Month 12 (V8).  Subjects will take 4 tablets twice a day provided in blister packs from 
Baseline Day 1 (V2) to Week 4 (V4) and in bottles from Week 4 (V4) to Month 12 (V8).  
For subjects, who have been de-escalated from 20 mg BID to lower dose in the preceding 
study A8241021, the investigator should contact the sponsor study clinician and medical 
monitor to discuss titration scheme.
Table 3.
Allocation to Study Treatments
Treatment Group
Study Treatment
Drug 
Administration
Duration
20 mg PF-02545920, 
Subjects receiving 
20 mg PF-02545920 
in the preceding 
A8241021 study
Days 1-365
Four 5 mg tablets of PF-02545920
Orally, BID
12 months
(Days 1-365)
20 mg PF-02545920, 
All other subjects 
Days 1-7
One 5 mg tablet of PF-02545920
Three placebo tablets for PF-02545920
Days 8-14
Two 5 mg tablets of PF-02545920
Two placebo tablets for PF-02545920
Days 15-21
Three 5 mg tablets of PF-02545920
One placebo tablet for PF-02545920
Days 22-365
Four 5 mg tablets of PF-02545920
Orally, BID
12 months
(Days 1-365)


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5.2. Breaking the Blind 
All subjects will receive 20 mg PF-02545920 BID starting on Day 22.  The initial titration 
period between Day 1 and Day 22 will be double blind. 
The method for breaking the blind will be an electronic process via IRT.  At the initiation of 
the study, the study site will be instructed on the method for breaking the blind.  Blinding 
codes should only be broken in emergency situations for reasons of subject safety.  The 
responsibility to break the treatment code in emergency situations resides with the 
investigator.  Whenever possible, it is requested the investigator or sub-investigator consult 
with a member of the study team prior to breaking the blind.  When the blinding code is 
broken, the reason must be fully documented and entered on the case report form (CRF)/data 
collection tool (DCT) and the Sponsor is to be notified.
5.3. Subject Compliance
Dosing compliance is documented in the accountability logs, the electronic Case Report 
Form (eCRF) and in the subject’s dosing diary.  On Day 1 subjects will be instructed on how 
to take their medication each day, twice a day, during outpatient dosing days.  A dosing diary 
will be given to the subject for the first four weeks, with instructions on how to record daily 
times of study drug administration.  The subject will bring the used and in-use medication 
blister cards and/or bottles back to the clinic at each visit.  At each visit, a tablet count will be 
done by the research staff, and the subject will be questioned about any missed or extra doses 
taken.  Checking blister packs and bottles will allow the site personnel to check on
administration compliance.
A subject may be considered non-compliant if they have missed more that 20% of the 
required doses since the first dose.
Medication Compliance Formula:
For example, if the subject is required to take 4 tablets twice daily for exactly 12 months
(365 days, 2,920 tablets prescribed) but according to the amount of drug returned the subject 
took 2280 tablets of study medication, percent compliance is calculated as follows:
Dosing record from Baseline to Week 4 should contain details of missed or lost doses for 
accurate compliance measurement.  Compliance will be assessed by pill count after Week 4.  
If compliance is less than 80% or greater than 120% at any visit, the reason(s) must be noted.  
Subjects should not make up for missed doses.  Missed dose(s) related to AEs should be 
discussed with the sponsor.


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5.4. Drug Supplies
The study medication will be as follows:
Table 4.
Drug Supplies
Dosage Forms
Compounds
Appearance
Active drug tablet 5 mg 
PF-02545920
White to off white small round tablets
Placebo tablets for 5 mg 
PF-02545920
Placebo
White to off white small round tablets
5.4.1. Dosage Form(s) and Packaging
PF-02545920 will be supplied by the sponsor as tablets containing 5 mg of active drug.  For 
treatment between Baseline Day 1 (V2) and Week 4 (V4), drug supplies will be packaged in 
blister packs with labels containing morning and evening administration and titration 
instructions.  The tablet count per blister pack will be appropriate for the dosing regimen and 
treatment period.  The blister pack also allows for an accurate blind de-escalation with 5 mg 
decrement, should the Principal Investigator assess that a subject requires a (temporary or 
permanent) dose adjustment due to intolerable AE(s) (See Appendix 1).  The blister card will 
have column labels for each tablet (A, B, C, D) to facilitate giving direction to the subject.  
Once AEs have resolved the PI will have the option to resume escalation. 
For treatment between Week 4 (V4) and Month 12 (V8), drug supplies will be packaged in 
high-density polyethylene (HDPE) bottles.
Pfizer will provide all study medication except for concomitant and rescue medications. 
5.4.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
the study drug.
The study medication will be dispensed using a drug management system at each visit from
V2 to V7.  Dispensing will be done by a qualified staff member via unique container 
numbers in either blister cards or bottles, in quantities appropriate for the study visit 
schedule. The subject should be instructed to maintain the product in the blister cards or 
bottles throughout the course of dosing and return the blister cards and/or bottles to the site at 
the next study visit. 
5.5. Administration
Subjects will be instructed to take the study medication twice a day (BID), morning and 
evening, at approximately the same time of day throughout the study, and if possible (ideally) 
at least one hour prior to, or two hours after meals.  Subjects will swallow the study 
medication whole, and will not manipulate or chew the medication prior to swallowing.  
Drug will be dispensed to the subject at each clinic visit starting at Baseline Day 1 (V2) and 
ending with Month 9 (V7).


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Between clinic visits, subjects will be responsible for establishing a process for reliable 
outpatient dosing to ensure dosing compliance.  To facilitate safety monitoring during the 
titration phase, a dosing diary will be supplied to the subject for the first four weeks and 
subjects will be instructed to record the time of each daily dose of study medication.  
Subjects will be instructed to bring the completed diary to Week 2 and Week 4 Visits, along 
with used and in-use blister packs containing the study medication.  The study staff will use 
bottles to assess compliance after the Week 4 Visit.
If a subject misses a scheduled morning dose, that dose should be taken as soon as possible, 
but not later than 6 hours beyond the scheduled time of administration.  If it is greater than 
6 hours beyond the scheduled dose, the subject should be instructed to skip that dose and 
resume dosing at the next regularly scheduled time.  Missed doses and reasons for missed 
doses should be recorded on the dosing diary.
5.6. Drug Storage
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational products are stored in a secured area, with controlled access under 
recommended storage conditions (controlled room temperature between 15-25C) and in 
accordance with applicable regulatory requirements.
Investigational product should be stored in its original packaging or container and in 
accordance with the drug label.  Storage conditions stated in the SRSD (Investigator 
Brochure) will be superseded by the storage conditions stated on the labeling. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  
Specific details regarding information the site should report for each excursion will be 
provided to the site.  Receipt of materials, door opening and closing, and other routine 
handling operations where the product(s) are briefly out of labeled temperature range are not 
considered excursions.  More specific details will be provided to the sites separately. 


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Site staff will instruct subjects on the storage requirements for medications they take home 
including how to report temperature excursions. 
PF-02545920 must not be used outside the context of this protocol.  Under no circumstances 
should the investigator or other site personnel supply PF-02545920 to other investigators, 
patients, or clinics, or allow supplies to be used other than directed by this protocol, without 
prior authorization from the sponsor.  The investigator must maintain adequate records 
documenting the receipt, use, loss, or other disposition of investigational product(s).  Pfizer 
may supply drug accountability forms that may be used, or may approve the use of an 
equivalent form.  The form must identify the investigational product, including batch or code 
numbers, and account for its disposition on a subject by subject basis, including specific 
dates and quantities.  Unused study drug, and unused or used study drug materials must be 
kept in a secure location for final accountability and reconciliation.  At the end of the clinical 
study, Pfizer will provide instructions as to the disposition of any unused investigational 
product.  The investigator must provide an explanation for any destroyed or missing study 
drug and/or study drug materials.
5.7. Drug Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  The subject will be instructed to return to all clinic 
visits with all (used and in-use) blister packs and/or bottles (and dosing diary at Week 2 and 
4 Visits) for accountability and compliance check.
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
All medications 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 
medication(s) at each clinic visit.  Medications taken within 8 weeks prior to the Screening 
Visit or between Screening and Baseline Visits in study A8241022 will be documented as 
prior medications.  Medications taken after the first dose of study medication in study 
A8241022 will be documented as concomitant medications.  Additionally, history of all prior 
and current treatments indicated for HD at any time must be recorded.  Concomitant 
medications include all vitamins, herbal remedies, nutritional supplements, over-the-counter, 
prescription medications, and prescription medical foods.
Antipsychotics, antidepressants and all permitted psychotropic medications need to be at 
stable doses for the duration of the study.  Medication regimen stability is defined as 
maintaining the same dosage of medications except for minor adjustments to manage drug 
specific tolerability issues.  Recognizing that physicians outside of the study may be 
managing the subject’s background antipsychotic and other psychotropic medications, 


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changes of medications and/or doses should be discussed with the sponsor study clinician 
and medical monitor to determine subject disposition.
Stable administration of antidepressants will be allowed, with the exception of tricyclics and 
monoamino-oxidase inhibitors (MAOIs).
Prescription medical food (eg, Axona) or prescription nutraceuticals marketed for HD 
(eg, creatine) or for movement disorders, which were prohibited during the study A8241021, 
are also prohibited in the study A8241022. 
The use of tetrabenazine is prohibited at any time during the study period. 
The use of amphetamine-like medications and stimulants is prohibited at any time during the 
study period.
Appendix 2 summarizes the drugs and classes of drugs allowed and prohibited as 
concomitant medications after the Screening visit (V1) and while on the study, until the end 
of the study Month 12 (V8), unless specified otherwise.
Acetaminophen/paracetamol may be used at doses of 1 g/day on an as needed basis.  
Limited use of non-prescription medications that are not believed to affect subject safety or 
the overall results of the study may be permitted on a case-by-case basis following approval 
by the sponsor’s medical monitor.
5.9. Rescue Medication
The use of any rescue medication should be discussed with study sponsor medical monitor or 
clinician prior to administration if at all possible.
Use of all “prn” medications on an “as needed” basis should be avoided within 24 hours prior 
to each clinic visit to minimize potential effects on the assessment scales, unless withholding 
such treatment is judged by the investigator to present a safety risk for the subject.
5.9.1. Rescue Medications for Anxiety/agitation
Short acting benzodiazepines (whose median half-life is between 2 and 15 hours) may be 
given, and only as needed (prn), not as a standing dose.
5.9.2. Rescue Medication for Insomnia
Insomnia medications are permitted for the duration of the study only if it is determined to be 
clinically necessary by the investigator.  Treatment for insomnia should be avoided within 
24 hours prior to each clinic visit to minimize potential effects on the assessment scales. 


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5.9.3. Rescue Medications for the Management of Extrapyramidal Symptoms 
(akathisia, dystonia, tardive dyskinesia)
Subjects may receive treatment with anticholinergics for acute extrapyramidal symptoms 
(EPS) throughout the conduct of the study at doses within the respective approved dosing 
ranges by oral (preferred) or injectable administration; however, prophylactic or preventative 
treatment (eg, prescribed daily or routinely to prevent EPS) will not be permitted.  Time and 
date documentation of the use of “as needed” (“prn”) anticholinergics for the treatment of 
acute EPS must be directly linked to time and date adverse event documentation of the 
specific target EPS eg, dystonia, parkinsonism, akathisia. Additional guidance is presented 
in Appendix 1.
6. STUDY PROCEDURES 
6.1. Screening
Screening Visit will take place on the same day as the Week 19 Visit for Study A8241021.
In preparation for the screening visit (prior to Week 19 for study A8241021), the investigator 
will assess subject eligibility for the open label study A8241022 using all data available from 
study A8241021, as described in detail in Section 7.4.  Pre-screening Checklist A will be 
provided to assist the site in documenting this review.
The investigator will review available data for study A8241021 at Week 19 (changes in 
medical history, medical procedures, concomitant medications, compliance) and confirm 
continued eligibility by the PI prior to proceeding to informed consent documentation.  
Screening Checklist B will be provided to assist the site in documenting this review.
The following activities will be completed during the clinic visit:

Obtain institutional review board/ethics committee (IRB/EC) approved written 
informed consent from the subject in accordance with local regulations before 
initiating any other screening procedures.

Obtain informed consent.  
 
 
  (
 
 
).

Review overall subject eligibility (Section 7.4).

File Record of Signed and Dated Pre-screening Checklist A.

Complete Screening Checklist B for review of study A8241021 data.

Review inclusion/exclusion criteria.
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
Obtain subject eight digit screening number from IRT.

Submit information required to sponsor (or designee) for Sponsor Eligibility 
Verification Process, at least 2 business days prior to planned randomization, as 
instructed during protocol training (Section 7.5). 

To prepare for study participation the subject will be instructed on the Lifestyle
Guidelines (Section 4.4) and concomitant medications restrictions required by 
protocol (Section 5.8).  Ensure instructions for Lifestyle Guidelines are documented
in the source documents. 

Remind the subject about the date of the next clinic visit at Baseline Day 1 (V2).
6.2. Study Period
6.2.1. Visit 2 - Baseline Day 1 (Randomization)
All visit windows will be relative to Baseline Day 1 (V2).  The Baseline Day 1 (V2) will be 
performed on the same day as the Week 26 visit for study A8241021.  Selected assessments 
from study A8241021 Week 26 clinic visit will be recorded and used for baseline, as 
specified below.
The following activities will be completed during the clinic visit

Document Sponsor Eligibility Confirmation PRIOR to randomization.

Review and document subject’s medical history, medical procedures, concomitant 
medications (Section 7.3).

Confirm continued subject eligibility (includes review of available data from 
Week 26 visit for study A8241021).

Document the following data obtained at Screening for study A8241021:

Subject’s number of CAG repeats obtained for A8241021 study to document 
continued eligibility (Section 7.2).

Demography data.

Height (centimeters).

Record results of the following assessments captured at Week 26 for Study 
A8241021:

Weight (kilograms).

Brief physical examination (Section 7.7.1).


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
Brief neurological examination (Section 7.7.3).

Single 12-lead ECG (Section 7.7.7).

Orthostatic vital signs (supine and standing blood pressure and pulse) and oral or 
tympanic body temperature (Section 7.7.2).

Contraception check.

Hematology (Section 7.7.4).

Blood chemistry (Section 7.7.4).

Serum pregnancy test for females of child bearing potential (sent to central lab)
(Section 7.7.5).

Urinalysis (Section 7.7.4).

 

C-SSRS (since last visit) for suicidality risk assessment (Section 7.7.6 7.7.6.1).

(Section 7.9.7).

UHDRS Total Motor Score (TMS), 
 
, 
 
(Section 7.9.1).

 (
 
) (Section 7.9.2).

 (
) (Section 7.9.3).

(Section 7.9.4):






CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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
(Section 7.9.5).

 (
) 
(Section 7.9.9).

Review of ANC and WBC for safety monitoring (Section 7.8).

(Section 7.9.8).
The following assessments will be performed:

Non-fasted blood sample may be collected for serum FSH (Section 7.7.4) (if 
requested by the investigator for female subjects, to confirm that FSH level is within 
the laboratory’s reference range for postmenopausal women).

Collect sample for urine pregnancy test (for females of child bearing potential)
(Section 7.7.5). 

Urine drug screen may be performed, if deemed necessary by the investigator
(Section 7.7.4).

Administer Clinical Global Impression Severity (CGI-S) scale (Section 7.9.6).

Obtain randomization number from selected automatic randomization system (IRT).

Dispense dosing diary.

Dispense study drug to subject for outpatient dosing.

Provide instructions to subject for outpatient dosing, including storage, 
administration, dosing diary use.

Provide instructions to subject on Adverse Event (AE) and Serious Adverse Event 
(SAE) collection and instructions for reporting such events to the investigator.

Remind the subject about the date of the next clinic visit at Week 2 (V3) and also to 
bring to the visit all (used and in-use) blister packs and dosing diary.
6.2.2. Visit 3 – Week 2/Day 14 (3 days)
The following activities will be completed during Week 2 visit (V3):

Review adverse events since last visit.

Review changes in the subject’s medical history, concomitant medications, and 
medical procedures since last visit.
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
Obtain vital signs (sitting blood pressure and pulse; oral or tympanic body 
temperature).

Contraception check.

Collect non-fasted blood sample for safety monitoring of ANC and WBC.

Complete C-SSRS (since last visit) for suicidality risk assessment.

Administer the UHDRS Total Motor Score (TMS).

Review ANC and WBC for safety monitoring.

Assess compliance based on observation of blister packs and review of dosing diary.

Dispense study drug to subject for outpatient dosing, with instructions to return to 
next clinic visit with all (used and in-use) blister packs and dosing diary.

Remind the subject about the date of the next scheduled Week 4 (V4).
6.2.3. Visit 4 – Week 4/Day 28 (3 days)
The following activities will be completed during Week 4 visit (V4):

Review adverse events since last visit.

Review changes in the subject’s medical history, concomitant medications, and 
medical procedures since last visit.

Obtain vital signs (sitting blood pressure and pulse; oral or tympanic body 
temperature).

Contraception check.

Collect non-fasted blood sample for safety monitoring of ANC and WBC.

. 

Complete C-SSRS (since last visit) for suicidality risk assessment.

Administer the UHDRS Total Motor Score (TMS).

Review ANC and WBC for safety monitoring.

Assess compliance based on observation of blister packs and review of dosing diary.

Collect dosing diary.
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
Dispense study drug to subject for outpatient dosing, with instructions to return to 
next clinic visit with all (used and in-use) blister packs and/or bottles.

Remind the subject about the date of the next scheduled Month 3 visit (V5).
6.2.4. Visit 5 – Month 3/Day 91 (7 days)
The following activities will be completed during Month 3 visit (V5):

Review adverse events since last visit.

Review changes in the subject’s medical history, concomitant medications, and 
medical procedures since last visit.

Obtain vital signs (sitting blood pressure and pulse; oral or tympanic body 
temperature).

Obtain standard 12-lead ECG (may be repeated if clinically indicated).

Contraception check.

Collect non-fasted blood sample for Hematology.

Serum pregnancy test for females of child bearing potential. 

. 

Complete C-SSRS (since last visit) for suicidality risk assessment.

Administer the UHDRS Total Motor Score (TMS).

Review ANC and WBC for safety monitoring.

Assess compliance based on counting of unused tablets in bottles.

Dispense study drug to subject for outpatient dosing, with instructions to return to 
next clinic visit with all (used and in-use) bottles.

Remind the subject about the date of the next scheduled Month 6 visit (V6).
6.2.5. Visit 6 –Month 6/ Day 182 (7 days)
The following activities will be completed during Month 6 visit (V6):

Review adverse events since last visit.

Review changes in the subject’s medical history, concomitant medications, and 
medical procedures since last visit.
CCI


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
Obtain weight (kilograms).

Perform brief physical examination.

Perform brief neurological examination.

Obtain standard 12-lead ECG (may be repeated if clinically indicated).

Obtain orthostatic vital signs (supine and standing blood pressure and pulse) and oral 
or tympanic body temperature.

Contraception check.

Collect non-fasted blood sample for routine laboratory tests, including the following 
tests:

Hematology;

Blood chemistry;

Obtain serum sample for pregnancy test for females of child bearing potential 
(sent to central lab).

Collect urine sample for urinalysis.

. 

Complete C-SSRS (since last visit) for suicidality risk assessment.

.

Administer the UHDRS Total Motor Score (TMS), 
 (
), 
 (Section 7.9.1).


 (
).

Complete CGI-I scale.

 (
).

 (
);

;

;
CCI
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CCI
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
;

;

.

.

 
.

Review ANC and WBC for safety monitoring.

Assess compliance based on counting unused tablets in bottles.

Dispense study drug to subject for outpatient dosing, with instructions to return to 
next clinic visit with all (used and in-use) bottles.

Remind the subject about the date of the next scheduled Month 9 visit (V7).
 
:

.

.

 (
 
).

.
6.2.6. Visit 7 – Month 9/Day 273 (7 days)
The following activities will be completed during Month 9 visit (V7):

Review adverse events since last visit.

Review changes in the subject’s medical history, concomitant medications, and 
medical procedures since last visit.

Obtain vital signs (sitting blood pressure and pulse; oral or tympanic body 
temperature).

Obtain standard 12-lead ECG (may be repeated if clinically indicated).

Contraception check.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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CCI
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
Collect non-fasted blood sample for Hematology.

Serum pregnancy test for females of child bearing potential. 

. 

Complete C-SSRS (since last visit) for suicidality risk assessment.

Administer the UHDRS Total Motor Score (TMS).

Review ANC and WBC for safety monitoring.

Assess compliance based on counting of unused tablets in bottles.

Dispense study drug to subject for outpatient dosing, with instructions to return to 
next clinic visit with all (used and in-use) bottles.

Remind the subject about the date of the next scheduled Month 12 visit (V8). 
6.2.7. Visit 8 – Month 12/Day 365 (7 days)
The following activities will be completed during Month 12 visit (V8):

Review adverse events since last visit.

Review changes in the subject’s medical history, concomitant medications, and 
medical procedures since last visit.

Obtain weight (kilograms).

Perform brief physical examination.

Perform brief neurological examination.

Obtain standard 12-lead ECG (may be repeated if clinically indicated).

Obtain orthostatic vital signs (supine and standing blood pressure and pulse) and oral 
or tympanic body temperature.

Contraception check.

Collect non-fasted blood sample for routine laboratory tests, including the following 
tests:

Hematology;

Blood chemistry;
CCI


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
Obtain serum sample for pregnancy test for females of child bearing potential 
(sent to central lab).

Collect urine sample for urinalysis.

 

Complete C-SSRS (since last visit) for suicidality risk assessment.

.

Administer the UHDRS Total Motor Score (TMS), 
 (
), 
 (Section 7.9.1).

.

 (
).

Complete CGI-I scale.

 (
).

 (
);

;

;

;

;

.


(
) 

Review ANC and WBC for safety monitoring.

Assess compliance based on counting unused tablets in bottles.

Remind the subject about the date of the next scheduled Follow up visit (V9).
CCI
CCI
CCI
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:

.

.

(
 
).

.
6.2.8. Early Termination Visit
Subjects who withdraw or are withdrawn from the study should undergo an early termination 
visit whenever possible, unless consent for participation is also withdrawn, in which case no 
further study related procedures should be performed (see Subject Withdrawal).
In case of Early Termination between Baseline Day 1 and Day 14 (exclusive), only safety 
assessments will be performed (no efficacy assessments).  If Early Termination occurs after 
Day 14 (inclusive), as many Month 12 (V8) assessments as possible should be completed.
6.2.9. Unscheduled Visit
Unscheduled visits may be performed at any time during the study, whenever necessary to 
assess or to follow-up on adverse events (AE) or serious adverse events (SAE) at the 
subject’s request, or as deemed necessary by the investigator.  The following clinical 
evaluations should take place, as medically warranted in the judgment of the investigator: 

Physical examination.

Neurological examination.

12-lead ECG, when clinically indicated to follow-up on any prior clinically 
significant ECG abnormalities.

Vital signs (supine and standing).

Laboratory safety assessments, when clinically indicated to follow-up on any prior 
clinically significant laboratory abnormality.

Review study drug compliance and accountability (if applicable).

Review and record adverse events (AE) and serious adverse events (SAE).

Review of prior and concomitant medications.

Subject education on how to maintain compliance.
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6.3. Follow-up Visit (V9)
The Follow-up Visit will occur between Day 372 and Day 379.
During the visit the investigator will:

Review adverse events since last visit.

Review changes in the subject’s medical history, concomitant medications, and 
medical procedures since last visit.

Perform brief physical examination.

Perform brief neurological exam.

Obtain vital signs (sitting blood pressure and pulse; oral or tympanic body 
temperature).

Collect non-fasted blood sample for safety monitoring of ANC and WBC.

Urine pregnancy test.

Complete C-SSRS (since last visit) for suicidality risk assessment.

Review ANC and WBC for safety monitoring.
6.4. Subject 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 the study site.  To the extent possible, subjects withdrawing from the 
study early should undergo an Early Termination visit, as described in Section Early 
Termination Visit, unless consent is also withdrawn.  Subjects removed from therapy for 
reasons of safety will continue to be followed for the collection of safety data until resolution 
or stabilization of any adverse events which resulted in study discontinuation.
Withdrawal of Consent: Subjects who request to discontinue study treatment will remain in 
the study and must continue to be followed for protocol specified follow-up procedures.  The 
only exception to this is when a subject specifically withdraws consent for any further 
contact with him/her or persons previously authorized by subject to provide this information.  
Subjects should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is from further 
treatment with study drug only or also from study procedures and/or post treatment study 
follow-up, and entered on the appropriate CRF page.  In the event that vital status (whether 
the subject is alive or dead) is being measured, publicly available information should be used 
to determine vital status only as appropriately directed in accordance with local law.


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If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record).  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the subject to return all unused investigational 
product(s), request the subject to return for an early termination visit, if applicable, and 
follow-up with the subject regarding any unresolved adverse events (AEs).
Lost to Follow-Up: 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 
as noted above.  Lost to follow-up is defined by the inability to reach the subject after a 
minimum of three documented phone calls, faxes, or emails as well as lack of response by 
subject to one 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.  If investigator’s use of third-party 
representative to assist in the follow-up portion of the study has been included in the 
subject’s informed consent, then the investigator may use a sponsor retained third-party 
representative to assist site staff with obtaining subject’s contact information or other public 
vital status data necessary to complete the follow-up portion of the study.  The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information.  If after all attempts, the subject 
remains lost to follow-up, then the last known alive date as determined by the investigator 
should be reported and documented in the subject’s medical records.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described in the Schedule of Activities.  However it is anticipated that from 
time to time there may be circumstances, outside of the control of the investigator, which 
may make it unfeasible to perform the test.  In these cases the investigator will take all steps 
necessary to ensure the safety and wellbeing of the subject.  When a protocol-required test 
cannot be performed, the investigator will document the reason for this and any corrective 
and preventive actions that he or she has taken to ensure that normal processes are adhered to 
as soon as possible.  The study team will be informed of these incidents in a timely fashion.  
The sites should do their best to perform the assessments in the recommended order as listed 
in Section 6 to maximize the likelihood to secure data for the primary and secondary 
endpoints.


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7.1. Review of Inclusion/Exclusion Criteria
All inclusion and exclusion criteria must be carefully reviewed and compared against the 
screening data from the subject.  Protocol deviations related to subject eligibility are of 
particular concern and will be specifically monitored for by the sponsor Inclusion/Exclusion 
criteria verification process, described below in Section 7.5. 
7.2. CAG Profiling Documentation
At Baseline Day 1 (V2), the investigator should document the genetic profile of CAG 
repeats, as recorded for study A8241021.  A critical feature of this criterion is the required 
documentation of a CAG repeat expansion 36.  A cut-off of CAG repeats 36 was selected 
based on the carrier probability of becoming symptomatic.
7.3. Medical History/Prior Medications/Procedures
At Baseline Day 1 (V2), the investigator should make all reasonable efforts to obtain an 
accurate and complete medical history and history of prior medication use (at least 8 weeks 
prior to Screening) when evaluating whether a subject is eligible for the study.  Dominant 
hand, potential color blindness, level of education, should also be documented, due to their 
relevance with task performance (
, 
).  If a subject’s medical history is unclear 
or information pertaining to a critical variable is conflicting, every reasonable step to secure 
accurate information should be attempted.  Documentation of the medical and medication 
histories over the protocol-defined time periods should be available for sponsor review 
during the source data verification process.  Questions about prior medications or eligibility 
should be directed to the sponsor Medical Monitor.
7.4. Site Eligibility Review
Pre-screening Activities
Investigator will assess subject eligibility for the open label study A8241022 using all data 
available from study A8241021.  First review of data will be performed and documented 
(Pre-screening Checklist A provided by the sponsor) prior to Screening Visit for this study 
A8241022 (Week 19 Visit for study A8241021). 
If subject meets the pre-screening requirements after this initial review, the second review 
will be performed and documented (Screening Checklist B provided by the sponsor) after 
completion of Week 19 Visit for study A8241021.  All data from Week 19 visit for Study 
A8241021 will be used for eligibility review, including but not limited to changes in medical 
history, medical procedures, concomitant medications, compliance. 
Site Eligibility Review
The site will review and document eligibility for the subject and provide documentation to 
the sponsor for the eligibility verification Process described below in Section 7.5.  The site 
will review all laboratory test results, pregnancy test, ANC and WBC, drug test results, 
against I/E criteria.
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7.5. Sponsor Eligibility Verification Process
Sponsor eligibility verification and documentation of completion is required for each subject.  
The sponsor or designee will verify all critical elements of the screening and enrollment 
process and will provide written authorization (eg, e-mail) concurring with the investigator 
assessment that the subject is eligible for enrollment into the study prior to Baseline Day 1 
(V2).  Such approval will be contingent upon the subject still meeting all eligibility criteria 
for randomization at Baseline Day 1 (V2).  The key elements to be reviewed by the sponsor 
may include HD diagnostic criteria, CAG repeats, medical history, concomitant medications, 
and selected screening safety assessments including out of range laboratory results, abnormal 
ECGs, and abnormal vital signs.  Full instructions on the Screening Verification process will 
be provided as part of site training.  It is critical that the sponsor be provided with all 
requested data at least 2 business days in advance of any scheduled Baseline Day 1 (V2). 
7.6. Blood Volume
Total blood sampling volume for the individual subjects is approximately 112 mL.  The 
actual times of blood sampling may change but the total blood volume collected will not 
increase.  Additional blood samples may be taken for safety assessments at times specified 
by Pfizer, provided the total volume taken during the study does not exceed 550 mL during 
any period of 30 consecutive days and the IRB/EC is notified of the blood collection.
Table 5.
Blood Volume
Sample Type
Blood 
Sample 
Volume 
(mL)
Number of Sampling Times
Total Volume
(mL)
Screening Bsl
V3
V4
V5
V6
V7
V8
FU
Routine lab tests 1
7
(1)
1
1
1
1
35
Safety lab 
monitoring 
(ANC/WBC)
7
1
1
1
21
Serum Pregnancy 
test 2
3
(1)
1
1
1
1
15
Serum FSH 2
5
1
5
( )
TOTAL
112
1.
Includes hematology and blood chemistry.
2.
Female only.
3.
Numbers in parentheses will be collected only if missed or abnormal in study A8241021.
This total volume does not include any discarded blood from pre-draws used to remove fluid 
from flushed catheters.
7.7. Safety Assessments
7.7.1. Brief Physical Examination
The brief physical examination will be performed to assess the subject’s health during the 
study and for any potential changes in physical status (including weight), as determined by 
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the investigator during the study.  Brief physical examinations will be performed by a study 
physician or a trained study nurse.
The brief physical examination will be focused on general appearance, the cardiovascular, 
pulmonary, abdominal exams, as well as towards any subject reported symptoms.  
Examination of other systems to explore reports of AEs should be conducted as needed by 
the investigator. 
The results of the brief physical examination from Week 26 Visit for study A8241021 will be 
reviewed at Baseline Day 1 (V2).  The brief physical examination will be performed at 
Month 6 (V6), at Month 12 (V8) or early termination, at Follow-up (V9) and during any 
unplanned visit as necessary for follow-up of AEs.
The physical examination will be documented in the source documents, and any clinically 
significant changes from baseline will be captured as an AE.
7.7.2. Vital signs
Vital signs will include blood pressure, pulse, and oral or tympanic body temperature.  For 
orthostatic vitals, blood pressure and pulse should be collected or recorded while the subject 
is in the supine and standing position at the following visits: Baseline Day 1 (V2), 
Month 6 (V6), Month 12 (V8) or early termination visit.  Blood pressure and pulse should be 
collected while the subject is sitting at all other visits. 
Qualified staff members will perform blood pressure measurement.  Blood pressure will be 
measured with the subject’s arm supported at the level of the heart, and recorded to the 
nearest mmHg.  If possible, blood pressure measurements will be taken from the same arm 
(opposite to the arm that is used for blood sample collection and preferably the dominant 
arm).  If there is a clinically important change in blood pressure from the previous recording, 
measurements will be repeated immediately to confirm the change. 
All scheduled blood pressure, and pulse measurements should be performed after the subject 
has rested quietly for at least 5 minutes.  The same size blood pressure cuff, which has been 
properly sized, will be used to measure blood pressure each time.  The use of automatic 
devices for measuring BP and pulse rate are acceptable, although, when done manually, pulse 
rate will be measured in the brachial/radial artery for at least 30 seconds.  Blood pressure and 
pulse rate should be obtained prior to the nominal time of the blood collection. 
The procedure for collecting orthostatic blood pressure, and pulse will be to 1) assess blood 
pressure after subject remains in supine position for a minimum of 5 minutes; 2) ask the 
subject to stand up for ~2 minutes; 3) assess blood pressure, and pulse immediately at the end 
of the two minutes, while the subject remains in standing position. 
Orthostatic hypotension is defined as a decrease of 20 mm Hg for systolic blood pressure or 
10 mm Hg for diastolic blood pressure after 2 minutes of standing from a supine position.  
Orthostatic hypotension may be symptomatic or asymptomatic.  Symptoms of orthostatic 
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Common symptoms include dizziness, lightheadedness, blurred vision, weakness, fatigue, 
nausea, palpitations, and headache.  Less common symptoms include syncope, dyspnea, 
chest pain, and neck and shoulder pain. 
If a subject has orthostatic symptoms suggestive of, but does not have documented 
orthostatic hypotension, repeated measurements of supine/standing blood pressure should be 
obtained, if possible in triplicate.  Lesser degrees of blood pressure reduction may still be 
considered clinically significant if the subject becomes symptomatic upon standing, 
especially in the presence of a significant increase in pulse rate (30 beats per minute, BPM). 
Body temperature will be measured either by placing a digital thermometer under the tongue 
for at least 30 seconds or by measuring tympanic temperature.  The temperature will be 
reported in degree Celsius.
7.7.3. Brief Neurological Examination
The brief neurological exam will consist of assessments of the cranial nerves, motor function, 
deep tendon reflexes, sensory exam, coordination and gait.  The exam should be recorded or 
performed to the extent needed to assess the subject for any potential changes in neurological 
status, as determined by the investigator, at Baseline Day 1 (V2), Month 6 (V6), 
Month 12 (V8) and Follow up (V9), or Early Termination, and during any unplanned visit, as 
necessary for follow-up of AEs.
The brief neurological examination results will not be recorded in the case report form 
(CRF).  All the neurological examination results must be recorded on the source documents, 
which will be monitored at the study site.  Abnormal neurological examination results 
deemed to be clinically significant and occurring after randomization will be captured as an 
AE.
7.7.4. Laboratory Tests
The screening/safety laboratory tests (hematology, chemistry, and urinalysis) may be 
obtained without regard to fasting status. 


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Table 6.
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count a
Total neutrophils 
(Abs)a
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea 
Creatinine
Glucose
HbA1c (for diabetics only)
Calcium
Phosphorus
Magnesium
Creatine kinase
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
ALT
AST
LDH
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Color 
Appearance
Specific Gravity
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Microscopy c
FSH d
Urine drug screen e
Urine pregnancy 
(hCG) f
Serum beta hCG f
Additional 
Hematology a
Additional Chemistry b
WBC count a
Total neutrophils 
(Abs)a
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase (repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
a
See Section 3.1 for the stopping criteria and related procedures for repeat WBC and neutrophil count 
assessments.
b
Additional testing for potential Hy's Law cases only.
c
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
d
At Baseline Day 1 (V2), investigator may request FSH to confirm postmenopausal status for females who 
have been amenorrheic for at least 12 consecutive months. 
e
At Baseline Day 1 (V2) and at any time at the discretion of the investigator. 
f
Women of childbearing potential: A serum pregnancy test result will be recorded at Baseline Day 1 (V2)
and serum pregnancy test will be performed at Month 3 (V5), Month 6 (V6), Month 9 (V7) and 
Month 12 (V8) or early termination.  A urine pregnancy test will be performed at Baseline Day 1 (V2) 
and at Follow-up (V9).  Note: At Baseline Day 1 (V2) both serum AND urine pregnancy tests will be 
performed or recorded (urine test for immediate readout and serum test for confirmation by central lab).
Minimum requirements for drug screening includes: phencyclidine (PCP), cocaine, 
cannabinoids, opiates/barbiturates, amphetamines, methadone and methylenedioxy 
methyamphetamine (MDMA, known as ecstasy).


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7.7.5. Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test for human chorionic 
gonadotropin (-hCG), with sensitivity of at least 25 mIU/mL will be reviewed at Baseline 
Day 1 (V2) and performed at Month 3 (V5) Month 6 (V6), Month 9 (V7), Month 12 (V8) or 
early termination.  Urine pregnancy test will be performed at Baseline Day 1 (V2) and at 
follow-up (V9).  At Baseline Day 1 (V2) serum pregnancy test result will be recorded from 
study A8241021 Week 26 Visit.  The urine test is done for immediate readout while the 
serum test is performed for confirmation by central lab.
Qualitative urine pregnancy tests must be sensitive to at least 25 mIU/mL.  Qualitative urine 
point-of-service pregnancy tests are to be conducted with the test kit provided or approved by 
the sponsor and in accord with instructions provided in its package insert.  Results from urine 
dipstick will be obtained prior to dosing.  A documented negative urine pregnancy result is 
required before the subject may receive the investigational product on Baseline Day 1 (V2).  
Pregnancy tests will also be done whenever one menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected, to confirm the subject 
has not become pregnant during the study).  Pregnancy tests may also be repeated as per 
request of IRB/ECs or if required by local regulations.  Subjects who have missed a 
menstrual period or who show an indeterminant or positive result on the qualitative 
point-of-service urine test may not further progress in the study until pregnancy is ruled out 
using further diagnostic testing (eg, a negative quantitative serum pregnancy test conducted 
at a certified laboratory).  A positive urine pregnancy test should be followed by a serum 
-hCG for confirmation.  The sponsor should be immediately notified and the study drug 
should be withheld until the serum -hCG test results are available.  In the case of a positive 
serum -hCG test, the subject will be immediately withdrawn from study medication but may 
remain in the study.  The outcome of the pregnancy will be followed according to relevant 
sponsor's processes. 
7.7.6. Assessment of Suicidal Ideation and Behavior (SIB)
7.7.6.1. Columbia Suicide Severity Rating Scale
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview-based rating scale to 
systematically assess suicidal ideation and suicidal behavior.33  The scale should be 
administered to the subject by an individual with appropriate training, who has also taken the 
specific rater training for the scale, which will be provided by an agent of the sponsor prior to 
the study start.  This scale will be recorded or administered (“since Last Visit”) at each study 
visit from Baseline Day 1 (V2) to Follow-up visit (V9), including early termination. 
If at any visit from baseline on, there are “YES” answers on items 4, 5 or on any behavioral 
question of the C-SSRS, a risk assessment should be done by a qualified clinician/qualified 
medical health practitioner to determine whether it is safe for the subject to continue to 
participate in the trial (see Suicidality Risk Assessment).  A suicidality narrative should be 
constructed for subjects who have undergone any post-baseline risk assessment, using 
information from the C-SSRS, prior screening and baseline information, the clinician 
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behavioral question of the C-SSRS on more than one occasion during a trial should be 
discontinued from the trial.
Suicidality adverse events or other clinical observations may, based on the judgment of the 
investigator, also trigger a risk assessment and a narrative.  When there is a positive response 
to any question on the C-SSRS, the investigator should determine whether an adverse event 
has occurred.
7.7.6.2. Suicidality Risk Assessment
At Screening, all subjects must be assessed for potential suicidality; data from study 
A8241021 will be used including the most recent assessments at Week 19 Visit for study 
A8241021.  Subjects felt to have significant suicidal ideation with actual plan and intent or 
suicidal behavior, must be evaluated by a clinician/qualified medical health practitioner 
(MHP) skilled in the evaluation of suicidality in the target population by virtue of training or 
experience (eg, psychiatrist, psychiatrist/licensed clinical psychologist, or neurologist 
experienced in assessing suicidality) who will determine if it is safe for the subject to 
participate in the trial.  If determined not to be safe, the subject will be excluded.  Specific 
criteria that indicate a need for such an assessment are:

Any history of serious or recurrent suicidal behavior.

Previous history of suicide behaviors in the past 10 years (a “YES” answer to any of 
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 
10 years).

Suicide ideation with actual intent and/or plan in the past year (a “YES” answer to 
C-SSRS questions 4 “some intent to act without specific plan” or 5 “specific plan and 
intent”) – See Columbia Suicide Severity Rating Scale.

Suicide ideation with actual intent and/or plan in the past year ( “ ”
 “
” 
 “
 
 
”) –
 
 (
).

In the investigator’s judgment a risk assessment or exclusion is warranted.
In the United States, a qualified MHP is a psychiatrist or licensed PhD level clinical 
psychologist.  In other countries, a qualified MHP has appropriate training in the assessment 
of suicide risk, according to local clinical practice standards and regulations, and would 
normally evaluate the risk for suicide in a subject.
7.7.7. Electrocardiogram (ECG)
ECGs should be collected at times specified in the STUDY PROCEDURES Section of this 
protocol.  Single 12-lead ECGs will be recorded or collected at on Baseline Day 1 (V2),
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Month 3 (V5), Month 6 (V6), Month 9 (V7), Month 12 (V8) or at early termination, and may 
be performed at Unscheduled Visit(s).
Subjects must rest in the supine position for at least 10 minutes before the ECG recording is 
started.  The ECG should be recorded during the period of rest required before blood 
collection and the measurements of orthostatic blood pressure and pulse.  A qualified 
physician will review the ECGs and any clinically important finding will be recorded on the 
appropriate CRF.  The investigator is responsible for providing interpretation of all ECGs.  
The results will include heart rate, PR interval, QRS interval, QT interval, and QTc interval, 
and assessment of rhythm and morphology.  If necessary (eg, suspected QTc prolongation), a 
manual reading of the ECG data will be performed.
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.
All ECGs will also be centrally read.  Instructions for transmission of ECGs to the vendor 
will be provided in the ECG vendor manual.
7.8. Special Safety Assessment
7.8.1. ANC and WBC Monitoring
WBC counts with differential will be recorded or performed at each study visit starting with 
Baseline Day 1 (V2).  The results of these assessments will be reviewed by the investigator 
as soon as possible once they are available, but no later than 2 business days after receipt of 
the lab results.  After reviewing the results, the investigator must confirm and document that 
the WBC and/or ANC do not meet stopping criteria (See Stopping Criteria) for the subject to 
continue in the study.  A separate source document will be provided to each site to assist in 
monitoring these criteria. 
7.8.2. Neutropenia Assessment
Subjects who meet any of the “subject stopping criteria” or the study stopping criteria for 
WBC or ANC should receive a hematology consultation and assessment for all potential 
etiologies of the WBC and ANC findings.  This assessment should adhere to clinical standard 
of care for evaluation of neutropenia, but at a minimum include the following assessments: 
clinical assessment for infections and physical examination; review of relevant past medical 
history, prior concomitant medications, and prior WBC and ANC counts when available; 
repeated complete blood count with WBC, ANC, and a peripheral blood smear; bone marrow 
sampling for subjects who have an ANC <500 unless medically contraindicated or otherwise 
unobtainable.  Additional assessments indicated by the standard of care for evaluation of 
neutropenia should be pursued in accordance with the investigator’s and consultant’s
judgment.


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7.9.
7.9.1. Unified Huntington’s Disease Assessment Scale (UHDRS) – TMS,
, 
In this study four subscales of the UHDRS will be administered to the subject by a trained 
certified rater from the site investigational staff (clinician): the Total Motor Score (TMS), 
 
 
.
The UHDRS is a clinical rating scale which has been developed by the Huntington Disease 
Study Group (HSG) to provide a uniform assessment of the clinical features and course of 
HD.33  The UHDRS scale has undergone reliability and validity testing and has been used as 
a major outcome measure in controlled clinical trials and observational studies.34  The 
components of the full UHDRS assess motor function, cognition, behavior and functional 
abilities. 
The total motor score (TMS) will be recorded from study A8241021 at Baseline 
Day 1 (V2) visit, and will be administered at each study visit from Week 2 (V3) to 
Month 12 (V8) and in case of early termination. 
The TMS assesses motor features of HD with standardized ratings of oculomotor function, 
dysarthria, chorea, dystonia, gait, and postural stability.  Some items (such as chorea and 
dystonia) require grading each extremity (face, bucco-oral-lingual, and trunk) separately.  
Eye movements require both horizontal and vertical grades.  The total motor impairment 
scores is the sum of all the individual motor ratings, with higher scores indicating more 
severe motor impairment than lower scores. 
The Total Maximum Chorea (TMC) is a subset of the TMS assessment.  It is composed of 
the scoring of 7 chorea assessments (face, orobuccolingual, trunk, right and left upper 
extremities, right and left lower extremities).  Each assessment is rated from 0 to 4 (absent to 
prolonged).  The TMC score can be derived from the TMS score at visits at which the TMS 
is collected.
 
 
 
 
 
 
 
 
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Administration and scoring guidelines will be provided to the investigator site during rater 
training sessions prior to initiation of the study.
7.9.2.
 
(
)
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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7.9.4.
 
 
 
 
 
 
 
 
 
7.9.4.1.
 
 
 
 
 
 
 
 
 
 
7.9.4.3.
 (
)
 
 
 
 
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7.9.4.4.
 (
)
 
 
 
 
 
 
 
 
 
7.9.4.5.
(
)
 
 
 
 
 
 
 
 
7.9.4.6.
 (
)
 
  
 
 
 
 
 
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7.9.5.
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
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7.9.5.1.
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7.9.5.2.
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7.9.5.3.
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7.9.5.4.
 
  
  
 
 
 
 
 
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7.9.6. Clinical Global Impression of Severity/Improvement (CGI-S/CGI-I)
The CGI-S/CGI-I is a global measure of severity of illness (CGI-S) and improvement or 
change (CGI-I) based on the clinician’s assessment of all available clinical data obtained 
from interviewing the subject.65
The CGI-S consists of a single 7-point rating score of illness severity that is based on how ill 
the subject is relative to other subjects he/she has had experience with.  Raters select one 
response based on the following question, “Considering your total clinical experience with 
this particular population, how ill is your subject at this time?” Scores are: 1, Normal, not ill 
at all; 2, Borderline ill; 3, Mildly ill; 4, Moderately ill; 5, Markedly ill; 6, Severely ill; or 
7, Among the most severely ill subjects. 
The CGI-I consists of a single 7-point rating of total improvement or change from baseline 
CGI-S, regardless of whether or not the change is due entirely to drug treatment.  Raters 
select one response based on the following question, “Compared to your subject’s condition 
at the beginning of treatment, how much has your subject changed?” Scores are: 1, Very 
much improved; 2, Much improved; 3, Minimally improved; 4, No change; 5, Minimally 
worse; 6, Much worse; or 7, Very much worse.
The CGI-S/CGI-I rater can have access to all clinical information related to subject severity 
and change, and does not need to be independent of other assessments.  However, the rater 
who assesses the initial CGI-S should be the clinician who rates overall change via the CGI-I 
during the study.
The CGI-S will be performed at Baseline Day 1 (V2).  The CGI-I will be administered at 
Month 6 (V6), Month 12 (V8), and in case of early termination.  This assessment will be 
administered by a trained rater from the site investigational team (eg, clinician).
7.9.7.
  
  
 
 
 
 
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7.10.
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7.10.2.
 
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
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Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the sponsor.
AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) from the 
time the subject has taken at least 1 dose of study treatment through the last subject visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease 

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;


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
Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength 
(eg, wrong number of tablets).  Such medication errors occurring to a study participant are to 
be captured on the medication error case report form (CRF) which is a specific version of the 
adverse event (AE) page, and on the SAE form when appropriate.  In the event of medication 
dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the medication error version of the 
adverse event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF 
page. 
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or


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
Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels 
concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined 
below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases)77 and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 


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present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or
if the value reaches 3 X ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases77 irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 


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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
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8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, or 
SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, these 
intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy occurs 
if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;


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An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male subject has been exposed (eg, because of treatment or environmental
exposure) to the investigational product prior to or around the time of conception 
and/or is exposed during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE 
has occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure. The information submitted should include the 
anticipated date of delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination) and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 


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Information Form to deliver to his partner. The investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to safety within 24 hours of Investigator’s awareness, 
using the SAE Report form, regardless of whether there is an associated AE/SAE.  Since the 
information does not pertain to a subject enrolled in the study, the information is not reported 
on a Case Report Form (CRF), however a copy of the completed SAE Report form is 
maintained in the study master file.
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 


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investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
This is an open-label extension study.  Subjects who complete the A8241021 study and are 
deemed eligible for this study per inclusion/exclusion criteria will be given the opportunity to 
enroll in this open label study.  It is estimated that up to 260 subjects may participate in this 
extension study.
9.2. Efficacy Analysis
All endpoints will be evaluated over the Full Analysis Set (FAS), which is the set of subjects 
who have an extension study baseline efficacy evaluation, took 1 dose of open-label study 
medication.  Subjects without post-dose measurements will not contribute to the analysis, 
except in the description of the baseline values.


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9.2.1. Analysis of Primary Endpoint 
The primary trial variables examine long-term safety and tolerability of therapy with 
20 mg BID of PF-02545920.  The primary analysis of long-term safety will be focused on 
Adverse events, weight, vital signs (pulse, blood pressure and body temperature), physical 
examination, neurological examination, electrocardiogram (ECG) and clinical laboratory 
findings (hematology, biochemistry and urinalysis).
The endpoints are:

The number and proportion of subjects with adverse events.

Assessment of clinical laboratory parameters.

Assessment of vital signs.

Assessment of ECG parameters.

White blood count (WBC) and absolute neutrophil count (ANC) at each visit.

Abnormal laboratory findings from baseline.

Frequency and severity of adverse events related to extrapyramidal symptoms (EPS) 
including dystonia and akathisia, as assessed by the investigator.

C-SSRS (suicide severity assessment).
Adverse events will be coded for analysis with MedDRA, and the number and percent of 
subjects reporting each event will be summarized. Descriptive statistics will be displayed to 
provide an overview of the safety results.  For categorical parameters, these consist of the 
number and percent of subjects in each category.  The denominator for percentages will be 
based on the number of subjects appropriate for the purpose of analysis.  For continuous 
parameters, descriptive statistics includes n, mean, standard deviation (SD), median, 
minimum, and maximum.  Subjects who prematurely discontinued the trial will be evaluated 
on the basis of data collected at each visit attended.
Safety analyses will be performed on the safety population, which includes all subjects who 
received at least 1 dose of study medication during the open-label period.
Further information about the safety analysis can be found in Section 9.5. 
9.2.2. Analysis of Secondary Endpoints
The efficacy variables are:

Change from baseline in the Total Motor Score (TMS) assessment of the Unified 
Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment.


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
Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS 
after 6 and 12 months of treatment.

Clinical Global Impression-Improvement score after 6 and 12 months of treatment. 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) and 
95% confidence interval will be provided to summarize results for the baseline and change 
from baseline values by visit.  A two-sided, paired t-tests at the 5% level of significance will 
also be used to summarize results.  Baseline is defined as the final visit (Week 26) in the 
preceding double-blind study A8241021.
Clinical Global Impression-Improvement score after 6 and 12 months of treatment will be 
evaluated with descriptive statistics that includes n, mean, standard deviation (SD), median, 
minimum, and maximum.  A two-sided, one-sample t-tests at the 5% level of significance 
will be applied to evaluate results.
Missing values will be imputed using last observation carried forward (LOCF) approach.  
Sensitivity analysis of the secondary variables using only observed cases (no imputation) will 
be performed to support the robustness of the conclusions drawn from the LOCF approach.
Exploratory analysis: The mean rates of change of TMS and TMC during the double-blind 
period (Week 0-26) will be compared with the mean rates of change in the open label period.  
A two-sided, paired t-tests at the 5% level of significance will be used to summarize results. 
Data for efficacy endpoints will be tested for normality assumption.  If normality assumption 
is substantial violated, appropriate variable transformations or non-parametric tests may be 
performed.
9.3.
 
9.4.
 
 
 
 
 
.
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.
9.5. Safety Analysis
Adverse events, ECGs, blood pressure, pulse rate and safety laboratory data will be reviewed 
and summarized on an ongoing basis during the study to evaluate the safety of subjects.  Any 
clinical laboratory, ECG, BP, and PR abnormalities of potential clinical concern will be 
described.  Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Physical examination and neurologic examination information collected during the course of 
the study will not be captured for inclusion into the study database, unless otherwise noted.  
However, any untoward findings identified on physical and/or neurologic examinations 
conducted after the administration of the first dose of study medication will be captured as an 
adverse event, if those findings meet the definition of an adverse event.  Demographic data 
collected at Screening will be included in the study database.  C-SSRS responses will be 
mapped onto the C-CASA scale, and the frequency distribution of the C-CASA scores 
(pre-dose/post-dose) will be reported.  No hypotheses associated with the C-SSRS or 
C-CASA scales will be tested.
9.5.1. Electrocardiogram (ECG) Analysis
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval and QRS interval will be summarized by treatment and time.  The number (%) of 
subjects with maximum post-dose QTc values and maximum increases from baseline in the 
following categories will be tabulated by treatment:
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Table 7.
Safety QTc
Borderline (msec)
Prolonged (msec)
Absolute Value
>=450 - <480
>=480
Absolute Change
30-<60
>=60
In addition, the number of subjects with corrected and uncorrected QT values >=500 msec 
will be summarized.
9.6. Interim Analysis 
No interim analysis will be performed in the study.
9.7. Data Monitoring Committee 
This study will use an External Data Monitoring Committee (E-DMC). 
An independent unblinded External DMC consisting of experts in movement disorder, 
hematology/clinical trial safety monitoring, and statistics will evaluate the safety of the trial 
on an ongoing basis.  Further detail on the composition and responsibility of the Data 
Monitoring Committee is outlined in a separate DMC charter.  The E-DMC will make 
recommendations related to the study continuation based on their safety review as described 
in the PDE10 program level DMC Charter.  For purposes of internal decision-making, an 
Executive Steering Committee (ESC) may be identified to liaise with the E-DMC to review 
E-DMC recommendations.  No members of the ESC will be involved in the day to day 
conduct of the study.  The results of the DMC review will not be shared with the study team, 
except for the key outcome (“Stop for unacceptable safety findings”, or “Continue”).  Further 
detail on the composition and responsibility of the E-DMC and ESC will be outlined in a 
separate DMC charter.
The program level external DMC was established in May 2013 for all PDE10 studies.  The 
DMC charter gets amended for addition of each new interventional protocol with 
PF-02545920.  The E-DMC meets on a regular basis and will evaluate this trial safety as 
soon as possible after the first approximately 20 subjects have completed Month 6 (V6), and 
then periodically at least twice a year thereafter.  The sponsor may request an ad hoc meeting 
earlier, and/or more frequent review of safety data by the E-DMC, should potential safety 
signals of concern arise from blinded medical review of adverse events and other safety data 
by the Pfizer medical monitor.  The timing of the E-DMC reviews may also be slightly 
adjusted to align with scheduled safety analysis for other studies, as specified in the DMC 
Charter.  More information on the frequency of the E-DMC reviews will be included in the 
DMC Charter. 
The E-DMC will be responsible for external monitoring of the safety of subjects in the study 
according to the charter.  Prior to every scheduled E-DMC safety review the E-DMC 
members will receive an unblinded data package that will include all available safety data.  
Additionally, serious adverse event (SAE) case reports and drug related discontinuations will 
be communicated to the E-DMC on an ongoing basis, as soon as the sponsor is notified. The 
recommendations made by the E-DMC to alter the conduct of the study will be forwarded to 


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Pfizer for final decision.  Pfizer will forward such decisions, which may include summaries 
of aggregate analyses of endpoint events and of safety data that are not endpoints, to 
regulatory authorities, as appropriate. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be subject to review by the institutional review board (IRB)/ethics 
committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 


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identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to International Conference on Harmonisation 
(ICH), according to local regulations, or as specified in the clinical study agreement (CSA), 
whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996),78 and the Declaration of Helsinki (World 
Medical Association, 1996 and 2008).79


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In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data is compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study subjects. The study 
site will maintain a confidential list of subjects who participated in the study linking their 
numerical code to the subject’s actual identity.  In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of subject personal data consistent with 
applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator will make the determination during the consent process whether the subject 
with HD does or does not have the requisite decision-making capacity to provide informed 
consent.  Such a determination should be made based on any local standards and 
requirements for determination of decision making capacity, and based on the clinical 
judgment and experience of the investigator in conducting research in this population. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. Subject Recruitment
Subject recruitment efforts are not required for this study because this is an extension study.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as the Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-02545920 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within approximately 30 days.  As directed by Pfizer, 
all study materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), and other public registries in accordance with 
applicable local laws/regulations. 
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product.
The timing of the posting depends on whether the Pfizer product is approved for marketing in 
any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug 
Administration Amendments Act of 2007 (FDAAA), ie, Food and Drug 
Administration (FDA)-approved products, Pfizer posts results within 1 year of the 


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primary completion date (PCD).  For studies involving products approved in any 
country, but not FDA approved, Pfizer posts results 1 year from last subject last visit 
(LSLV);

For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of US regulatory approval, or 
1 year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US);

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within 1 year of discontinuation of the program (if 
there are no plans for outlicensing, or within 2 years if outlicensing plans have not 
completed).
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
www.pfizer.com
Pfizer posts clinical trial results on www.pfizer.com for all Pfizer-sponsored interventional 
studies in patients that assess the safety and/or efficacy of an FDA-approved Pfizer product 
with a LSLV on or after 27-Sep-2007 for which Basic Results were posted on 
www.clinicaltrials.gov.
EudraCT
Pfizer posts clinical trial results on EudraCT in accordance with Commission Guideline 
2012/C 302/03 Guidance on posting and publication of result-related information on clinical 
trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and 
Article 41(2) of Regulation (EC) No 1901/2006 for studies with centers in the European 
Economic Area and with LSLV on or after 01-May-2004, regardless of the marketing status 
of the compound.
15.2. Publications by Investigators
Pfizer has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the investigational 
drug. However, to ensure against inadvertent disclosure of confidential information or 
unprotected inventions, the investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to Pfizer at 
least 30 days before they are submitted for publication or otherwise disclosed. If any patent 


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action is required to protect intellectual property rights, the investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.


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(2002).
79.
Williams, J. R. The Declaration of Helsinki and public health. Bulletin of the World 
Health Organization 86, 650-652 (2008).
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Appendix 1. Guidance on Clinical Management of Subjects with Acute Extrapyramidal 
Symptoms - EPS (reported AE of dystonia, akathisia, tardive dyskinesia)
Safety Profile of PF-02545920
In a healthy volunteer study with PF-02545920, a rate of 6-8% of dystonia was observed at 
15 mg with titration.  One subject out of 24 schizophrenic subjects experienced dystonia after 
multiple doses of 20 mg without titration.  In the 28 day study in schizophrenic subjects 
(A8241012), one subject was discontinued due to dystonia (20 mg titrated).  Study 
A8241018 showed that overall PF-02545920 was safe and well tolerated in psychiatrically 
stable subjects with schizophrenia on a stable regimen of antipsychotic and other adjunctive 
psychotropic medications treated with PF-02545920 titrated to 15 mg BID.  4 AEs of 
dystonia were observed (3 mild, 1 moderate), 2 AEs of oromandibular dystonia (1 mild, 
1 severe) and 5 AEs of EPS (4 mild).
Based on the safety profile of PF-02545920 established with prior completed studies, it is 
predicted that 10% or less of the subjects on a titrated dose of 20 mg of PF-02545920 may 
experience this type and severity of AE requiring clinical management and intervention (in a 
cohort of N=75, this rate of occurrence would correspond to 7 or 8 subjects in the 20 mg dose 
group).
Prior studies in healthy volunteers show that dystonia due to administration of PF-0545920 
responds to a single administration of anticholinergics within 24 hours.  As a result it is 
recommended to perform a follow-up visit with the subject to re-evaluate symptoms within 
24 hours from the onset (see latest Investigator Brochure).
As described in STUDY TREATMENTS, the dosing of four tablets (5 mg each) allows for 
de-escalation with a 5 mg decrement, should the Principal Investigator assess that a subject 
requires a dose adjustment (temporary or permanent) due to intolerable AE.  For example, a 
subject may be instructed to take only three tablets instead of four tablets for a total dose of 
15 mg rather than the full 20 mg dose.  Any subsequent dose reduction will proceed in a 
similar manner.  Once AEs have resolved the PI will have the option to resume escalation.


PF-02545920
A8241022
Final Protocol, 23 October 2014
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Figure 2.
Guidance for Clinical Management of EPS


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Final Protocol, 23 October 2014
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Page 108
Appendix 2. Drugs and Classes of Drugs Allowed and Prohibited as Concomitant 
Medications
Summary of drugs and classes of drugs allowed and prohibited as concomitant medications 
after the Screening visit (V1) and while on the study, until the end of the study 
Month 12 (V8), unless specified otherwise. 
The use of any rescue medication should be discussed with study sponsor medical monitor or 
clinician prior to administration if at all possible.
“prn” (as needed) is defined as no more than three times per week.
Drug/Class
As Needed Use
Chronic Use
Antihypertensive drugs
ACE Inhibitors
N
Y
Aldosterone receptor antagonists
N
Y
Alpha 2 agonist antihypertensives (clonidine, guanabenz, guanfacine, 
methyldopa)
N
N
Angiotensin II receptor antagonists
N
Y
Beta Blockers
N
Y
Calcium channel blockers (except verapamil, diltiazem)
N
Y
Guanadrel
N
N
Guanethidine
N
N
Ketanserin
N
N
Metyrosine
N
N
CNS acting drugs
Anorexics
N
N
Anticholinergics
Y (rescue)
N
Anticonvulsants (except valproic acid and lamotrigine)
N
N
Antidepressants (except tricyclic antidepressants (TCA) and MAOIs)
N
Y
Antiemetics with dopamine antagonist activity
N
N
Anti-Parkinson medications (including levodopa, levodopa-carbidopa, 
dopamine receptor agonists -eg, pramipexole, ropinirole, 
apomorphine-, MAOIs, amantadine)
N
N
Antipsychotics (except clozapine, see below)
N
Y
Benzodiazepines (only short acting benzodiazepines allowed as 
rescue therapy)
Y (rescue)
Y
Clozapine
N
N
Lamotrigine
N
Y
Lithium
N
N
Narcotics/opioid / analgesics
Y (prn)
N
Nonbenzodiazepines hypnotics 
Y
Y
Promethazine
N
N
Psychostimulants
N
N
Tetrabenazine
N
N
Valproic acid
N
Y
CYP3A4 inducers and inhibitors
Atazanavir
N
N
Amiodarone
N
N
Cimetidine
N
N


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Drug/Class
As Needed Use
Chronic Use
Carbamazepine
N
N
Clarithromycin
N
N
Diltiazem
N
N
Erythromycin
N
N
Fluvoxamine
N
N
Grapefruit, grapefruit juice, pomelos, related fruits
N
N
Indinavir
N
N
Itraconazole
N
N
Ketoconazole
N
N
Mibefradil
N
N
Nefazodone
N
N
Nelfinavir
N
N
Oxcarbazepine
N
N
Phenobarbital
N
N
Phenytoin
N
N
Rifabutin
N
N
Rifampin
N
N
Rifapentine
N
N
Ritonavir
N
N
Saint John’s Wort (Hypericum perforatum)
N
N
Troleandomycin
N
N
Verapamil
N
N
Miscellaneous Drugs
Anticoagulants (except aspirin, clopidogrel)
N
N
Antihistamines, sedating (except diphenhydramine)
Y (24 hr)
N
Antihistamines, non-sedating (loratadine, ceftazidine, fexofenadine)
Y
Y
Asthma drugs (inhaled)
Y
Y
Contraceptives (oral and injectable)
Y
Y
Cough/Cold preparations (except those containing diphenhydramine)
Y
N
Herbals
N
N
Hormones (except estrogen replacement therapy)
N
N
Insulin
N
N
Nonsteroidal anti-inflammatory drugs (NSAIDS)
Y
Y
Nutraceuticals, prescription and non-prescription
N
N
Proton pump inhibitors
Y
Y
Steroids (inhaled, topical, ophthalmic only)
Y
Y
Thyroid Hormone Replacement Therapy
N
Y
Tryptophan
N
N

SAP_000.pdf: 
Protocol A8241022 (PF-02545920) Statistical Analysis Plan
DMB02-GSOP-RF02 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE 31-Jan-2013
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Page 1
Statistical Analysis Plan 


Protocol A8241022 (PF-02545920) Statistical Analysis Plan
DMB02-GSOP-RF02 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE 31-Jan-2013
PFIZER CONFIDENTIAL
Page 2
Protocol A8241022
AN OPEN LABEL EXTENSION STUDY TO INVESTIGATE THE LONG TERM 
SAFETY, TOLERABILITY AND EFFICACY OF PF-02545920 IN SUBJECTS WITH 
HUNTINGTON’S DISEASE WHO PREVIOUSLY COMPLETED STUDY A8241021 
Statistical Analysis Plan 
(SAP)
Version:
4.0
Author:
 (Global Innovative Pharma Business–Statistics)
 (Research Statistics)
Date:
29-Mar-2017
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
APPENDICES ...........................................................................................................................5
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................7
2.1. Study Design .............................................................................................................9
2.2. Study Objectives .......................................................................................................9
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................10
3.1. PK/PD Unblinding ..................................................................................................10
4. HYPOTHESES AND DECISION RULES.........................................................................11
4.1. Statistical Hypotheses .............................................................................................11
4.2. Statistical Decision Rules........................................................................................12
5. ANALYSIS SETS ...............................................................................................................12
5.1. Full Analysis Set .....................................................................................................12
5.2. ‘Per Protocol’ Analysis Set .....................................................................................12
5.3. Safety Analysis Set..................................................................................................12
5.4. Other Analysis Sets .................................................................................................12
5.5. Treatment Misallocations........................................................................................12
5.6. Protocol Deviations.................................................................................................12
6. ENDPOINTS AND COVARIATES ...................................................................................12
6.1. Safety Endpoint(s)...................................................................................................12
6.2. Adverse Events........................................................................................................13
6.3. Laboratory Safety Tests ..........................................................................................13
6.3.1. WBC and Neutrophil Monitoring...............................................................14
6.3.2. Neutropenia Assessment.............................................................................14
6.4. Vital Signs...............................................................................................................14
6.5. Electrocardiogram (ECG)........................................................................................15
6.6. Suicidal Ideation and Behavior (SIB) Assessments During the Clinical Trial .......15
6.7. 
 
.........................................................................................................16
6.8. Efficacy Endpoint(s) ...............................................................................................17
6.8.1. Unified Huntington’s Disease Assessment Scale (UHDRS)......................18
6.8.2.
 (
)........................................................19
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6.8.3.
.......................................................................20
6.8.4.
.................................................................................22
6.8.5. Clinical Global Impression of Severity/Improvement (CGI-S/CGI-I).......24
6.8.6.
..............................................................................25
6.8.7.
 (
) .........................................................25
6.9. 
.......................................................................................................26
6.10. 
.........................................................................................................26
6.11. PD Endpoints.........................................................................................................26
6.12. 
..............................................................................26
7. HANDLING OF MISSING VALUES ................................................................................26
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................27
8.1. Statistical Methods ..................................................................................................27
8.2. Statistical Analyses .................................................................................................27
8.2.1. Analysis of Secondary Endpoints...............................................................27
8.2.2.
.............................................................28
8.3. Analysis of Safety Data...........................................................................................28
8.3.1. Safety Analysis ...........................................................................................28
8.3.2. Treatment and Disposition of Subjects.......................................................28
8.3.3. Demographic Data and Clinical Examination Data....................................29
8.3.4. Discontinuation(s).......................................................................................29
8.3.5. Adverse Events...........................................................................................29
8.3.6. Suicidal Ideation and Behavior...................................................................29
8.3.7. Laboratory Data..........................................................................................29
8.3.8. Physical Exam/Weight................................................................................29
8.3.9. Vital Signs ..................................................................................................30
8.3.10. ECG ..........................................................................................................30
8.3.11. Prior and Concomitant Treatments...........................................................30
8.3.12. Screening and Other Special Purpose Data ..............................................30
8.4. 
........................................................................................................31
8.4.1. 
..........................................................................31
8.5. Summary of Efficacy Analyses...............................................................................32
9. REFERENCES ....................................................................................................................34
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LIST OF TABLES
Table 1.
C-CASA Suicidality Events and Codes................................................................36
Table 2.
C-SSRS Mapped to C-CASA - Suicidality Events and Codes.............................36
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs.....................................................35
Appendix 2. C-SSRS Mapped to C-CASA..............................................................................36
Appendix 3. Definition and Use of Visit Windows in Reporting............................................37


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Version 3 is amended from version 2 to include the following:
Change
Date
Section(s) Affected
Statistician
Updated the FAS 
definition
Feb. 15, 2017
Section 5.1
Added the 
improvement directions 
for efficacy endpoints
Feb. 15, 2017
Section 6.8
 
 
Feb. 15, 2017
Section 6.8.2
 
 
 
Feb. 15, 2017
Section 6.8.3
 
Feb. 15, 2017
Section 6.8.7
Feb. 15, 2017
Section 6.12
Update Statistical 
Method
Feb. 15, 2017
Section 8.1
Update Statistical 
Analyses
Feb. 15, 2017
Section 8.2
Update Summary of 
Efficacy Analyses
Feb. 15, 2017
Section 8.5
Version 4 is amended from version 3 to include following:
Change
Date
Section(s) Affected
Statistician
Modified Statistical 
Method to exclude the 
ET data due to 
unexpected study 
termination.
Mar. 29, 2017
Section 8.1
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2. INTRODUCTION
HD is an autosomal dominant neurodegenerative disease that targets the corticostriatal 
system and results in (1) progressive movement disorder, generally presenting as chorea in 
the early stages of the disease; (2) progressive cognitive disturbance culminating in 
dementia; and (3) various behavioral disturbances that may precede the emergence of 
diagnostic motor signs and can vary, depending on the disease state. The mean age of onset 
is 35-44 years and the median survival time is 15-18 years after onset. 
HD is caused by an expansion of a CAG trinucleotide in the first exon of the IT15 gene on 
the short arm of chromosome 4, which codes for the huntingtin (Htt) protein.  The CAG 
repeats are translated into polyglutamine repeats (polyQ) that confer toxic activity to 
huntingtin and lead to widespread corticostriatal pathology and ultimately to neuronal death 
most prominent in the striatum.  Htt gene alleles containing ≥36 CAG repeats are disease 
causing.  
The diagnosis of HD relies on characteristic clinical findings and the detection of an 
expansion of 36 or more CAG repeats in the Htt gene, often associated with a positive family 
history. 
The neuropathological hallmark of HD is the accumulation of aggregates of mutated Htt in 
neurons and the progressive loss of medium spiny neurons (MSNs), beginning in the tail of 
the caudate nucleus with subsequent progression to the ventromedial striatum2 with 
significant, albeit less pronounced, neuronal loss in other subcortical and cortical structures.
Depending on the species, MSNs account for approximately 74% (humans) to more than 
90% (rodents) of the striatal neuronal population.  MSNs are the output system of the 
striatum, and they receive glutamate input from cortical pyramidal cells, which also undergo 
substantial degeneration and loss in HD.  Although damage occurs in other brain regions, 
corticostriatal circuitry pathology and dysfunction appear to be the primary substrate of the 
cognitive, behavioral and motor abnormalities that characterize HD. Impairment in the 
corticostriatal circuitry is also present in transgenic mice and rats expressing mutant Htt as
demonstrated by electrophysiological studies in corticostriatal brain slices from these 
animals and by in vivo recordings from basal ganglia structures. Aberrant frontostriatal 
connectivity in response to cognitive tasks is present in pre-symptomatic HD subjects and 
worsens as the disease progresses.  There also appears to be an association between 
connectivity strength of frontostriatal circuits and several clinical measures and genetic 
markers, including Unified Huntington's Disease Rating Scale motor score, predicted years 
to manifest symptom onset, as well as CAG repeat length.
Phosphodiesterase 10A (PDE10A) is an enzyme that has an important role in the regulation 
of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) 
levels and is highly enriched in the medium-sized spiny neurons of the striatum.  Reduced 
PDE10A mRNA and protein levels have been found in homogenates from the striatum of HD 
patients. Results from a recent pilot PET imaging study with the PDE10A ligand [F] 
MNI-659, showed decreased PDE10A binding sites in HD stage I/II patients, as expected 
considering the degeneration of MSNs in HD.  A cross-sectional study on quantification of 
PDE10A levels in pre-manifest, early and mid-stage disease HD subjects and healthy 


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volunteers is currently ongoing at the Karolinska Institute. Preliminary results from this 
study confirmed previous reports suggesting that PDE10A enzyme expression in the brains of 
HD subjects is compatible with further clinical development of PF-02545920 for the 
symptomatic treatment of HD. Preclinical HD models have demonstrated that PDE10A 
enzyme levels ≥20% of normal can elicit robust biochemical signatures by increasing cyclic 
nucleotide signaling in response to PDE10A inhibition.
PF-02545920 is a potent and highly selective inhibitor of PDE10A in in vitro systems being 
developed for symptomatic treatment of both HD and schizophrenia (Note as of Jan 2015: 
the development of this compound for schizophrenia has been terminated based on lack of 
efficiacy for study A8241019).  In vivo PF-02545920 administration resulted in increased 
striatal levels of cGMP and cAMP and in the putative activation of a number of downstream 
signaling molecules regulated by cyclic nucleotide cascades in MSNs, leading to overall 
increased striatal activation and decreased locomotor hyperactivity.  The presence of 
mutated huntingtin has been found to impair cAMP signaling and cAMP responsive-element 
binding protein (CREB) mediated transcription of genes responsible for neurotransmitter 
synthesis, release and signaling pathway as well as the production of brain derived 
neurotrophic factor (BDNF).  Inhibition of PDE10A has been found to modulate striatal 
signaling towards neuroprotective pathways, to decrease neurodegenerative changes in the 
striatum of animal models of HD and to restore cAMP dependent CREB signaling.  The 
accumulated data strongly support targeting of the deficient cAMP and cGMP signaling as a 
therapeutic strategy to correct cortico-striatal-thalamic-cortical circuitry dysfunction and 
relieve both motor and cognitive symptoms of HD. 
Preclinical studies conducted in collaboration with the CHDI Foundation, Inc. demonstrated 
that PDE10A inhibition is effective in reversing multiple parameters of aberrant excitability 
of MSNs, and in improving elements of corticostriatal connectivity in brain slices derived 
from symptomatic R6/2 and Q175 knock-in mice.  Chronic (4 months) dosing of Q175 HD 
transgenic mice with PF-02545920 significantly improved dysfunction of the corticostriatal 
circuits, which develops with disease progression.
Moreover, recent studies in two additional transgenic models of HD, BACHD mice and 
BACHD rats showed that both acute and chronic (2 weeks) administration of 
PF-02545920 results in functional improvement of indirect pathway activity.  Most 
importantly, in vivo functional improvement measured as a reversal of the impaired 
subthalamic nucleus firing rate, was demonstrated in the full length mHtt transgenic BACHD 
rat, following acute treatment with PF-02545920. 
In summary, these preclinical observations suggest that treatment with 
PF-02545920 preferentially activates the function of the indirect pathway of the basal 
ganglia which is primarily impaired in the earlier stages of HD and thus may lead to 
functional normalization of affected corticostriatal brain circuitry.  For this reason, the 
PDE10A inhibitor, PF-02545920, may offer HD patients amelioration of motor and 
cognitive symptoms, and potentially slow disease progression.


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2.1. Study Design
This study is a 12 month open label extension study of PF-02545920 20 mg dosed BID 
following study A8241021. 
The study includes a Screening visit (V1) to assess eligibility followed by a Baseline visit 
(V2) and visits after 2 weeks, 4 weeks, 3 months, 6 months, 9 months, and 12 months of 
treatment. The final scheduled visit is a Follow-up visit 7-14 days after the last dose. 
Screening visit (V1) and Baseline visit (V2) will coincide with Week 19 and Week 26 Visits 
from study A8241021, respectively. For the Screening visit (V1) and Baseline visit (V2) 
procedures and assessments, the investigator will use data collected during Week 19 and 
Week 26 visits for study A8241021, respectively.  Subjects, who meet study entry criteria, will 
be assigned to the 20 mg BID dose. During the 12-month treatment phase, subjects will 
return for study assessments at Week 2 (V3), Week 4 (V4), Month 3 (V5), Month 6 (V6), 
Month 9 (V7), Month 12 (V8), and for a Follow-up visit (V9). 
Subjects, who were assigned to the 20 mg PF-02545920 dose group in the preceding 
A8241021 study, will continue to receive 20 mg PF-02545920 in this study without any 
titration.  All other subjects will be titrated to the 20 mg BID dose as follows: 5 mg BID for 
7 days, 10 mg BID for 7 days, 15 mg BID for 7 days, then 20 mg BID for the remainder of 
the treatment phase.  Titration is in place to reduce incidence of AEs, frequent monitoring is 
in place for neutropenia, and an option for de-escalation by 5 mg decrements (temporary or 
permanent) will be available should the investigator consider the AE intolerable.
Subjects who are discontinued (Early Termination) at or after Day 14 should complete as 
many of the Month 12 (V8) assessments as possible.  Subjects should return to complete the 
Follow-up visit whenever possible. 
Based on the total number of 260 subjects expected to be randomized in study A8241021, up 
to 260 subjects may take part in this open label extension. 
 
(
)
.
2.2. Study Objectives
Primary Objective:

To assess long-term safety and tolerability of 20 mg BID of PF-02545920 in subjects 
with HD.
Secondary Objectives:

To assess motor function after 6 and 12 month oral dosing with 20 mg BID of 
PF-02545920 in subjects with HD. 

To assess the efficacy of 6 and 12 month oral dosing with 20 mg BID of 
PF-02545920 on chorea severity in subjects with HD.
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
To assess whether 6 and 12 month oral dosing with 20 mg BID of PF-02545920 can 
improve overall clinical impression in subjects with HD.
:

 

 

 

 

 

 

3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis will be performed in the study.
3.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The primary trial variables examine long-term safety and tolerability of therapy with 20 mg 
BID of PF-02545920. The primary analysis of long-term safety will be focused on Adverse 
events, weight, vital signs (pulse, blood pressure and body temperature), electrocardiogram 
(ECG), clinical laboratory findings (hematology, biochemistry and urinalysis), suicidal
ideation and behavior (SIB) assessments and white blood count (WBC) and absolute 
neutrophil count (ANC). No formal statistical hypothesis will be conducted for the primary 
trail variables.
The secondary efficacy variables are:

Change from baseline in the Total Motor Score (TMS) assessment of the Unified 
Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment.

Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS 
after 6 and 12 months of treatment.

Clinical Global Impression-Improvement score after 6 and 12 months of treatment. 
Change from baseline in change in TMS and TMC will be calculated, decreases indicate 
improvement. The null hypothesis is that the change from baseline to a certain time-point is 
greater or equal to 0. The corresponding alternative hypothesis is that change from baseline 
to a certain time-point is less than 0. If the true mean change from baseline is denoted by µ 
then the hypothesis tested will be:
H0: µ ≥ 0
Ha: µ < 0
For Clinical Global Impression-Improvement (CGI-I) score a lower score indicates 
improvement. The null hypothesis is that the CGI-I value at a certain time-point is greater or 
equal to 4 (no change to very much worse). The corresponding alternative hypothesis is that 
the CGI-I value to a certain time-point is less than 4 (very much improved to minimally 
improved). If the true mean change from baseline is denoted by µ then the hypothesis tested 
will be:
H0: µ ≥4
Ha: µPF <4
Both the change from baseline for all subjects (pooled) and by three cohorts (defined by dose 
level in A8241021 study: PF-20mg, PF-5mg, or Placebo) will be analyzed.
Statistical hypotheses for exploratory endpoints will be specified in a similar fashion as 
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4.2. Statistical Decision Rules
All one-sided tests for secondary and exploratory endpoints are described as to be performed 
using the nominal alpha-level of 0.025, this corresponds to a two-sided test with alpha-level 
of 0.05. In addition to the p-values, two-sided 95% confidence intervals will be provided.
5. ANALYSIS SETS
5.1. Full Analysis Set
All efficacy endpoints will be evaluated over the Full Analysis Set (FAS), which is the set of 
subjects who have an open label extension study baseline efficacy evaluation and have 
completed at least the Week 2 visit with a valid UHDRS TMS score, and took ≥1 dose of 
open-label study medication.  Subjects without post-dose measurements will not contribute to 
the analysis, except in the description of the baseline values.
5.2. ‘Per Protocol’ Analysis Set 
No Per Protocol analysis will be conducted.
5.3. Safety Analysis Set
All subjects who entered the extension study with at least one dose of study medication will 
be included in the safety analyses.
5.4.
 
5.5. Treatment Misallocations 
Subjects who are undergoing the titration phase and do not titrate in the intended order will 
reported under the dose level they actually received.
5.6. Protocol Deviations
The criteria and determination of protocol violation/deviations will be determined by Pfizer 
prior to database release.
6. ENDPOINTS AND COVARIATES
6.1. Safety Endpoint(s)
Primary Endpoints: In this section, the safety endpoints that will be measured during the 
study are detailed.  Where applicable, details of the endpoints to be derived and definition of 
baseline are also provided.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

The number and proportion of subjects with adverse events.

Assessment of clinical laboratory parameters.
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
Assessment of vital signs.

Assessment of ECG parameters.

White blood count (WBC) and absolute neutrophil count (ANC) at each visit.

Abnormal laboratory findings from baseline.

Frequency and severity of adverse events related to extrapyramidal symptoms (EPS) 
including dystonia and akathisia, as assessed by the investigator.

C-SSRS (suicide severity assessment).

Adverse events, weight, vital signs (pulse, blood pressure and body temperature), 
physical examination, neurological examination, electrocardiogram (ECG) and 
clinical laboratory findings (hematology, biochemistry and urinalysis).  The endpoints 
are:

The number and proportion of subjects with adverse events.

Assessment of clinical laboratory parameters.

Assessment of vital signs.

Assessment of ECG parameters.

White blood count (WBC) and absolute neutrophil count (ANC) at each visit.

Abnormal laboratory findings from baseline.

Frequency and severity of adverse events related to extrapyramidal symptoms 
(EPS) including dystonia and akathisia, as assessed by the investigator.

C-SSRS (suicide severity assessment).
6.2. Adverse Events
All AEs occurring during the course of the study will be coded using the most current 
MedDRA coding dictionary. 
All AEs (serious and non-serious) reported from the first day of study treatment through and 
including 28 calendar days after the last administration of the study drug will be considered 
treatment emergent AEs (TEAEs).
6.3. Laboratory Safety Tests
Safety laboratory tests will be performed as described in the protocol. 


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To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.  The assessment will take into 
account whether each subject’s test result is within or outside the laboratory reference range 
for the particular laboratory parameter.
Assessment results collected at Week 26 for Study A8241021 will be used for Baseline 
Day 1.
6.3.1. WBC and Neutrophil Monitoring
WBC counts with differential will be recorded or performed at each study visit starting with 
Baseline Day 1 (V2).  The results of these assessments will be reviewed by the investigator as 
soon as possible once they are available, but no later than 2 business days after receipt of the 
lab results.  After reviewing the results, the investigator must confirm and document that the 
WBC and/or ANC do not meet stopping criteria (See Protocol Section 3.1) for the subject to 
continue in the study.
6.3.2. Neutropenia Assessment
Subjects who meet any of the “subject stopping criteria” or the study stopping criteria for 
WBC or ANC should receive a hematology consultation and assessment for all potential 
etiologies of the WBC and ANC findings.  This assessment should adhere to clinical standard 
of care for evaluation of neutropenia, but at a minimum include the following assessments: 
clinical assessment for infections and physical examination; review of relevant past medical 
history, prior concomitant medications, and prior WBC and ANC counts when available; 
repeated complete blood count with WBC, ANC, and a peripheral blood smear; bone 
marrow sampling for subjects who have an ANC <500 unless medically contraindicated or 
otherwise unobtainable.  Additional assessments indicated by the standard of care for 
evaluation of neutropenia should be pursued in accordance with the investigator’s and 
consultant’s judgment.
6.4. Vital Signs
Vital signs will include blood pressure, pulse, and oral or tympanic body temperature. For 
orthostatic vitals, blood pressure and pulse should be collected or recorded while the subject 
is in the supine and standing position at the following visits: Baseline Day 1 (V2), Month 
6 (V6), Month 12 (V8) or early termination visit.  Blood pressure and pulse should be 
collected while the subject is sitting at all other visits. 
The following vital signs endpoints will be determined:

The maximum decrease and increase from baseline over all measurements taken 
postdose for supine and standing systolic and diastolic blood pressures;

Postural differences (supine – standing) for systolic and diastolic blood pressures and 
for pulse rate.


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The maximum increase from baseline will be calculated by first subtracting the baseline
value from each post dose measurement to give the change from baseline. The maximum of
these values over the respective period will then be selected, except in the case where a
subject does not show an increase. In such an instance, the minimum decrease should be
taken.
Similarly, the maximum decrease from baseline will be determined by selecting the
minimum value of the changes from baseline. In cases where a subject does not show a
decrease, the minimum increase should be taken.
6.5. Electrocardiogram (ECG)
Single 12 lead ECGs will be recorded at Baseline Day 1 (V2), and collected at Month 3 (V5), 
Month 6 (V6), Month 9 (V7) and Month 12 (V8), or at early termination, and may be 
performed at Unscheduled Visit(s).
Subjects must rest in the supine position for at least 10 minutes before the ECG recording is 
started.  The ECG should be recorded during the period of rest required before blood 
collection and the measurements of orthostatic blood pressure and pulse.  A qualified 
physician will review the ECGs and any clinically important finding will be recorded on the 
appropriate CRF.  The investigator is responsible for providing interpretation of all ECGs.  
The results will include heart rate (RR), PR interval, QRS interval, QT interval, and correct 
QT (QTc) interval, and assessment of rhythm and morphology.  If necessary (eg, suspected 
QTc prolongation), a manual reading of the ECG data will be performed.
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT / (RR)**1/3 where RR = 60/HR (if not provided).
6.6. Suicidal Ideation and Behavior (SIB) Assessments During the Clinical Trial
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview-based rating scale to 
systematically assess suicidal ideation and suicidal behavior33.  The scale should be 
administered to the subject by an individual with appropriate training, who has also taken 
the specific rater training for the scale, which will be provided by an agent of the sponsor 
prior to the study start.  This scale will be recorded or administered (“since Last Visit”) at 
each study visit from Baseline Day 1 (V2) to Follow-up visit (V9), including early 
termination. 
C-SSRS responses will be mapped to the Columbia Classification Algorithm of Suicide 
Assessment (C-CASA). (See Appendix 2).
The following 3 endpoints are key endpoints for suicidality data analysis and evaluation: 

Suicidal Behavior;

Suicidal Ideation;

Suicidal Behavior or Ideation.


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Suicidal behavior: A subject is said to have suicidal behavior if the subject has experienced 
any of the following events (C-CASA event codes 1-3): 

Completed suicide;

Suicide attempt; or

Preparatory acts toward imminent suicidal behavior.
Suicidal ideation: Any observed suicidal ideation maps to a single C-CASA category.  The 
C-SSRS, for example, includes five ideation questions (that map to C-CASA category 4) 
with increasing severity. 
Subjects with new onset suicidality: A subject will be considered to have a new onset of 
suicidality if the subject reported no ideation and no behavior at the baseline assessment 
(note that self-injurious behavior, no suicidal intent [C-CASA code 7] is not considered to be 
suicidal ideation or behavior) and reported any behavior or ideation post-baseline.  Data 
observed at screening is not considered in the definition of new onset.
Subjects with worsening suicidality relative to baseline: A subject will be considered to have 
a worsening of suicidality if the subject moved to a lower numbered C-CASA category 
(observed in categories 1-4) than was reported at baseline.  Movement within C-CASA 
categories 5-9 would not be considered worsening.  In addition, worsening will be considered 
within the suicide ideation C-CASA category 4 if there is an increase in severity identified in 
the C-SSRS which captures additional granularity on suicide ideation. A subject who reports 
only ideation at baseline and who reports any behavior post-baseline is considered to 
have worsened.  Data observed at screening is not considered in the definition of
worsening.
6.7.
 
(
)
 
 
 
 
 
 
 
 
 
 
 
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6.8. Efficacy Endpoint(s)
Secondary Endpoints:

Change from baseline in the Total Motor Score (TMS) assessment of the Unified 
Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment.  The 
score decreases indicate improvement.

Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS 
after 6 and 12 months of treatment.  The score decreases indicate improvement.

Clinical Global Impression-Improvement score after 6 and 12 months of treatment.  
The score decreases indicate improvement.
:
:

 
:

 
 

 
: 

 
 
 
:

 
 
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
 
 

 
:

 
 

 
 

 

.
6.8.1. Unified Huntington’s Disease Assessment Scale (UHDRS)
In this study four subscales of the UHDRS will be administered to the subject by a trained
certified rater of the site investigational staff (clinician): the Total Motor Score (TMS),
 (
, 
.
The UHDRS is a clinical rating scale which has been developed by the Huntington Disease
Study Group (HSG) to provide a uniform assessment of the clinical features and course of
HD.  The UHDRS scale has undergone reliability and validity testing and has been used as a 
major outcome measure in controlled clinical trials and observational studies. 
.
The total motor score (TMS) will be recorded from study A8241021 at Baseline Day 
1 (V2) visit, and will be administered at each study visit from Week 2 (V3) to Month 12 (V8) 
and in case of early termination.
The TMS assesses motor features of HD with standardized ratings of oculomotor function, 
dysarthria, chorea, dystonia, gait, and postural stability.  Some items (such as chorea and 
dystonia) require grading each extremity (face, bucco-oral-lingual, and trunk) separately.  
Eye movements require both horizontal and vertical grades.  The total motor impairment 
scores is the sum of all the individual motor ratings, with higher scores indicating more 
severe motor impairment than lower scores. 
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The Total Maximum Chorea (TMC) is a subset of the TMS assessment.  It is composed of 
the scoring of 7 chorea assessments (face, orobuccolingual, trunk, right and left upper 
extremities, right and left lower extremities).  Each assessment is rated from 0 to 4 (absent to 
prolonged).  The TMC score can be derived from the TMS score at visits at which the TMS 
is collected.
 
 
 
 
.
 
 
.
 
 
 
Administration and scoring guidelines will be provided to the investigator site during rater 
training sessions prior to initiation of the study.
6.8.2.
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)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.
6.8.3.
 
 
 
 
 
 

 
 (
). 
 
 
 
 
 
 
 
 
 
 
 
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
 (
). 
 (
).
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
 
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
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
(
).
 (
)
 
 
 
 
 
 
 
 
 
 
 
 
:
1.
 
 
 
2.
 
 
 

 

 
 
6.8.4.
 
 
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





 
 
 
 
 
  
 
 
 
 
 



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:
 
 
 
 

 
6.8.5. Clinical Global Impression of Severity/Improvement (CGI-S/CGI-I)
The CGI-S/CGI-I is a global measure of severity of illness (CGI-S) and improvement or 
change (CGI-I) based on the clinician’s assessment of all available clinical data obtained 
from interviewing the subject. 
The CGI-S consists of a single 7-point rating score of illness severity that is based on how ill 
the subject is relative to other subjects he/she has had experience with.  Raters select one 
response based on the following question, “Considering your total clinical experience with 
this particular population, how ill is your subject at this time?” Scores are: 1, Normal, not ill 
at all; 2, Borderline ill; 3, Mildly ill; 4, Moderately ill; 5, Markedly ill; 6, Severely ill; or 
7, Among the most severely ill subjects. 
The CGI-I consists of a single 7-point rating of total improvement or change from baseline 
CGI-S, regardless of whether or not the change is due entirely to drug treatment.  Raters 
select one response based on the following question, “Compared to your subject’s condition 
at the beginning of treatment, how much has your subject changed?” Scores are: 1, Very 
much improved; 2, Much improved; 3, Minimally improved; 4, No change; 5, Minimally 
worse; 6, Much worse; or 7, Very much worse.
The CGI-S/CGI-I rater can have access to all clinical information related to subject severity 
and change, and does not need to be independent of other assessments.  However, the rater 
who assesses the initial CGI-S should be the clinician who rates overall change via the CGI-I 
during the study.
The CGI-S will be performed at Baseline Day 1 (V2).  The CGI-I will be administered at 
Month 6 (V6), Month 12 (V8), and in case of early termination.  This assessment will be 
administered by a trained rater from the site investigational team (eg, clinician).
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6.8.6.
 
:

 
6.8.7.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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6.9.
6.10.
 
 
6.11. PD Endpoints 
None.
6.12.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
For scales used in this study (eg, UHDRS), no missing response will be allowed in the study.  
A query will be sent to the site if there is missing response.
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Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
Deviations, missing concentrations and anomalous values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
The Safety population will be used in the analyses of the safety data. The FAS analysis set 
will be utilized for efficacy endpoints.
All efficacy endpoints will be summarized descriptively at each visit for all subjects as well 
as separated by three groups (ie, from PF 20mg, from PF 5mg, and from Placebo).  90%CI 
will be provided for the mean.  Plots with the mean over time with 90%CI will be generated 
for all subjects as well as by three different groups. 
Baseline and change from baseline for each efficacy endpoints will also be summarized 
descriptively at each visit for all subjects as well as separated by three groups.  Plots with 
mean change from baseline over time with 90%CI will be generated for all subjects as well 
as by three different groups.
Due to the unexpected termination of the study, any early termination visits (ET), which 
occurred on and after Dec. 16th, 2016, will not be included in the summary tables and plots.  
These data will be listed only. 
8.2. Statistical Analyses 
8.2.1. Analysis of Secondary Endpoints
The efficacy variables are:

Change from baseline in the Total Motor Score (TMS) assessment of the Unified 
Huntington Disease Rating Scale (UHDRS) after 6 and 12 months of treatment.

Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS 
after 6 and 12 months of treatment.


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
Clinical Global Impression-Improvement score after 6 and 12 months of treatment. 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) and 
90% confidence interval will be provided to summarize results for each visit.  The baseline 
and change from baseline values will be summarized as well by visit.  A two-sided, 
paired t-tests at the 10% level of significance will also be used to summarize results.  The 
paired t-tests will be done on all subjects and on three different groups.  Baseline is defined 
as the final visit (Week 26) in the preceding double-blind study A8241021.
Clinical Global Impression-Improvement score after 6 and 12 months of treatment will be 
evaluated with descriptive statistics that includes n, mean, standard deviation (SD), median, 
minimum, and maximum.  A two-sided, one-sample t-tests at the 5% level of significance 
will be applied to evaluate results.
Plots will be generated for mean change from baseline as well as mean over time as 
described in Section 8.1.
8.2.2.
 
 
 
 
8.3. Analysis of Safety Data
8.3.1. Safety Analysis
A set of summary tables will be produced to evaluate any potential risk associated with the 
safety and toleration of administering PF-02545920. 
The safety and other endpoints detailed here will be listed and summarized in accordance 
with sponsor reporting standards, where the resulting data presentations will consist of 
subjects from the safety analysis set.  All safety endpoints will be summarized for all subjects 
as well as separated by three groups (ie, from PF 20mg, from PF 5mg, and from Placebo). 
8.3.2. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for FAS, safety (adverse events and laboratory data), and 
pharmacokinetics. Frequency counts will be supplied for subject discontinuation(s). 
Data will be reported in accordance with the sponsor reporting standards.
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8.3.3. Demographic Data and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, weight, body mass index 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
Medical history will be summarized and listed.
8.3.4. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized.
Data will be reported in accordance with the sponsor reporting standards.
8.3.5. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards. 
8.3.6. Suicidal Ideation and Behavior
A frequency distribution of C-CASA scores (predose/post dose) will be reported.  No 
hypotheses associated with the C-SSRS or C-CASA scales will be tested.
The denominator used in the percentages will be the number of subjects assessed for suicidal
ideation and behavior (SIB).  For worsening, the denominator would include the subset of 
subjects who had any level of suicidality reported at baseline.  For new onset, the 
denominator would include the subset of subjects with no suicidality reported at baseline.
A subject listing of C-CASA categories as well as the underlying C-SSRS scale data will be 
presented. 
In addition, a summary table with the number and percent of subjects within each C-CASA 
category at baseline, and at any time post-baseline without regard to baseline will be 
reported.
8.3.7. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 6.3.
A listing of subjects who meet any of the study stopping criteria for WBC or ANC counts 
will be presented.
8.3.8. Physical Exam/Weight
Physical examination data will be presented in a data listing and summary table using counts 
and percentages.  Summary of new/intensified physical examination findings from Baseline 
to Month 12/ET will be presented.


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Body weight absolute values and change from baseline will be summarized using descriptive 
statistics.
8.3.9. Vital Signs 
Absolute values and changes from baseline in standing, supine and postural changes for 
systolic and diastolic blood pressure and pulse rate will be summarized, time postdose and 
day, according to sponsor reporting standards.  Tables will be paged by parameter. 
Baseline will be defined as the predose recordings on Day 1(V2).
Maximum absolute values and changes from baseline for vital signs (for supine and standing) 
will also be summarized descriptively by using categories as defined in Appendix 1.  
Numbers and percentages of subjects meeting the categorical criteria will be provided.  All 
planned and unplanned postdose timepoints will be counted in these categorical summaries.  
All values meeting the criteria of potential clinical concern will be listed.
Standing vital signs will be listed only.
8.3.10. ECG
Absolute values and changes from baseline in PR, QT, QRS, heart rate (RR) and QTcF will 
be summarized, time postdose and day using sponsor reporting standards.  Tables will be 
paged by parameter.
ECG endpoints and changes from baseline (QTcF, PR, QRS) will also be summarized 
descriptively by using categories as defined in Appendix 1 (for QTc these correspond to ICH 
E141).  Numbers and percentages of subjects meeting the categorical criteria will be 
provided.  All planned and unplanned postdose timepoints will be counted in these 
categorical summaries.  All values meeting the criteria of potential clinical concern will be 
listed.
Listings of subjects with any single postdose value 500 msec will also be produced for 
QTcF.
8.3.11. Prior and Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
Frequency and type of medication will be summarized categorically. 
8.3.12. Screening and Other Special Purpose Data
Serum FSH concentrations and urine drug screen will be obtained at screening (for drug 
screen, and at any time at the discretion of the investigator).


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8.4.
8.4.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.5. Summary of Efficacy Analyses 
Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates/ 
Strata
Missing Data
Interpretation
from Baseline UHDRS 
Total Motor Score
FAS
Paired t-test
NA
Excluded
Secondary Analysis
from Baseline UHDRS 
Total Maximum Chorea 
Score
FAS
Paired t-test
NA
Excluded
Secondary Analysis
CGI-I
FAS
One-Sample t-test
NA
Excluded
Secondary Analysis
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Endpoint
Analysis 
Set
Statistical Method 
Model/ Covariates/ 
Strata
Missing Data
Interpretation
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9. REFERENCES 
1.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.


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Appendix 1. Categorical Classes for ECG and Vital Signs 
Categories for QTcF
QTcF (ms)
450≤ max. <480
480≤ max.<500
max. ≥500
QTcF (ms) 
increase from 
baseline
30≤ max. <60
max. ≥60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline 
>200 and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) 
increase from 
baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Standing pulse rate (bpm)
min. <40
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Appendix 2. C-SSRS Mapped to C-CASA
Table 1.
C-CASA Suicidality Events and Codes
Event 
Code
Event
1
Completed suicide
2
Suicide attempt
3
Preparatory acts towards imminent suicidal behavior
4
Suicidal ideation
5
Self-injurious behavior, intent unknown
6
Not enough information, fatal
7
Self-injurious behavior, no suicidal intent
8
Other, accident, psychiatric; mental 
9
Not enough information, non fatal
* Note: Event Codes 5, 6, 8 and 9 are not applicable to prospectively collected data
Table 2.
C-SSRS Mapped to C-CASA - Suicidality Events and Codes
C-CASA 
Event Code
C-CASA Event
C-SSRS Response
1
Completed suicide
As captured in the safety database
2
Suicide attempt
“Yes” on “Actual Attempt”
3
Preparatory acts towards 
imminent suicidal behavior
“Yes” on any of the following:

”Aborted attempt”, or

“Interrupted attempt”, or

“Preparatory Acts or Behavior”
4
Suicidal ideation
“Yes” on any of the following:

“Wish to be dead”, or

“Non-Specific Active Suicidal Thoughts”, 
or

“Active Suicidal Ideation with Any 
Methods (Not Plan) without Intent to Act”, 
or

“Active Suicidal Ideation with Some Intent 
to Act, without Specific Plan”, or

“Active Suicidal Ideation with Specific 
Plan and Intent”
7
Self-injurious behavior, no 
suicidal intent
“Yes” on “Has subject engaged in Non-suicidal 
Self-Injurious Behavior?”


Protocol A8241022 (PF-02545920) Statistical Analysis Plan
DMB02-GSOP-RF02 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE 31-Jan-2013
PFIZER CONFIDENTIAL
Page 37
Appendix 3. Definition and Use of Visit Windows in Reporting
Statistical analyses for full analysis set will be based on time intervals that are constructed 
according to the duration of treatment. The planned time interval definitions are summarized 
below. 
Scheduled Visit 
number 
Time interval 
(label) 
Time interval (days)
Target time point 
(day)
1
Screening1
[-52,-46]
-49
2
Baseline2
[-7,0]
0
3
Week 2
[11, 17]
14
4
Week 4
[25, 31]
28
5
Month 3
[84, 98]
91
6
Month 6
[168, 196]
182
7
Month 9
[266, 280] 
273
8
Month 12
[351, 379]
365
9
Follow-up
[373, 385] 
379
1.Screening visit will take place during the Week 19 Visit for study A8241021. 
2.Assessment results collected at Week 26 for Study A8241021 will be used for Baseline Day 1 (V2).
If data obtained from the multiple visits are included in the same interval, the one closest to 
the target date in that time interval will be used for analysis.  If two visits are equally distant 
from the target date, then the later one will be used. 
The study day associated with a given date will be calculated as: (date of interest) – (first 
dosing date) + 1.  Consequently, Day 0 indicates the day before Day 1, the first dosing date
in the study.
The baseline reference period for assessing treatment emergent adverse events (TEAEs) will 
be the period prior to Day 1.
The frequency distribution of study days for each visit will be reviewed by clinician to 
expand visit windows for the analyses, if necessary, before locking and unblinding the 
database.