Clinical trial NCT02534038
Conditions: Disinhibition Syndrome
Keywords: Disinhibition
Sponsor: Avanir Pharmaceuticals
Start date: 2015-12-01; Completion date: 2017-10-03
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Treatment of disinhibition syndrome in participants with Neurodegenerative Disorder.

Detailed description:
Eligible participants for this study must have a diagnosis of Neurodegenerative Disorder and must exhibit disinhibition syndrome of sufficient severity to warrant treatment.

This is a multicenter, randomized, double-blind, placebo-controlled, cross-over study consisting of two 6-week treatment periods.

Approximately 12 participants will be enrolled at approximately 2 centers in the United States.

Following screening procedures for assessment of inclusion and exclusion criteria, eligible participants will be randomized into the study.

Arms: arm 1: Placebo drug to be taken twice a day for 6 weeks arm 2: Participants randomized to AVP-786 will take one dose of AVP-786 once a day and one dose of placebo once a day for the first 7 days; from day 8, participants will receive AVP-786 twice a day for 5 weeks.
Interventions: intervention 1: AVP-786 intervention 2: Placebo
Intervention descriptions: intervention 1: d6-DM/Q intervention 2: matching placebo

Protocol documents:
Prot_SAP_000.pdf: 
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CONFIDENTIAL AND PROPRIETARY 
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Protocol 15-AVP-786-203 
Version 1.0 
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TABLE OF CONTENTS 
Table of Contents ...................................................................................................................................... 2 
List of Tables ............................................................................................................................................ 5 
List of Figures .......................................................................................................................................... 5 
List of Abbreviations ................................................................................................................................. 6 
Protocol Agreement ................................................................................................................................... 8 
Study Synopsis .......................................................................................................................................... 9 
1 
Background and Clinical Rationale .............................................................................................. 16 
 17 
 17 
2 
Study Objectives ........................................................................................................................... 18 
3 
Study Design ................................................................................................................................. 19 
4 
Study Population ........................................................................................................................... 21 
4.1 
Inclusion Criteria ............................................................................................................. 21 
4.2 
Exclusion Criteria ............................................................................................................ 23 
4.3 
Patient Withdrawal from the Study.................................................................................. 24 
5 
Study Treatments .......................................................................................................................... 26 
5.1 
Treatments Administered ................................................................................................. 26 
5.1.1 Description of Study Medications ........................................................................ 26 
5.1.2 Composition of AVP-786 ..................................................................................... 26 
5.1.3 Packaging ............................................................................................................. 27 
5.1.4 Labeling ................................................................................................................ 27 
5.1.5 Storage of Clinical Supplies ................................................................................. 27 
5.1.6 Study Medication Administration ........................................................................ 28 
5.2 
Accountability of Study Supplies .................................................................................... 29 
5.2.1 Receipt of Supplies ............................................................................................... 29 
5.2.2 Record of Dispensing ........................................................................................... 29 
5.2.3 Unused Supplies ................................................................................................... 29 
5.3 
Methods of Assigning Patients to Treatment Groups ...................................................... 29 
5.3.1 Randomization ...................................................................................................... 29 
5.3.2 Blinding/Masking ................................................................................................. 30 


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5.4 
Patient Compliance .......................................................................................................... 30 
. 30 
. 30 
. 31 
6 
Study Assessments and Procedures .............................................................................................. 32 
6.1 
Efficacy ............................................................................................................................ 32 
6.1.1 Neuropsychiatric Inventory (NPI) ........................................................................ 32 
6.1.2 Frontal Behavioral Inventory (FBI) ...................................................................... 32 
6.1.3 Modified Clinical Global Impression of Severity of Illness 
(mCGIS) ............................................................................................................... 33 
6.1.4 Modified Clinical Global Impression of Change Rating (mCGIC)...................... 33 
6.1.5 Patient Global Impression of Change (PGIC) ...................................................... 34 
6.1.6 Quality of Life (QoL) ........................................................................................... 34 
6.1.7 Quality of Relationships (QoR) ............................................................................ 34 
6.1.8 Interpersonal Reactivity Index (IRI) .................................................................... 34 
6.1.9 Center for Neurologic Study-Lability Scale (CNS-LS) ....................................... 34 
6.1.10 Mini-Mental State Examination (MMSE) ............................................................ 35 
6.1.11 Cornell Scale for Depression in Dementia (CSDD) ............................................. 35 
6.1.12 Stroop Color and Word Task with 
 
 .................................................................................. 35 
. 36 
6.2 
Pharmacokinetics (PK) .................................................................................................... 36 
6.3 
Safety ............................................................................................................................... 37 
6.3.1 Adverse Events ..................................................................................................... 37 
6.3.2 Physical and Neurological Examinations ............................................................. 39 
6.3.3 Vital Signs ............................................................................................................ 40 
6.3.4 Clinical Laboratory Tests ..................................................................................... 40 
6.3.5 Pregnancy Test ..................................................................................................... 40 
6.3.6 Electrocardiograms ............................................................................................... 40 
6.3.7 Sheehan Suicidality Tracking Scale (S-STS) ....................................................... 41 
6.4 
Schedule of Evaluations and Procedures ......................................................................... 41 
6.4.1 Description of Study Procedures .......................................................................... 41 


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7 
Data Management ......................................................................................................................... 51 
7.1 
Data Collection ................................................................................................................ 51 
8 
Statistical Methods ........................................................................................................................ 52 
8.1 
Analysis Populations ........................................................................................................ 52 
8.2 
Demographic and Baseline Characteristics ..................................................................... 52 
8.3 
Efficacy Analysis ............................................................................................................. 52 
8.3.1 Study Endpoints ................................................................................................... 52 
8.3.2 Primary and Secondary Efficacy Analysis ........................................................... 53 
8.4 
Safety Analysis ................................................................................................................ 53 
8.5 
Sample Size Calculations ................................................................................................. 53 
9 
Administrative Procedures ............................................................................................................ 54 
9.1 
Institutional Review Board Approval .............................................................................. 54 
9.2 
Informed Consent Form ................................................................................................... 54 
9.3 
Patient’s Diary Card ......................................................................................................... 54 
9.4 
Electronic Case Report Forms ......................................................................................... 54 
9.5 
Quality Assurance ............................................................................................................ 55 
9.5.1 Documentation ..................................................................................................... 55 
9.5.2 Monitoring ............................................................................................................ 55 
9.6 
Record Retention ............................................................................................................. 56 
9.7 
Source Data ...................................................................................................................... 56 
9.8 
Data Handling .................................................................................................................. 56 
9.9 
Laboratory Procedures ..................................................................................................... 56 
9.10 
Guidelines for Good Clinical Practice ............................................................................. 56 
9.11 
Conditions for Amending the Protocol ............................................................................ 56 
9.12 
Conditions for Terminating the Study ............................................................................. 57 
9.13 
Confidentiality of Study Documents and Patient Records ............................................... 57 
9.14 
Reports ............................................................................................................................. 57 
9.15 
Publications ...................................................................................................................... 57 
9.16 
Audits/Inspections ........................................................................................................... 57 
10 
References ..................................................................................................................................... 59 
11 
Appendices .................................................................................................................................... 63 


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List of Tables 
Table 1 
 Schedule of Evaluations and Visits ............................................................................. 14 
Table 2 
 Composition of Investigational Product ..................................................................... 27 
 
List of Figures 
Figure 1 
Study Schematic........................................................................................................... 13 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AD 
Alzheimer’s Disease 
ALT/SGPT 
Alanine aminotransferase/serum glutamic-pyruvic transaminase 
ANCOVA 
Analysis of covariance 
AST/SGOT 
Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
beta-hCG 
Beta subunit of human chorionic gonadotropin 
BID 
twice daily 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
BvFTD 
behavioral variant of frontotemporal dementia 
CBD 
corticobasal degeneration  
CD-ROM 
Compact disc read-only-memory 
CFR 
Code of Federal Regulations 
CGIC 
Clinical Global Impression of Change 
CGIS 
Clinical Global Impression of Severity of Illness 
CK 
Creatine kinase 
CNS 
Central nervous system 
CNS-LS 
Center for Neurologic Study-Lability Scale  
CRO 
Contract research organization 
CSDD 
Cornell Scale for Depression in Dementia  
CYP 
Cytochrome P450 
DLB 
dementia with Lewy bodies 
DM 
Dextromethorphan 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EP 
European Pharmacopeia 
FBI 
Frontal Behavioral Inventory 
FDA 
US Food and Drug Administration 
FRsBe 
Frontal-Subcortical Behavior Scale  
FTD 
frontotemporal dementia  
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMP 
Good Manufacturing Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 


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Abbreviation 
Definition 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRI 
Interpersonal Reactivity Index 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward 
MAOI 
Monoamine oxidase inhibitor 
mCGIC 
Modified Clinical Global Impression of Change 
mCGIS 
Modified Clinical Global Impression of Severity of Illness 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MM 
Medical Monitor 
MMSE 
Mini-Mental State Examination 
NDD 
Neurodegenerative Disorder 
NF 
National Formulary 
NPI 
Neuropsychiatric Inventory 
NPI-NH 
Neuropsychiatric Inventory - Nursing Home version 
OTC 
Over–the-counter 
PBA 
pseudobulbar affect 
PGIC 
Patient Global Impression of Change 
pH 
Potential Hydrogen 
PK 
Pharmacokinetics 
PR 
The P-R interval from an ECG tracing 
PSP 
progressive supranuclear palsy 
Q 
Quinidine 
QoL 
Quality of Life 
QoR 
Quality of Relationships 
QRS 
The Q-R-S complex from an ECG tracing 
QT 
QT interval from an ECG tracing 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using the Fridericia’s formula 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
SOC 
System organ class 
SSRI 
Selective serotonin reuptake inhibitor 
S-STS 
Sheehan Suicidality Tracking Scale 
TCA 
Tricyclic antidepressant 
TEAE 
Treatment-emergent adverse event 
USP 
United States Pharmacopoeia 
WBC 
White blood cell 


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Protocol 15-AVP-786-203 
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PROTOCOL AGREEMENT 
Protocol Title: 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Cross-over Study to Assess the 
Safety, Tolerability and Efficacy of AVP-786 for the Treatment of Disinhibition in Patients with 
Neurodegenerative Disorders 
Protocol Number: 15-AVP-786-203  
This document is a confidential communication of Avanir Pharmaceuticals. The recipient agrees that no 
unpublished information contained within this document or protocol will be disclosed or published 
without prior consent and written approval from Avanir. An exception to this agreement may be made for 
the purposes of ethical or regulatory review, in which case this document may be disclosed to an Ethics 
Review Board or any authorized representative of a national authority as required by regulation. 
The signatures of the principal investigator and representative of the sponsor below constitute their 
approval of this protocol and further provide the necessary assurances that: 
1. This study will be conducted according to Good Clinical Practice (GCP) and to all stipulations, as 
specified in both clinical and administrative sections of the protocol including the Declaration of 
Helsinki. 
2. The conduct and results of this study will be kept confidential, and the electronic case report forms 
(eCRFs) and other pertinent data will become the property of Avanir Pharmaceuticals. 
3. The protocol contains all necessary information required to conduct the study, as outlined in the 
protocol, and that the study will not be initiated without the approval of an appropriate Institutional 
Review Board (IRB). 
4. All participants in this study will provide written informed consent in accordance with the 
requirements specified in the Code of Federal Regulations (21 CFR Parts 50, 56, 312) and/or the 
Declaration of Helsinki. All participants will also be informed that their medical records will be kept 
confidential except for review by Avanir or its representatives, the U.S. Food and Drug 
Administration (FDA), or other regulatory agencies if applicable. 
 
 
 
 
Principal Investigator Signature 
 
Date 
Principal Investigator Name:_____________________________ 
 
 
 
 
 
 
Avanir Representative Signature 
 
Date 
Avanir Representative Name:
 
 


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STUDY SYNOPSIS 
Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Cross-over Study to 
Assess the Safety, Tolerability, and Efficacy of AVP-786 for the Treatment of Disinhibition in Patients 
with Neurodegenerative Disorders 
Study Objectives 
The objectives of the study are to evaluate the safety, tolerability, and efficacy of AVP-786 compared to 
placebo, for the treatment of disinhibition in patients with Neurodegenerative Disorders (NDD) including 
frontotemporal dementia, Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, 
dementia with Lewy bodies, vascular cognitive disorders, or Huntington’s disease. 
Study Population 
Number of Patients:  Approximately 12 patients will be enrolled at 2 centers; approximately 6 patients at 
each center. 
Condition/Disease:  Disinhibition syndrome in patients with a diagnosis of a NDD including 
frontotemporal dementia, Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, 
dementia with Lewy bodies, vascular cognitive disorders, or Huntington’s disease.  The definition of 
disinhibition syndrome will be based on the disinhibition criteria developed to identify patients with the 
behavioral variant of frontotemporal dementia (BvFTD)1 which includes descriptions of disinhibited 
behavior in three general areas:  socially inappropriate behavior, loss of manners and decorum, and 
impulsive, rash, and careless actions.    
Key Inclusion Criteria:   
 
Patients with a documented diagnosis of a NDD with a duration of at least 3 months prior to 
Baseline;  
 
Patients with behaviors from 2 of the 3 categories of disinhibited behavior from the definition of 
the behavioral variant of frontotemporal dementia;1  
 
 
A score of ≥ 4 on the 3 core disinhibition questions of the Frontal Behavioral Inventory (FBI) at 
the Screening and Baseline visits;  
 
Availability of a caregiver known to the patient and who is able and willing to comply with all 
required study procedures, ensuring that the patient attends all study visits and takes the study 
medication as instructed. 
Key Exclusion Criteria:   
 
Patients with symptoms of disinhibition that are not secondary to NDD (e.g., substance use, 
traumatic brain injury [TBI]);  
 


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 
 
A complete list of inclusion/exclusion criteria is presented in Section 4 of the study protocol. 
Study Design 
Design: This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, cross-over study.  A 
schematic of the study design is presented in Figure 1. 
Duration: The study duration is approximately 22 weeks with up to 4 weeks of screening, 14 weeks of 
treatment and 4 weeks of safety follow-up.   
Study Treatment:  The investigational product is AVP-786 (deuterated [d6]-dextromethorphan 
hydrobromide [d6-DM]/quinidine sulfate [Q]).  Two doses of AVP-786 will be evaluated by titration, 
d6-DM 
 mg/Q 
 mg and d6-DM 28 mg/Q 4.9 mg, hereafter referred to as AVP-786-
 and 
AVP-786-28/4.9, respectively. 
Control:  AVP-786 Placebo capsules of identical appearance and excipients to study medication will be 
used as control. 
Randomization: Eligible patients will be randomized into this 2x2 crossover study in a 
 ratio at the 
Baseline visit to receive either treatment sequence 1 AB (period 1: A, period 2: B) or treatment sequence 
2 BA (period 1: B, period 2: A), where A is AVP-786 and B is placebo.  
Dose Regimen:  Study medication will be administered orally twice daily (BID, 1 capsule in the morning 
and 1 capsule in the evening approximately 12 hours apart) throughout the study.  
Period 1 
 
Patient randomized to treatment sequence 1 AB will start with AVP-786-
 once a day in the 
morning and placebo in the evening for the first 7 days of the study.  From Day 8, patients will 
receive AVP-786-
 BID for 14 days.  From Day 22, patients will receive AVP-786-28/4.9 
BID for the remaining 3 weeks of period 1.  
 
Patients randomized to treatment sequence 2 BA will be dosed with placebo BID during period 1  
A 2-week washout period will follow period 1 (Days 44 to 56).  For the washout period, suffient supply 
of placebo will be dispensed in a single-blind manner to patient/caregiver to ensure continuity and study 
medication compliance. 
 
Period 2: 
Patients who complete period 1 and the 2-week wash-out period are eligible to participate in period 2 of 
the study.  In Period 2, patients will be assigned to study treatment as follows: 
 
Patients who received AVP-786 in period 1 (treatment sequence 1 AB) will receive placebo BID 
for the entire 6-week duration of period 2. 


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 
Patients who received placebo in period 1 (treatment sequence 2 BA) will start with 
AVP-786-
 once a day in the morning and placebo in the evening for the first 7 days of 
period 2.  From Day 64, patients will receive AVP-786-
 BID for 14 days.  From Day 78, 
patients will receive AVP-786-28/4.9 BID for the remaining 3 weeks of period 2. 
Assessments and Visits  
The study includes a total of 9 scheduled clinic visits and 1 safety follow-up phone call.  Patients will 
attend clinic visits at Screening (Day -28 to -1), in period 1: on Day 1 (Baseline), Day 8 (Week 1), Day 22 
(Week 3), Day 43 (Week 6), and in period 2: on Day 57 (Week 8), Day 64 (Week 9), Day 78 (Week 11), 
and Day 99 (Week 14).  A safety follow-up phone call will be made 30 days after the last clinic visit (Day 
129).  Study procedures will be performed at each visit as outlined in the Schedule of Evaluations and 
Visits (Table 1).  
Response Measures 
Efficacy  
Primary measure: Primary efficacy will be assessed using the Disinhibition domain of the 
Neuropsychiatric Inventory (NPI)  
Secondary measures:  Secondary efficacy measures include total NPI, NPI total caregiver distress score, 
NPI Disinhibition domain caregiver distress, Frontal Behavioral Inventory (FBI) total score, FBI 
disinhibition core questions score (questions 15, 16, and 17), Modified Clinical Global Impression of 
Severity of Illness (mCGIS), Modified Clinical Global Impression of Change (mCGIC), Patient Global 
Impression of Change (PGIC), Quality of Life (QoL), Quality of Relationships (QoR), Interpersonal 
Reactivity Index (IRI), Center for Neurologic Study-Lability Scale (CNS-LS), Mini Mental State 
Examination (MMSE), Cornell Scale for Depression in Dementia (CSDD), Stroop color and word task 
Pharmacokinetics 
Plasma concentrations of d6-DM, its metabolites, and Q will be measured. 
Safety and Tolerability  
Safety and tolerability of AVP-786 will be assessed by reported adverse events (AEs), physical and 
neurological examinations, vital signs, clinical laboratory assessments, resting 12-lead electrocardiograms 
(ECGs), and Sheehan Suicidality Tracking Scale (S-STS). 
Pregnancy tests will be conducted for females of childbearing potential. 
General Statistical Methods and Types of Analyses 
Analysis Populations 
Two analysis populations will be used, modified intent-to-treat (mITT), and safety.  The mITT population 
includes all patients randomized in the study who have at least one post-baseline efficacy assessment, and 


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will be used for all analyses of efficacy.  The safety population includes all patients who received study 
treatment, and will be used for all analyses of safety.  Patients in the safety population will be summarized 
based on their actual study treatment received.  
Efficacy Analyses 
The primary efficacy endpoint of the study is the change from Baseline to Week 6 in each study period in 
the Disinhibition domain of the NPI.  Treatment group comparison will be performed using an analysis of 
covariance (ANCOVA) model.  The model includes fixed effects of treatment, period, treatment 
sequence, and covariate of baseline value.  A point estimate of the treatment difference and the 
corresponding 95% confidence intervals will be provided.  Secondary efficacy endpoints will be analyzed 
similarly.  Summaries of 
and 
 results will be provided. 
Safety Analyses 
Safety analyses will consist of data summaries for biological parameters and AEs.  Safety analyses will be 
tabulated by treatment group across the 2 periods.  
Sample Size Calculation 
This is a proof-of-concept (POC) study and as such, no data is available on which to base power 
calculations. Based on prior clinical studies, randomizing approximately 12 patients is a reasonable 
number to assess POC. 


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Figure 1 
Study Schematic 
 


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Table 1 
Schedule of Evaluations and Visits 
 
 
Period 1 
Washout 
Period 
Period 2 
Procedure 
Visit: 
Screening 
Baseline4 
Visit 
23 
Visit 
34 
Visit 
44 
 
Visit 
54 
Visit 
63 
Visit  
74 
Visit 
84/ET5 
Study Day: 
Day  
-28 to -1 
Day  
1 
Day  
8 
Day 
22 
Day  
43 
 
Day 
57 
Day 
64 
Day  
78 
Day 
99 
End of Study 
Week: 
Week  
-4 to -1 
 
Week 
1 
Week 
3 
Week 
6 
 
Week 
8 
Week 
9 
Week 
11 
Week 
14 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Risk assessment for falls (worksheet) 
X 
 
 
 
 
 
 
 
 
 
Review of prior and concomitant medications 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Physical and neurological examination 
X 
 
 
 
X 
 
X 
 
 
X 
Vital signs and weight6 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Hematology, chemistry, and urinalysis 
X7 
 
 
 
X 
 
X 
 
 
X 
Urine pregnancy test8 
X 
X 
 
 
X 
 
X 
 
 
X 
PK blood sample 
 
 
 
 
X 
 
 
 
 
X 
Resting 12-lead ECG  
X9 
X10 
X 
X 
X10 
 
X10 
X 
X 
X10 
Review of adverse events11 
 
X 
X 
X 
X 
 
X 
X 
X 
X11 
 
X 
 
 
 
X2 
 
 
 
 
X2 
 
 
X12 
 
 
X2,12 
 
 
 
 
X2,12 
FBI 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
NPI 
X 
X 
X1 
X1 
X 
 
X 
X1 
X1 
X 
mCGIS 
 
X 
 
 
 
 
X 
 
 
 
mCGIC 
 
 
 
X 
X 
 
 
 
X 
X 
PGIC 
 
 
 
X 
X 
 
 
 
X 
X 
QoL  
 
X 
 
 
X 
 
X 
 
 
X 
QoR 
 
X 
 
 
X 
 
X 
 
 
X 
CNS-LS 
 
X 
 
 
X 
 
X 
 
 
X 
MMSE 
 
X 
 
 
X 
 
X 
 
 
X 


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Period 1 
Washout 
Period 
Period 2 
Procedure 
Visit: 
Screening 
Baseline4 
Visit 
23 
Visit 
34 
Visit 
44 
 
Visit 
54 
Visit 
63 
Visit  
74 
Visit 
84/ET5 
Study Day: 
Day  
-28 to -1 
Day  
1 
Day  
8 
Day 
22 
Day  
43 
 
Day 
57 
Day 
64 
Day  
78 
Day 
99 
End of Study 
Week: 
Week  
-4 to -1 
 
Week 
1 
Week 
3 
Week 
6 
 
Week 
8 
Week 
9 
Week 
11 
Week 
14 
CSDD 
X 
 
 
 
X 
 
X 
 
 
X 
Stroop color and word task 
 
X12 
 
 
X12 
 
X 
 
 
X12 
IRI 
 
X 
 
 
X 
 
X 
 
 
X 
S-STS 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Administer first dose of study medication in clinic 
 
X 
 
 
 
 
X 
 
 
 
Administer last dose of study medication in clinic 
 
 
 
 
X 
 
 
 
 
X 
Dispense study medication and diary card 
 
X 
X 
X 
X13 
 
X 
X 
X 
 
Review and return unused study medication and 
diary card 
 
 
X 
X 
X 
 
X 
X 
X 
X 
CNS-LS = Center for Neurologic Study-Lability Scale; CSDD = Cornell Scale for Depression in Dementia; ECG = electrocardiogram;
 FBI = Frontal Behavioral Inventory; 
; IRI = interpersonal Reactivity Index; mCGIC = Modified Clinical 
Global Impression of Change; mCGIS = Modified Clinical Global Impression of Severity of Illness; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; 
PGIC = Patient Global Impression of Change; PK = pharmacokinetics; QoL = Quality of Life; QoR = Quality of Relationships; S-STS = Sheehan Suicidality Tracking Scale 
1 
Perform NPI Disinhibition domain only 
2 
and 
scan should be completed within 7 days of Visit 4 and within 7 days of Visit 8.    
3 
Visit 2 and Visit 6 have a +3 days window 
4 
All study visits have a +/- 3 days window (except Visit 2 and Visit 6) 
5  
Early Termination visit for patients who withdraw prior to study completion 
6 
Weight should be measured at the baseline visit only 
7 
Thyroid function tests (TSH, and reflex T3 and T4 if TSH is abnormal) should be performed at the Screening Visit 
8 
Urinary beta-hCG test will be performed for females of childbearing potential only 
9 
ECG will be performed in triplicate at Screening 
10  
ECG will be performed pre-dose and post-dose 
11 
A safety follow-up call must be made 30 days after the last clinic visit (on Day 129) to review adverse events 
12 
Stroop color and word task should be performed in conjunction with 
 
13 
Sufficient supply of placebo will be dispensed to all patients (single-blind) for the washout period, for continuity and medication compliance purposes.   
 


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1 
BACKGROUND AND CLINICAL RATIONALE 


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2 
STUDY OBJECTIVES 
The objectives of the study are to evaluate the safety, tolerability, and efficacy of AVP-786 compared to 
placebo, for the treatment of disinhibition in patients with NDD including frontotemporal dementia, 
Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy 
bodies, vascular cognitive disorders, or Huntington’s disease.   


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3 
STUDY DESIGN 
This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, cross-over design study.  
The study duration is approximately 22 weeks and consists of a 4-week screening period, 2 treatment 
periods of 6-week duration each (period 1 and period 2), a 2-week washout period between the treatment 
periods, and a 4-week safety follow-up period following period 2.  
 
Sequence 
Screening 
Period 1 
Washout Period 
Period 2 
Follow-up 
Phone call 
Study Day 
Day -28 to -1 
Day 1 to 43 
Day 44-56 
Day 57 to 99 
Day 129 
 
Approximately 12 patients will be enrolled at 2 centers, with approximately 6 patients at each center. 
Eligible patients will be randomly assigned at the Baseline visit to receive AVP-786 or matching placebo. 
Study medication will be administered orally twice daily from Day 1 through Day 43 during period 1 and 
Day 57 through Day 99 during period 2.  The first and last dose of study medication will be administered 
in the clinic on Day 1 (Baseline visit) and Day 99 (Visit 8), respectively.  Patients (or caregivers) will self-
administer study medication on all other study days.  Screening must occur within 4 weeks prior to 
randomization.  
Period 1 
Following screening procedures for assessment of inclusion and exclusion criteria, eligible patients will 
be randomized into this 2x2 crossover study in a 
ratio to receive either treatment sequence 1 AB 
(period 1: A, period 2: B) or treatment sequence 2 BA (period 1: B, period 2: A), where A is AVP-786 
and B is placebo.  Study medication (active or placebo) will be administered orally BID (1 capsule in the 
morning and 1 capsule in the evening approximately 12 hours apart) throughout the treatment period. 
 
Patient randomized to treatment sequence 1 AB will start with AVP-786-
 once a day in 
the morning and placebo in the evening for the first 7 days of the study.  From Day 8, patients 
will receive AVP-786-
 BID for 14 days. From Day 22, patients will receive 
AVP-786-28/4.9 BID for the remaining 3 weeks of period 1.  
 
Patients randomized to treatment sequence 2 BA will be dosed with placebo BID during 
period 1.  
A 2-week washout period will follow period 1 (Days 44 to 56).  For the washout period, suffient supply of 
placebo will be dispensed in a single-blind manner to patient/caregiver to ensure continuity and study 
medication compliance. 
 
Period 2: 
Patients who complete period 1 and the 2-week wash-out period are eligible to participate in period 2 of 
the study.  In period 2, patients will be assigned to study treatment as follows: 


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 
Patients who received AVP-786 in period 1 (treatment sequence 1 AB) will receive placebo 
BID for the entire 6-week duration of period 2. 
 
Patients who received placebo in period 1 (treatment sequence 2 BA) will start with 
AVP-786-
 once a day in the morning and placebo in the evening for the first 7 days of 
period 2.  From Day 64, patients will receive AVP-786-
 BID for 14 days.  From 
Day 78, patients will receive AVP-786-28/4.9 BID for the remaining 3 weeks of period 2. 
 
Patients who complete period 2 will have a safety follow-up phone call on Day 129, 30 days after the last 
clinic visit. 
All study medication including AVP-786-
, AVP-786-28/4.9, and placebo capsules are of identical 
appearance in order to maintain the integrity of the blind. 
 
 


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4 
STUDY POPULATION 
Patients enrolled in this study must have a diagnosis of a NDD including frontotemporal dementia, 
Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy 
bodies, vascular cognitive disorders, or Huntington’s disease. 
Patients must exhibit disinhibition syndrome of sufficient severity to warrant treatment and to exhibit a 
reduction in severity if the intervention is successful.  The definition of disinhibition syndrome used is 
based on the criteria developed to identify patients with the behavioral variant of frontotemporal 
dementia1 which includes descriptions of disinhibited behavior in three general areas:  socially 
inappropriate behavior, loss of manners and decorum, and impulsive, rash, and careless action, and have 
been shown to have good intra rater reliability.35   
Eligible patients must have a caregiver that is able and willing to comply with all required study 
procedures, ensuring that the patient attends all study visits and takes the study medication as instructed.  
Caregivers will also be instructed to keep a study diary, to report any changes in patient’s status, including 
adverse events, standard of care setting (e.g., becoming a resident in an assisted living facility) and to 
provide their impression and assessment regarding the investigational treatment.  In order to qualify as a 
caregiver for this study, the individual should spend time with the patient at least 2 hours per day on 
4 separate days per week. 
4.1 
Inclusion Criteria 
1. Males and females 50 to 90 years of age, inclusive. 
2. Documented diagnosis of a Neurodegenerative Disorder including frontotemporal dementia, 
Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration 
(CBD), dementia with Lewy bodies (DBL), vascular cognitive disorders, or Huntington’s disease, 
at least 3 months prior to Baseline. 
3. The patient has behavior from 2 of the 3 categories below  of disinhibited behavior from the 
definition of the behavioral variant of frontotemporal dementia 
 
Socially inappropriate behavior:  Examples of behaviors that violate social norms include 
inappropriately approaching, touching or kissing strangers, verbal or physical aggression, 
public nudity or urination, inappropriate sexual acts and criminal behavior (such as theft 
or shoplifting). 
 
Loss of manners or decorum:  Examples include inappropriate laughter, cursing or 
loudness, offensive jokes or opinions, or crude or sexually explicit remarks.  Patients may 
also display a general lack of etiquette (e.g. failing to wait in line, eating with mouth 
open), loss of respect for interpersonal space and a lack of response to social cues (e.g. 
patient will continue talking despite other’s attempts to end a conversation). Some 
patients with FTD exhibit poor hygiene or grooming (e.g. wearing malodorous, stained, 
torn or inappropriate clothing) or impolite physical behaviors (e.g. flatulence, scratching 
or fondling private parts, picking teeth, belching or spitting). 


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 
Impulsive, rash or careless actions:  These include reckless driving, new-onset gambling, 
stealing (usually food or ‘shiny’ objects), buying or selling objects without regard for 
consequences, or indiscriminate sharing of personal information (e.g. credit card 
information, social security number).  
4. 
5. The behavioral changes are not due to a pre-existing major psychiatric disorder (e.g., 
schizophrenia, bipolar disease, etc.) and are not due to the direct effect of systemic illness, drug 
action, or substance use.  
6. A score of ≥ 4 on the 3 core disinhibition questions of the Frontal Behavioral Inventory (FBI) at 
Screening and Baseline. 
7. The patient has stable cardiac, pulmonary, hepatic, and renal function. 
8. 
9. If female of childbearing age, must have been practicing a medically-acceptable method of birth 
control for at least 1 month prior to randomization and continue with the same method during the 
entire study duration (oral contraceptive tablets, hormonal implant device, hormone patch, 
intrauterine device, diaphragm and contraceptive cream or foam, condom with spermicide, or 
abstinence) or be surgically sterile or post-menopausal.  All male patients must follow the same 
methods of birth control with partners of childbearing potential during the entire study duration. 
10.
11.
12.


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13.
14.
15.
16. Availability of a caregiver known to the patient and who is able and willing to comply with study 
procedures, including not administering any prohibited medications during the course of the study 
and ensuring that the patient attends all study visits. 
17. Caregiver must provide a signed informed consent form (ICF) after the nature and risks of study 
participation have been fully explained. 
18. Patients must have at least eight years of education and should have previously (in pre-AD 
condition) been capable of reading, writing, and communicating effectively with others in 
English. 
4.2 Exclusion Criteria 
1. Caregiver is unwilling or unable, in the opinion of the investigator, to comply with study 
instructions. 
2. Patients with symptoms of disinhibition that is not secondary to NDD (e.g., substance use, 
systemic illness, or TBI). 
3. 
4. 
5. 
6. Patients with myasthenia gravis. 
7. 
8. 
9. Patients with co-existent clinically significant or unstable systemic diseases that could confound 
the interpretation of the safety results of the study (e.g., malignancy [except skin basal-cell 
carcinoma or untreated prostate cancer], poorly controlled diabetes, poorly controlled 
hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, 


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dilated cardiomyopathy, or unstable valvular heart disease).  Certain other non-metastatic cancer 
may be allowed. Each case to be evaluated individually with the Medical Monitor (MM). 
10.
11.
12.
13.
14.
15.
16.
17.
18.
4.3 
Patient Withdrawal from the Study  
Patients and caregivers will be advised verbally and in the written ICF that they have the right to 
withdraw from the study at any time without prejudice or loss of benefits to which they are otherwise 
entitled.  The investigator or sponsor may discontinue a patient from the study in the event of an 
intercurrent illness, adverse event, other reasons concerning the health or well-being of the patient, or in 
the case of lack of cooperation, non-compliance, protocol violation, or other administrative reasons.  If a 
patient does not return for a scheduled visit, every effort should be made to contact the patient.  In any 
circumstance, every effort should be made to document patient outcome, if possible.  The investigator 
should inquire about the reason for withdrawal, request the caregiver return all unused investigational 
product (IP), and follow-up with the patient regarding any unresolved adverse events.  
In addition, patients who present a QTc interval (QTcF) >500 msec (unless due to ventricular pacing) or a 
QTc interval change from the screening ECG of >60 msec at any time after randomization, will be 
withdrawn from the study.  The QTc values will be assessed for clinical significance and recorded. 
Patients who withdraw prior to study completion will be asked to return to the clinic to complete the 
Visit 8 (end of study) assessments. 


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If the patient withdraws from the study, and consent is withdrawn by the caregiver and/or patient’s 
representative 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. 


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5 
STUDY TREATMENTS 
5.1 
Treatments Administered 
5.1.1 
Description of Study Medications 
Clinical study medication will be provided as hard,
gelatin capsules 
.  Each 
capsule of the study medication contains 1 of the following: 
 
28 mg of d6-DM and 4.9 mg of Q (USP, EP):  AVP-786-28/4.9 
 
 mg of d6-DM and 
 mg of Q (USP, EP):  AVP-786-
 
 
AVP-786 placebo 
Drug supplies will be provided to the site in double-blind, individual, pre-labeled containers as described 
below. 
 
Day 1 (Baseline): Bundle consisting of one AM bottle with 10 capsules and one PM bottle with 10 
capsules. 
 
Day 8 (Visit 2): Bundle consisting of one AM bottle with 17 capsules and one PM bottle with 17 
capsules. 
 
Day 22 (Visit 3):  Bundle consisting of one AM bottle with 24 capsules and one PM bottle with 24 
capsules.  
Sufficient supply of AVP-786 placebo will be provided to the site to dispense to the patients in a single-
blind manner on Day 43 (Visit 4), for the 2-week washout period.  
All medication used in this study will be prepared, packaged, and labeled in accordance with Good 
Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines, and applicable laws and regulations. 
5.1.2 
Composition of AVP-786 


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Table 2 
Composition of Investigational Product 
Ingredient (amounts in mg) 
AVP-786-28/4.9  
AVP-786-
 
AVP-786 
Placebo 
d6-Dextromethorphan hydrobromide  
28.00 
0 
Quinidine sulfate USP, EP 
4.90 
0 
Croscarmellose sodium NF 
Microcrystalline cellulose NF 
Colloidal silicone dioxide NF 
Magnesium stearate NF 
Total  
(average weight) 
Total 
EP = European Pharmacopoeia; NF = National Formulary; USP = United States Pharmacopoeia 
 
5.1.3 
Packaging 
Clinical study medication (capsules) will be packaged into 50cc HDPE bottles with matching child 
resistant closure/cap.  Bottles will contain 10 capsules, 17 capsules, and or 24 capsules each.  Capsules 
will be configured as provided to the clinical research center in bottles labeled with a code specific to each 
drug product and strength and clearly marked as AM or PM bottles.  Bottles with the same code, one AM 
bottle and one PM bottle, will be bundled together and clearly identified with the specific code, storage 
condition, protocol number and an investigational drug warning.  The unblinded site pharmacist will 
assign individual bundle kit for each patient based on the randomized Medication List.  
5.1.4 
Labeling 
The bottle label will consist of 2 panels, with 1 detachable panel that will be removed and affixed to the 
study medication Dispensing Log page at time of dispensing.  Space will be provided on both panels of 
the label to record Patient Number, the Visit Week, and Dispensing Date.  The bottle label will consist of 
1 panel, containing protocol number, product name, randomized Med ID Code, investigational drug 
warning, dosage instructions, AM or PM, company name and address, and AM or PM clearly marked. All 
investigational product labels comply with all applicable federal and local regulations. 
5.1.5 
Storage of Clinical Supplies 
Clinical supplies must be stored in compliance with label requirements in a secure place and kept at room 
temperature; 25°C (77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F). 


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5.1.6 
Study Medication Administration 
An unmasked site pharmacist will dispense study medication using the randomized Medication List.     
Period 1: At Baseline (Day 1), Visit 2 (Day 8), and Visit 3 (Day 22), study medication will be dispensed 
and administered as follows:  
 
Day 1 (Baseline):  Patients will be dispensed a 1-week medication kit containing one AM 
bottle and one PM bottle.  Each bottle will contain 10 capsules.  Patients will be 
administered 1 capsule from the AM bottle in the morning and 1 capsule from the PM bottle 
in the evening, approximately 12 hours apart for 7 days. 
 
Day 8 (Visit 2):  Patients will be dispensed a 2-week medication kit containing one AM 
bottle and one PM bottle.  Each bottle will contain 17 capsules.  Patients will be 
administered 1 capsule from the AM bottle in the morning and 1 capsule from the PM bottle 
in the evening, approximately 12 hours apart for 14 days. 
 
Day 22 (Visit 3): Patients will be dispensed a 3-week medication kit containing one AM 
bottle and one PM bottle.  Each bottle will contain 24 capsules.  Patients will be 
administered 1 capsule from the AM bottle in the morning and 1 capsule from the PM bottle 
in the evening, approximately 12 hours apart for 21 days. 
Washout period: At Day 43 (Visit 4), study medication will be dispensed as follow: 
 
Patients will be dispensed a 2-week medication kit containing one AM bottle and one PM 
bottle.  Each bottle will contain 17 capsules.  Patients will be administered 1 capsule from 
the AM bottle in the morning and 1 capsule from the PM bottle in the evening, 
approximately 12 hours apart for 14 days. 
Period 2:  At Day 57 (Visit 5), Day 64 (Visit 6), and Day 78 (Visit 7), study medication will be dispensed 
and administered as follows:  
 
Day 57 (Visit 5):  Patients will be dispensed a 1-week medication kit containing one AM 
bottle and one PM bottle.  Each bottle will contain 10 capsules.  Patients will be 
administered 1 capsule from the AM bottle in the morning and 1 capsule from the PM bottle 
in the evening, approximately 12 hours apart for 7 days. 
 
Day 64 (Visit 6): Patients will be dispensed a 2-week medication kit containing one AM 
bottle and one PM bottle.  Each bottle will contain 17 capsules.  Patients will be 
administered 1 capsule from the AM bottle in the morning and 1 capsule from the PM bottle 
in the evening, approximately 12 hours apart for 14 days. 
 
Day 78 (Visit 7): Patients will be dispensed a 3-week medication kit containing one AM 
bottle and one PM bottle.  Each bottle will contain 24 capsules.  Patients will be 
administered 1 capsule from the AM bottle in the morning and 1 capsule from the PM bottle 
in the evening, approximately 12 hours apart for 21 days. 
All study medication will be supplied and administered in a double-blind manner throughout the entire 
duration of the study. 


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5.2 
Accountability of Study Supplies 
5.2.1 
Receipt of Supplies 
The investigator is responsible for maintaining an inventory of each shipment of study medication 
received and comparing it with the accompanying Drug Accountability Report/Material Shipping Form.  
The investigator will verify the accuracy of the information on the form, sign and date it, and return the 
form to the sponsor or its representative.  All study medication supplied is for use only in this study and 
should not be used for any other purpose.  All randomized Med ID numbers will also be recorded and 
tracked at the site using the Drug Accountability Log. 
5.2.2 
Record of Dispensing 
Accurate recording of all study medication dispensing for individual patients will be made in the 
appropriate section of the patient’s eCRF.  This eCRF will contain the following information: (i) the 
initials and patient number to whom the drug was dispensed; (ii) the date(s) and quantity of the drug 
dispensed to the patient.  
Additionally, the detachable panel of the two-panel label on each blister card will be removed and affixed 
to the study medication Subject Drug Dispensing Log page at the time of dispensing.  Space is provided 
on both panels of the blister card label to record patient number, the visit week and dispensing date.   
5.2.3 
Unused Supplies 
At the end of the study, all unused study medication must be inventoried on the Drug Accountability Log 
and returned to the sponsor or its representative, along with a completed and signed Drug Accountability 
Report/Material Shipping Form.  If any study medication is lost or damaged, it should be indicated on the 
form.  
5.3 
Methods of Assigning Patients to Treatment Groups 
5.3.1 
Randomization 
For this 2x2 cross over study, patients will be randomized in a 
 ratio within investigation site into 
2 treatment sequence: AB or BA, where A = AVP-786 and B = Placebo.  
 
  
 
  
  
 
Eligible patients will be randomized at the Baseline visit to receive either treatment sequence AB or BA in 
a double-blind manner according to a randomization scheme devised by Avanir or its representative. 


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5.3.2 
Blinding/Masking 
Blinding will be maintained by providing capsules of the 2 doses of AVP-786 and placebo that are 
identical in appearance.  The sponsor, patients, caregivers, investigator, or other study personnel will not 
be aware of a patient’s treatment assignment.  In the event that it becomes medically necessary to identify 
which treatment a patient has received, the blind can be broken.  In that event, the investigator is to 
contact Avanir’s medical monitor or representative to request the unblinding of a patient.   
5.4 
Patient Compliance 
Patients and caregivers will be instructed to bring any unused study medication and empty containers to 
the clinic on Days 8, 22, 43, 57, 64, 78, and 99 (Visits 2 to 8).  For this study, compliance will be defined 
as when a patient takes at least 80% of their scheduled doses. Caregivers will be provided with diary cards 
and will be instructed to record daily the number of capsules taken and the time of administration.  Diary 
cards will be collected on Days 8, 22, 43, 57, 64, 78, and 99 (Visits 2 to 8), or at the time of early study 
discontinuation.  


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6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Efficacy 
Samples of all the scales and questionnaires to be used during the study are attached as Appendices. 
6.1.1 
Neuropsychiatric Inventory (NPI) 
The NPI 
 is a validated clinical instrument for evaluating psychopathology in a variety of 
disease settings, including dementia.29  The NPI is a retrospective caregiver-informant interview covering 
12 neuropsychiatric 
symptom 
domains; 
delusions, 
hallucinations, 
agitation/aggression, 
depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, 
aberrant motor behaviors, sleep and nighttime behavioral disturbances, and appetite/eating disorders.  The 
scripted NPI interview includes a compound screening question for each symptom domain, followed by a 
list of interrogatives about domain-specific behaviors that is administered when a positive response to a 
screening question is elicited.  Neuropsychiatric manifestations within a domain are collectively rated by 
the caregiver in terms of both frequency (0 to 4) and severity (1 to 3), yielding a composite symptom 
domain score (frequency x severity).  Frequency and severity rating scales have defined anchor points to 
enhance the reliability of caregiver responses.  Caregiver distress is rated for each positive 
neuropsychiatric symptom domain on a scale anchored by scores of 0 (not distressing at all) to 
5 (extremely distressing).   
The NPI will be administered to the patient’s caregiver at Screening (Day -28 to -1), Day 1 (Baseline), 
Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 (Visit 8). 
The Disinhibition domain only of the NPI will be administered to the patient’s caregiver at Day 8 
(Visit 2), Day 22 (Visit 3), Day 64 (Visit 6), and Day 78 (Visit 7). 
The NPI domains are evaluated for behaviors within the past 4 weeks.  However, it also depends on the 
visit intervals from Baseline.  The longest or maximum interval is within the past 4 weeks, as the NPI was 
validated based on this interval.  Therefore, for Visits 2 and 6 the evaluation will be within the past 
1 week, for Visit 5 the evaluation will be within the past 2 weeks, for Visits 3 and 7 will be within the past 
3 weeks and for Visits 4 and 8 will be within the past 4 weeks. 
6.1.2 
Frontal Behavioral Inventory (FBI) 
The FBI is a 24-item questionnaire that is often used to assess frontal lobe dementia 
.30  It 
includes questions on inappropriateness, excessive jocularity, and poor judgment and impulsivity.  Each 
item is measured on a 4-point scale (rated as 0 = none, 1 = mild, occasional, 2 = moderate, 3 = severe, 
most of the time) and is dependent on the caregiver’s response.  
When interview of the potential study patient confirms that the individual has disinhibited behavior, then 
the disinhibition will be scored by using the 3 core disinhibition questions of the FBI (Questions 15, 16 
and 17).  These generally parallel the behavioral variant of frontotemporal dementia (BvFTD) criteria and 


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include questions on inappropriateness, excessive jocularity, and poor judgment and impulsivity.1  Each 
question is scored 0-3 and a minimum score of 4 (out of 9 possible) is required for study entry. 
The FBI will be administered to the patient’s caregiver at all clinic visits; Screening (day -28 to -1), Day 1 
(Baseline), Day 8 (Visit 2), Day 22 (Visit 3), Day 43 (Visit 4), Day 57 (Visit 5), Day 64 (Visit 6), Day 78 
(Visit 7), and Day 99 (Visit 8). 
6.1.3 
Modified Clinical Global Impression of Severity of Illness 
(mCGIS) 
The CGIS is an observer-rated scale that measures illness severity and is one of the most widely used 
brief assessment tools in psychiatry research.   
The Early Clinical Drug Evaluation Program (ECDEU) version of the CGIS is the most widely used 
format of this validated tool, and asks that the clinician rate the patient relative to their past experience 
with other patients with the same diagnosis, with or without collateral information.  The CGIS has proved 
to be a robust measure of efficacy in many clinical drug trials36–40 and is easy and quick to administer, 
provided that the clinician knows the patient well.41  
Reliability and validity of CGI have been tested in multiple studies, including patients with dementia, 
schizophrenia and affective disorders.  Overall, CGI showed high correlation (r: ~90%) with other 
assessment instruments and it has also shown positive significant relationships and concurrent validity 
with other clinician’s rating.  In addition, the scale has good sensitivity to change over time.42–44 
The CGIS is a 7-point (1-7) scale (1 = normal, not at all ill; 7 = among the most extremely ill patients) and 
is assessed for overall clinical status.  The CGIS used in this protocol is modified to also assess severity of 
disinhibition on a 7-point scale (1 = normal, not at all disinhibited; 7 = among the most extremely 
disinhibited patients) (mCGIS, 
).  The mCGIS will be assessed at Day 1 (Baseline) and  Day 
57 (Visit 5). 
6.1.4 
Modified Clinical Global Impression of Change Rating (mCGIC) 
The CGIC is a 7-point scale that requires the clinician to rate the change of the patient’s condition at the 
time of assessment, relative to the clinician’s past experience with the patient’s condition at admission.  
The CGIC used in this protocol is modified to also assess severity of disinhibition on a 7-point scale  
(mCGIC, 
). Considering total clinical experience, a patient is assessed for change of 
disinhibition symptoms and overall clinical status as 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 mCGIC will be administered at Day 22 (Visit 3), Day 43 (Visit 4), Day 78 (Visit 7), and Day 99 
(Visit 8).  At Day 22 (Visit 3) and Day 43 (Visit 4), the mCGIC will be completed to assess change from 
the Baseline visit (Day 1).  At Day 78 (Visit 7) and Day 99 (Visit 8), the mCGIC will be completed to 
assess change from Day 57 (Visit 5).   


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6.1.5 
Patient Global Impression of Change (PGIC) 
The PGIC 
 is a 7-point (1-7) scale used to assess treatment response, and it is rated as: 
1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally 
worse; 6 = Much worse; or 7 = Very much worse.41 
The PGIC will be administered at Day 22 (Visit 3), Day 43 (Visit 4), Day 78 (Visit 7), and Day 99 
(Visit 8) and will focus on the patient’s disinhibition symptoms.   
6.1.6 
Quality of Life (QoL) 
The QoL scale 
 is a 10-cm visual analog scale used to assess quality of life.  Visual analog 
scales have been widely used in pain assessment45 and their psychometric properties have been 
established.  This scale has been used previously in patients with PBA treated with AVP-923.46   
The QoL scale will be used to assess the impact of disinhibition on the global subjective well-being of the 
patient.  It will be administered at Day 1 (Baseline), Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 
(Visit 8). 
6.1.7 
Quality of Relationships (QoR) 
The QoR scale 
 is a 10-cm visual analog scale used to assess quality of relationships of the 
patient. Like the QoL, the QoR scale has been used previously in patients with PBA treated with 
AVP-923.46  
The QoR will be used to assess the impact of disinhibition on the relationships of the patient.  It will be 
administered at Day 1 (Baseline), Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 (Visit 8). 
6.1.8 
Interpersonal Reactivity Index (IRI) 
The IRI 
 is a 28-item questionnaire that measures empathy defined as reactions of one 
individual to the observed experiences of another.47  It consists of 4 subscales; perspective taking, fantasy, 
empathic concern and personal distress.  Each subscale is made up of 7 different items that are answered 
on a 5-point Likert scale ranging from ‘does not describe me well’ to ‘describes me very well’.   
The IRI will be administered at Day 1 (Baseline), Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 (Visit 8). 
6.1.9 
Center for Neurologic Study-Lability Scale (CNS-LS) 
The CNS-LS 
 is a 7-item questionnaire designed to be completed by the patient or patient’s 
caregiver that provides a quantitative measure of the perceived frequency of pseudobulbar affect (PBA) 
episodes.  It is composed of 2 subscales measuring labile laughter (4 items) and labile crying (3 items).  
The CNS-LS requires approximately 5 minutes to be completed.   
The CNS-LS will be administered at Day 1 (Baseline), Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 
(Visit 8). 


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6.1.10 
Mini-Mental State Examination (MMSE) 
The MMSE 
 is a brief 30-point questionnaire test that is used to screen for cognitive 
impairment.  It is commonly used in medicine to screen for dementia.  It is also used to estimate the 
severity of cognitive impairment at a specific time and to follow the course of cognitive changes in an 
individual over time, thus making it an effective way to document an individual’s response to treatment.  
The MMSE scale comprises 11 questions or simple tasks concerning orientation, memory, attention, and 
language to evaluate the patient’s cognitive state.48  It requires only 5 to 10 minutes for a trained rater to 
administer it. 
The MMSE will be administered at Day 1 (Baseline), Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 
(Visit 8). 
6.1.11 
Cornell Scale for Depression in Dementia (CSDD) 
The CSDD 
 was specifically developed to assess signs and symptoms of major depression 
in patients with dementia.49  Because some of these patients may give unreliable reports, the CSDD uses a 
comprehensive interviewing approach that derives information from the patient and the caregiver.  
Information is elicited through two semi-structured interviews; an interview with a caregiver and an 
interview with the patient.  The interviews focus on depressive symptoms and signs occurring during the 
week preceding the assessment.  The CSDD takes approximately 20 minutes to administer.  
Each item is rated for severity on a scale of 0-2 (0 = absent, 1 = mild or intermittent, 2 = severe).  The 
item scores are added.  Scores above 10 indicate a probable major depression, scores above 18 indicate a 
definite major depression, and scores below 6 as a rule are associated with absence of significant 
depressive symptoms. 
The CSDD will be administered at Screening (Day -28 to Day -1), Day 43 (Visit 4), Day 57 (Visit 5), and 
Day 99 (Visit 8). 
6.1.12 
Stroop Color and Word Task with 
 
 
 
The Stroop color and word task is a standard measure that is useful for measuring cognitive flexibility and 
processing speed.  A sample of the Stroop task to be performed in this study is provided in 
.  
 
  
 
  In this task, subjects are asked to identify the color in which words 
are written.  The color can be the same as the word (so-called congruent trial) or the color of the word can 
be different (so-called incongruent trial).  If the color and the word do not match (i.e. for incongruent 
trials, for example the word “blue” shown in red color), cognitive interference occurs which involves 
activation of a functional network in the prefrontal cortex50. 
The Stroop task probes semantic interference, which means that naming the ink color of incongruent 
stimuli is slower than for neutral or congruent stimuli.  On the other hand semantic facilitation explains 
the finding that naming the ink of congruent stimuli is faster (e.g. when the ink color and the word match). 


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Both semantic interference and facilitation disappear when the task consists of reading the word instead of 
naming the color.  This fact has been sometimes called Stroop asynchrony, and has been explained by a 
reduced automatization when naming colors compared to reading words. 
For patients with compromised executive functioning, the Stroop color interference task is an important 
tool to map the functioning of the prefrontal cortex.  
 
  
 
  
 
 
 
The Stroop task with the 
 will be performed at Day 1 (Baseline), Day 43 (Visit 4), and Day 99 
(Visit 8).  The Stroop task alone (without 
) will be performed at Day 57 (Visit 5).   
 
  In addition, the 3 summary scores of the Stroop (based 
on the number of items completed on each of the three stimulus conditions) and the Stroop interference 
score will be used to assess the patient’s cognitive flexibility and reaction to cognitive stress at baseline 
and compare performance between the placebo and active drug stages of the study.  
6.2 
Pharmacokinetics (PK) 
At Visit 4 (Day 43) and Visit 8 (Day 99), patients will have a blood sample collected between 0 to 3 hours 
after the morning dose of study medication for analysis of plasma levels of d6-DM, d6-DM metabolites 
and Q.  The time when the patient was administered the dose of study medication and the time of the 
blood draw will be recorded on the eCRF.  Plasma samples will be separated by centrifugation and then 
frozen at -20° C until assayed at the analytical unit.  


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6.3 
Safety 
6.3.1 
Adverse Events 
6.3.1.1 
Definitions 
An AE is any untoward medical occurrence or unintended change (including physical, psychological, or 
behavioral) from the time ICF is signed, including inter-current illness, which occurs during the course of 
a clinical trial after treatment has started, whether considered related to treatment or not.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  Changes associated with normal growth and development 
that do not vary in frequency or magnitude from that ordinarily anticipated clinically are not AEs (e.g., 
onset of menstruation occurring at a physiologically appropriate time). 
Clinical AEs should be described by diagnosis and not by symptoms when possible (e.g., cold, seasonal 
allergies, instead of “runny nose”). 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than specified in 
the protocol and higher than known therapeutic doses.  It must be reported irrespective of outcome even if 
toxic effects were not observed. 
AEs will be graded on a 3-point scale and reported in detail as indicated on the eCRF: 
 
Mild:  
easily tolerated, causing minimal discomfort and not interfering with  
normal everyday activities 
 
Moderate:  
sufficiently discomforting to interfere with normal everyday activities 
 
Severe:  
incapacitating and/or preventing normal everyday activities 
The relationship of each AE to study medication should be determined by the investigator using the 
following explanations: 
 
Not related:  
the event is clearly related to other factors such as the patient’s clinical state, 
therapeutic interventions, or concomitant medications administered to the patient 
 
Unlikely related:  
the event is most likely produced by other factors such as the patient’s clinical 
state, therapeutic interventions, or concomitant medications administered to the 
patient; and does not follow a known response pattern to the study medication 
 
Possibly related:  
the event follows a reasonable temporal sequence from the time of drug 
administration; and/or follows a known response pattern to the study medication; 
but could have been produced by other factors such as the patient’s clinical state, 
therapeutic interventions, or concomitant medications administered to the patient 
 
Related:  
the event follows a reasonable temporal sequence from the time of drug 
administration; and follows a known response pattern to the study medication; 
and cannot be reasonably explained by other factors such as the patient’s clinical 


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state, therapeutic interventions, or concomitant medications administered to the 
patient 
6.3.1.2 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any AE occurring at any dose that results in any of the following 
outcomes: 
1. Death 
2. Life-threatening experience (one that places the patient, in the view of the initial reporter, at 
immediate risk of death from the AE as it occurred, i.e., it does not include an AE that, had it 
occurred in a more severe form, might have caused death) 
3. Persistent or significant disability/incapacity (disability is a substantial disruption of a person’s 
ability to conduct normal life functions) 
4. In-patient hospitalization or prolongation of hospitalization 
5. Congenital anomaly/birth defect 
Important medical events that may not result in death, or be life-threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the 
patient or require medical or surgical intervention to prevent one of the outcomes listed in the definition. 
The terms “cancer” and “overdose” are not considered to be SAEs, but if a patient experiences cancer or 
overdose, they are still reportable as AEs. 
Pregnancy is not considered to be an AE or an SAE, unless a complication occurs that meets the 
requirements for an AE or SAE, but must be reported on a pregnancy report form.  Women who are 
pregnant or likely to become pregnant are excluded from this study.  In the event a patient becomes 
pregnant during the study, study medication must be discontinued, a pregnancy report form must be 
completed to capture potential drug exposure during pregnancy, and the pregnancy must be reported 
within 24 hours of notice.  Any pregnant patient must be followed until the outcome of her pregnancy is 
known (i.e., normal delivery, abnormal delivery, spontaneous/voluntary/therapeutic abortion).  The 
pregnancy (i.e., the mother and the fetus) must be followed up through delivery with regard to outcome.  
A pregnancy report form must also be completed in the event that a female partner of a male patient 
becomes pregnant within 30 days after his last dose of study medication or study completion, whichever is 
greater.  
The term ‘severe’ is a measure of intensity; thus a severe AE is not necessarily serious.  For example, 
nausea of several hours duration may be rated as severe, but may not be clinically serious. 


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6.3.1.3 
Reporting 
Caregivers will be queried regarding AEs at each visit after the Screening visit (Day 1 [Baseline], Days 8, 
22, 43, 57, 64, 78, and 99 [Visits 2-8]).  A phone call will be made on Day 129 (± 3-days) to review any 
newly reported AE after receiving and up to 30 days after the last dose of study medication.   
A death occurring during the study, or which comes to the attention of the investigator within 30 days 
after stopping the treatment whether considered treatment-related or not, must be reported to the sponsor. 
For all SAEs, including an abnormal laboratory test value, the investigator must inform Avanir’s MM by 
telephone no later than 24 hours after becoming aware of the event.  Subsequently, the SAE must be 
assessed for the following details: seriousness of event, start date, stop date, intensity, frequency, 
relationship to test drug, action taken regarding test drug, treatment required, and outcome to date.  These 
details must be recorded on the clinical study AE form that is provided.  This form should be transmitted 
by fax and the details given by telephone to the contact numbers below. 
SAE reporting by FAX or e-mail correspondence  
FAX:  
 
E-mail: 
 
SAE hotline (24-hour/7 days a week) 
Phone: 
 
Such preliminary reports will be followed by detailed descriptions later, which may include copies of 
hospital case reports, autopsy reports, and other related documents when requested. 
The Institutional Review Board (IRB) will be notified of such an event in writing as soon as is practical in 
compliance with federal and local regulations. 
6.3.1.4 
Procedures to be Followed in the Event of Abnormal Test Values 
Any patients with clinically significant abnormal laboratory test results may be required by the MM to 
have a repeat test 1 week later or earlier, if medically indicated.  Clinically significant laboratory 
abnormalities may be a basis for exclusion from study entry. 
6.3.2 
Physical and Neurological Examinations 
Physical and neurological examinations will be performed at Screening (Day -28 to Day -1), Day 43 
(Visit 4), Day 57 (Visit 5), and Day 99 (Visit 8), and include assessments of head, eyes, ears, nose, throat, 
lymph nodes, skin, extremities, respiratory, gastrointestinal, musculoskeletal, cardiovascular, and nervous 
systems.   
The physical and neurological examinations should be performed by the same person each time, whenever 
possible.  Physical and neurological examination abnormalities determined by the investigator to be 
clinically significant at Screening should be recorded as medical history. Any clinically significant 
changes in physical and neurological examination findings from the screening examination should be 
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6.3.3 
Vital Signs 
Vital signs, systolic and diastolic blood pressure (BP; mm Hg), heart rate (beats/minute), respiratory rate 
(breaths/minute) and body temperature (ºF) should be recorded at all clinic visits.  
6.3.4 
Clinical Laboratory Tests 
The following clinical laboratory assessments are to be performed at Screening (Day -28 to Day -1), 
Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 (Visit 8): 
 
Blood chemistry (calcium, magnesium, phosphorus, glucose, sodium, potassium, chloride, 
carbon dioxide, blood urea nitrogen [BUN], serum creatinine, uric acid, albumin, total 
bilirubin, 
alkaline 
phosphatase, 
lactate 
dehydrogenase 
[LDH], 
aspartate 
aminotransferase/serum 
glutamic 
oxaloacetic 
transaminase 
[AST/SGOT], 
alanine 
aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT], creatine kinase [CK], 
gamma-glutamyl transferase [GGT], triglycerides, total protein, and total cholesterol) 
 
Hematology (red blood cell [RBC] count, hemoglobin, hematocrit, white blood cell [WBC] 
count, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, platelet count, and 
morphology) 
 
Urinalysis (pH, specific gravity, protein, glucose, ketones, blood, leucocyte esterase, nitrates, 
and microscopic appearance) 
 
Thyroid function tests (TSH, and reflex T3 and T4 if TSH is abnormal) at Screening visit only 
Any patients with clinically significant abnormal laboratory test results may be required by the MM to 
have a repeat test 1 week later or earlier, if medically indicated.  Clinically significant laboratory 
abnormalities may be a basis for exclusion from study entry. 
6.3.5 
Pregnancy Test 
A urine pregnancy test will be performed on females of childbearing potential at Screening (Day -28 to 
Day -1), Baseline (Day 1), Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 (Visit 8). 
All female patients of childbearing potential should be instructed to use appropriate birth control methods 
until 4 weeks following the last dose of study medication.  
6.3.6 
Electrocardiograms 
A resting 12-lead ECG will be performed at all clinic visits.  At Screening (day 28 to -1), ECG will be 
performed in triplicate.  At Day 1 (Baseline), Day 43 (Visit 4), Day 57 (Visit 5), and Day 99 (Visit 8), two 
ECGs will be performed; one prior to study medication dosing and one 2-3 hours after dosing.   
ECG data will be recorded at the study center and will include general findings, heart rate (beats/minute) 
the Q-R-S complex from an ECG tracing (QRS) and the P-R interval from an ECG tracing (PR) and QTc 
intervals (milliseconds).  ECG abnormalities present at Screening will be recorded as medical history. 
Any changes from the ECG status at screening that are deemed to be clinically significant by the 


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investigator will be captured as AEs.  Any clinically significant abnormal ECG should be discussed with 
the MM and, if necessary be repeated within a 1-week period. 
6.3.7 
Sheehan Suicidality Tracking Scale (S-STS)  
The S-STS 
 is a prospective scale that assesses treatment-emergent suicidal thoughts and 
behaviors.56  Each item of the S-STS is scored on a 5-point Likert scale (0 = not at all; 1 = a little; 
2 = moderately; 3 = very; and 4 = extremely). The S-STS can be analyzed as individual item scores, 
suicidal ideation subscale score, suicidal behavior subscale score, or total score.  For the screening visit, 
the timeframe for the items on the scale will be ‘in the past 6 months’ and for all other visits it will be 
‘since last visit’.   
The S-STS will be assessed at. Screening (Day -28 to -1), Day 1 (Baseline), Day 8 (visit 2), Day 22 (Visit 
3), Day 43 (Visit 4), Day 57 (Visit 5), Day 64 (Visit 6), Day 78 (Visit 7), and Day 99 (Visit 8).  Any 
change in the S-STS score indicating the presence of suicidality should be evaluated by the investigator 
and reported to the MM. 
6.4 
Schedule of Evaluations and Procedures 
A schedule of evaluations and procedures is provided in Table 1. 
6.4.1 
Description of Study Procedures 
6.4.1.1 
Screening Visit (Days -28 to -1) 
The following procedures will be performed at Screening (within 28 days prior to Day 1). 
1. The investigator will provide the patients, authorized representative and/or their caregivers with 
informed consent and/or assent documents and will explain the rationale for the study, providing 
ample time for participants, authorized representatives, and/or caregivers to ask questions. 
2. Medical history, including patient demographics, and any prior and concomitant medications use 
(including OTC medications, vitamins, and supplements) will be reviewed and recorded. 
3. Review inclusion/exclusion criteria. 
4. Physical and neurological examination findings and vital signs measurements (including BP, heart 
rate, respiratory rate, and body temperature) will be recorded.  
5. Risk assessment for falls will be performed. 
6. A blood and urine specimen will be collected for safety laboratory assessments.  
7. A urine pregnancy test will be performed for females of childbearing potential only. 
8. Resting 12-lead ECG will be performed in triplicate. 
9. 


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10. The following tests will be completed: 
 
NPI 
 
FBI 
 
CSDD 
 
S-STS  
Following screening procedures for assessment of inclusion and exclusion criteria, the site will complete a 
protocol eligibility form and submit to the MM for approval.  Patients deemed eligible by the PI and the 
MM will be randomized into the study.  Patients who have ECG or laboratory test results outside of the 
reference normal range that the investigator considers to be clinically significant, and may put the patient 
at a higher risk with study participation, will not be enrolled. 
6.4.1.2 
Baseline Visit (Day 1) 
The Baseline visit should occur in the morning.  The following procedures will be performed at the 
Baseline Visit (Day 1): 
Before dosing: 
1. Inclusion/exclusion criteria will be reviewed. 
2. Vital signs and weight will be measured and recorded.  
3. Caregivers will be queried regarding patient’s AEs and concomitant medication use (including OTC, 
vitamins, and supplements). 
4. A urine pregnancy test will be performed for females of childbearing potential only. 
5. The following tests will be completed: 
 
NPI 
 
FBI 
 
CGIS 
 
QoL 
 
QoR 
 
CNS-LS 
 
MMSE 
 
Stroop color and word task with 
 
 
IRI 
 
S-STS 


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6. A resting 12-lead ECG will be performed (twice this visit - pre and post dose). 
Patients will be randomized once it is determined that they satisfy all of the inclusion and exclusion 
criteria (on the basis of the screening and baseline assessments described above) and will be assigned with 
a study medication kit number.  
Study Medication Dosing: 
The first dose of study medication will be administered from the AM-label bottle at the clinic regardless 
of the time of day.   
After Dosing: 
7. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication. 
8. The caregiver will be queried regarding AEs. 
9. Patient’s diary card and sufficient study medication will be dispensed for a 1-week treatment period. 
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient 1 capsule of study medication from the 10-count, 
AM-label bottle in the morning and 1 capsule of study medication from the 10-count, PM-label bottle in 
the evening, approximately every 12 hours ± 4 hours, for 7 days.  
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures.  They will also be instructed to consult with the study site prior to the patient 
taking any non-study medications.  These requirements will be reviewed in person, and written 
instructions will be provided to the patient and their caregiver.  Caregivers will also be instructed to bring 
to the clinic any unused study medication at each study visit.  Caregivers will be queried at the end of 
each visit to be certain they understand what is required of them. 
6.4.1.3 
Visit 2 (Day 8 + 3-day window) 
Caregiver is advised to administer to the patient the morning dose of study medication within 2 hours 
prior to the clinic appointment. 
The following procedures will be performed:  
1. Vital signs will be measured and recorded. 
2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication.  
3. The following tests will be completed: 
 
NPI –Disinhibition domain only 
 
FBI 


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 
S-STS 
4. The caregiver will be queried regarding patient’s AEs and concomitant medication use (including 
OTC medications, vitamins, and supplements). 
5. Patient’s diary card will be collected and reviewed for compliance. 
6. Returned, unused study medication will be accounted for compliance. 
7. Patient diary card and sufficient study medication for a 2-week treatment period will be dispensed. 
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule from 
the 17-count, AM-label bottle in the morning and 1 capsule from the 17-count, PM-label bottle in the 
evening, approximately every 12 hours ± 4 hours) for 14 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures including how to complete the Patient’s diary card.  They will also be 
instructed to consult with the study site prior to the patient taking any non-study medications. These 
requirements will be reviewed in person, and written instructions will be provided to the patient and their 
caregiver.  Caregivers will also be instructed to bring to the clinic any unused study medication at each 
study visit.  Caregivers will be queried at the end of each visit to be certain that they understand what is 
required of them. 
6.4.1.4 
Visit 3 (Day 22 ± 3-day window) 
Caregiver is advised to administer to the patient the morning dose of study medication within 2 hours 
prior to the clinic appointment. 
The following procedures will be performed:  
1. Vital signs will be measured and recorded. 
2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication.  
3. The following tests will be completed: 
 
NPI –Disinhibition domain only 
 
CGIC 
 
PGIC 
 
FBI 
 
S-STS 
4. The caregiver will be queried regarding patient’s AEs and concomitant medication use (including 
OTC medications, vitamins, and supplements). 


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5. Patient’s diary card will be collected and reviewed for compliance. 
6. Returned, unused study medication will be accounted for compliance. 
7. Patient diary card and sufficient study medication for a 3-week treatment period will be dispensed.  
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule from 
the 24-count, AM-label bottle in the morning and 1 capsule from the 24-count, PM-label bottle in the 
evening, approximately every 12 hours ± 4 hours) for 21 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures.  They will also be instructed to consult with the study site prior to the patient 
taking any non-study medications.  These requirements will be reviewed in person, and written 
instructions will be provided to the patient and their caregiver.  Caregivers will also be instructed to bring 
to the clinic any unused study medication at each study visit.  Caregivers will be queried at the end of 
each visit to be certain that they understand what is required of them. 
6.4.1.5 
Visit 4 (Day 43 ± 3-day window) 
Visit 4 (Day 43) should occur in the morning.  The last dose of study medication will be administered at 
the clinic after the required procedures are performed. 
The following procedures will be performed:  
1. Physical and neurological examination findings and vital signs measurements (including BP, heart 
rate, respiratory rate, and body temperature) will be recorded.  
2. The caregiver will be queried regarding patient’s AEs and concomitant medication use (including 
OTC, vitamins, and supplements). 
3. A blood specimen will be collected within 3 hours after the morning dose of study medication for PK 
analysis and for safety laboratory assessments 
4. A urine sample will be collected for urinalysis. 
5. A urine pregnancy test will be performed for females of childbearing potential only. 
6. A resting 12-lead ECG will be performed (twice this visit - pre and post dose).  
7. 
 
8. The following tests will be completed: 
 
NPI 
 
FBI 
 
CGIC 


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 
PGIC 
 
QoL 
 
QoR 
 
CNS-LS 
 
MMSE 
 
CSDD 
 
Stroop color and word task with 
 
 
IRI 
 
S-STS 
9. The patient’s diary card will be collected and reviewed for compliance. 
10. Returned, unused study medication will be accounted for compliance. 
11. Patient diary card and sufficient study medication for a 2-week treatment period will be dispensed. 
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule from 
the 17-count, AM-label bottle in the morning and 1 capsule from the 17-count, PM-label bottle in the 
evening, approximately every 12 hours ± 4 hours) for 14 days.  Caregivers will also be instructed to bring 
to the clinic any unused study medication.  Caregivers will be queried at the end of each visit to be certain 
that they understand what is required of them. 
6.4.1.6 
Visit 5 (Day 57 ± 3-day window) 
Visit 5 (day 57) should occur in the morning.  The following procedures will be performed: 
Before Dosing: 
1. Physical and neurological examination findings and vital signs measurements (including BP, heart 
rate, respiratory rate, and body temperature) will be recorded.   
2. Caregivers will be queried regarding patient’s AEs and concomitant medication use (including OTC, 
vitamins, and supplements). 
3. A blood and urine specimen will be collected for safety laboratory assessments.  
4. A urine pregnancy test will be performed for females of childbearing potential only. 
5. The following tests will be completed: 
 
NPI 
 
FBI 


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 
CGIS 
 
QoL 
 
QoR 
 
CNS-LS 
 
MMSE 
 
CSDD 
 
Stroop color and word task 
 
IRI 
 
S-STS 
6. A resting 12-lead ECG will be performed (twice this visit - pre and post dose). 
Study Medication Dosing: 
The first dose of study medication will be administered from the AM-label bottle at the clinic regardless 
of the time of day.   
After Dosing: 
7. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication. 
8. The caregiver will be queried regarding AEs. 
9. Returned, unused study medication will be accounted for compliance. 
10. Patient’s diary card and sufficient study medication will be dispensed for a 1-week treatment period. 
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient 1 capsule of study medication from the 10-count 
AM-label bottle in the morning and 1 capsule of study medication from the 10-count, PM-label bottle in 
the evening, approximately every 12 hours ± 4 hours, for 7 days.  
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures.  They will also be instructed to consult with the study site prior to the patient 
taking any non-study medications.  These requirements will be reviewed in person, and written 
instructions will be provided to the patient and their caregiver.  Caregivers will also be instructed to bring 
to the clinic any unused study medication at each study visit.  Caregivers will be queried at the end of 
each visit to be certain they understand what is required of them. 


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6.4.1.7 
Visit 6 (Day 64 + 3-day window) 
Caregiver is advised to administer to the patient the morning dose of study medication within 2 hours 
prior to the clinic appointment. 
The following procedures will be performed:  
1. Vital signs will be measured and recorded. 
2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication.  
3. The following tests will be completed: 
 
NPI –Disinhibition domain only 
 
FBI 
 
S-STS 
4. The caregiver will be queried regarding patient’s AEs and concomitant medication use (including 
OTC medications, vitamins, and supplements). 
5. Patient’s diary card will be collected and reviewed for compliance. 
6. Returned, unused study medication will be accounted for compliance. 
7. Patient diary card and sufficient study medication for a 2-week treatment period will be dispensed.  
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule from 
the 17-count, AM-label bottle in the morning and 1 capsule from the 17-count, PM-label bottle in the 
evening, approximately every 12 hours ± 4 hours) for 14 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures.  They will also be instructed to consult with the study site prior to the patient 
taking any non-study medications.  These requirements will be reviewed in person, and written 
instructions will be provided to the patient and their caregiver.  Caregivers will also be instructed to bring 
to the clinic any unused study medication at each study visit.  Caregivers will be queried at the end of 
each visit to be certain that they understand what is required of them. 
6.4.1.8 
Visit 7 (Day 78 ± 3-day window 
Caregiver is advised to administer to the patient the morning dose of study medication within 2 hours 
prior to the clinic appointment. 
The following procedures will be performed:  
1. Vital signs will be measured and recorded. 


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2. A resting 12-lead ECG will be performed between 2 and 3 hours (± 15 minutes) after taking the 
morning dose of study medication.  
3. The following tests will be completed: 
 
NPI –Disinhibition domain only 
 
CGIC 
 
PGIC 
 
FBI 
 
S-STS 
4. The caregiver will be queried regarding patient’s AEs and concomitant medication use (including 
OTC medications, vitamins, and supplements). 
5. Patient’s diary card will be collected and reviewed for compliance. 
6. Returned, unused study medication will be accounted for compliance. 
7. Patient diary card and sufficient study medication for a 3-week treatment period will be dispensed.   
Patient/Caregiver Instruction 
Caregivers will be instructed to administer to the patient the study medication twice-daily (1 capsule from 
the 24-count, AM-label bottle in the morning and 1 capsule from the 24-count, PM-label bottle in the 
evening, approximately every 12 hours ± 4 hours) for 21 days. 
The investigator and/or clinical coordinator will give patients and caregivers detailed instructions 
regarding study procedures.  They will also be instructed to consult with the study site prior to the patient 
taking any non-study medications.  These requirements will be reviewed in person, and written 
instructions will be provided to the patient and their caregiver.  Caregivers will also be instructed to bring 
to the clinic any unused study medication at each study visit.  Caregivers will be queried at the end of 
each visit to be certain that they understand what is required of them. 
6.4.1.9 
Visit 8 (Day 99 ± 3-day window) / Early Termination 
Visit 8 (Day 99) should occur in the morning.  Patients who withdraw prior to study completion are 
required to complete study procedures as listed in Visit 8 within 48 hours of the last dose of study 
medication.  There is no specific time frame for the 12-lead ECG, and sample blood/urine specimen 
collection (safety labs sample) for early termination patients. 
The last dose of study medication will be administered to the patient from the AM-label bottle at the clinic 
regardless of the time of day. 
The following procedures will be performed:  
1. Physical and neurological examination findings and vital signs measurements (including BP, heart 
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2. The caregiver will be queried regarding patient’s AEs and concomitant medication use (including 
OTC, vitamins, and supplements). 
3. A blood specimen will be collected within 3 hours after the morning dose of study medication for PK 
analysis and for safety laboratory assessments 
4. A urine sample will be collected for urinalysis. 
5. A urine pregnancy test will be performed on females of childbearing potential only. 
6. A resting 12-lead ECG will be performed (twice this visit - pre and post dose).  
7. 
  
8. The following tests will be completed: 
 
NPI 
 
FBI 
 
CGIC 
 
PGIC 
 
QoL 
 
QoR 
 
CNS-LS 
 
MMSE 
 
CSDD 
 
Stroop color and word task with 
 
 
IRI 
 
S-STS 
9. The patient’s diary card will be collected and reviewed for compliance. 
10. Returned, unused study medication will be accounted for compliance. 
6.4.1.10 
Safety Follow-up Call (Day 129 ± 3-day window) 
A phone call will be made on Day 129 (± 3-days) to review any newly reported AE after receiving and up 
to 30 days after the last dose of study medication.     
 


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7 
DATA MANAGEMENT 
7.1 
Data Collection 
The sponsor or designated representative (e.g., CRO) will perform the data management activities in 
accordance with the data management plan (DMP).  The DMP will outline the systems and procedures to 
be used in the study. 
Clinical study data will be reported (captured) by study site personnel on eCRFs.  An eCRF must be 
completed for every subject enrolled in the study.  The eCRF data will be entered by trained study-site 
personnel and then reviewed for completeness and accuracy and electronically signed by the investigator 
or authorized designee.  All study-site personnel must use a password protected user account to enter, 
review, or correct study data.  Electronic signature procedures shall comply with the CFR Title 21 Part 11.  
Passwords will be strictly confidential. 
All eCRF data will be exported from the electronic data capture (EDC) system and transferred to the 
sponsor or representative.  The sponsor or representative will also receive electronic transfers of non-
eCRF data from third-party vendors as appropriate.  The electronic data format of all transfers will be 
agreed upon with the sponsor or representative and documented in the DMP or vendor data transfer 
requirements document as appropriate. 
The clinical monitoring staff will perform source data verification (SDV) of the data recorded in the EDC 
system with source documents at the clinical study sites according to the data management plan and 
clinical monitoring plan.  The data will be subjected to consistency and validation checks within the EDC 
system with supplemental data reviews performed outside of the EDC system.   
Medical History and Adverse events will be coded using a current version of Medical Dictionary for 
Regulatory Activities (MedDRA), and concomitant medications using a current version of the WHO Drug 
Dictionary.  The sponsor or representative will perform a medical safety review of the coding. 
Completed eCRF images with a date- and time-stamped electronic audit trail indicating the user, the data 
entered, and any reason for change (if applicable) will be archived at the investigator’s site and archived 
with backup at the sponsor’s site. 


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8 
STATISTICAL METHODS 
8.1 
Analysis Populations 
Two analysis populations will be used, modified intent-to-treat (mITT), and safety.  The mITT population 
includes all patients randomized in the study who had at least one post-baseline efficacy assessment, and 
will be used for all analyses of efficacy.  The safety population includes all patients who received study 
treatment, and will be used for all analyses of safety.  Patients in the safety population will be summarized 
based on their actual study treatment received. 
8.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics. 
8.3 
Efficacy Analysis 
8.3.1 
Study Endpoints 
Primary Endpoint: 
The primary efficacy endpoint is the change from Baseline to Week 6 for each study period, in the 
Disinhibition domain of the NPI.  
Secondary Efficacy Endpoints: 
Change from Baseline (raw value for mCGIC and PGIC) for the following: 

Total NPI score

NPI Total Caregiver Distress

NPI Disinhibition domain Caregiver Distress

FBI Total score

FBI Disinhibition core questions score (questions 15, 16, and 17)

mCGIC

PGIC

QoL

QoR

IRI

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
MMSE

CSDD

Stroop color and word task
8.3.2 
Primary and Secondary Efficacy Analysis 
The primary efficacy endpoint is the change from Baseline to Week 6 for each study period, in the 
Disinhibition domain of the NPI.  Treatment group comparison will be performed using an analysis of 
covariance (ANCOVA) model.  The model includes fixed effects of treatment, period, treatment 
sequence, and covariate of baseline value.  A point estimate of the treatment difference and the 
corresponding 95% confidence intervals will be provided. Missing value will be imputed by the last 
observation carry forward (LOCF). 
Secondary efficacy endpoints will be analyzed similarly as the primary efficacy end points.  Summaries of 
 and 
 results will be provided. 
8.4 
Safety Analysis 
Safety will be assessed by the following measurements:  AEs, physical and neurological examination, 
vital signs, urine pregnancy test, clinical laboratory assessments, resting 12-lead ECG, and S-STS. 
Safety analyses will consist of data summaries for AEs, biological parameters and S-STS.  Safety analyses 
will be tabulated by treatment groups across the 2 periods.  
Adverse Events 
AEs will be coded using the MedDRA.  The percentages of patients experiencing 1 or more AEs will be 
summarized by treatment, system organ class (SOC), deaths, nonfatal SAEs, AEs, AEs resulting in study 
discontinuation, and treatment-emergent AEs (TEAE).  TEAEs are those AEs that occur after the first 
dose of study medication up until 30 days after last dose.   
Vital Signs and ECGs 
Summary statistics of absolute values and percentage change from baseline for BP (diastolic and systolic), 
heart rate, respiratory rate, and ECG parameters will be provided.  All values outside a pre-defined normal 
range will be highlighted in the individual patient data listings. 
Clinical Laboratory Values 
Laboratory parameters will be summarized via descriptive statistics and via shifts in results in respect to 
normal ranges between baseline and end of treatment as increased, decreased, or no change.  
8.5 
Sample Size Calculations 
This is a proof-of-concept (POC) study and, as such, no data is available on which to base power 
calculations. Based on prior clinical studies, randomizing approximately 12 patients is a reasonable 
number to assess POC. 


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9 
ADMINISTRATIVE PROCEDURES 
9.1 
Institutional Review Board Approval 
Institutional Review Boards must meet the guidelines set out by the FDA and conform to local laws and 
customs where appropriate.  Written IRB approval for the protocol and the signed ICF must be obtained 
and transmitted to Avanir Pharmaceuticals or representative before the study can be initiated.  The IRB 
must be informed of and approve all protocol amendments.  The investigator will ensure that this study is 
conducted in full conformance with the laws and regulations of the US (see, Appendix 15, Investigator 
Responsibilities).  The complete text of the World Medical Association Declaration of Helsinki is given in 
Appendix 16. 
9.2 
Informed Consent Form 
The ICF will follow the principles outlined in the current version of the Declaration of Helsinki. For each 
patient found to be eligible for the study, informed consent will be obtained from the patient (if the patient 
is capable in the judgment of the investigator to provide informed consent) or the authorized 
representative.  For patients that are not capable of providing informed consent, but are capable of 
providing assent, the patient will be asked to provide assent.  If the patient is not capable of providing 
assent, the investigator will document the reasons why and maintain that documentation with the other 
informed consent documents.  The patient’s caregiver will also be asked to provide informed consent as 
they will be providing data on themselves and the patient, as well as, being responsible for ensuring 
compliance from the patient between study visits. 
The patients and/or patient’s authorized representative and the caregiver will be properly informed of the 
purpose of the study.  The patients and/or patient’s authorized representative and the caregiver will be 
alerted to any anticipated AE that may be encountered with the study medication.  A signed ICF will be 
obtained from all patients and/or patient’s authorized representative, and the caregiver prior to patient 
entry into this study.  Patients and/or patient’s authorized representative and the caregiver will be 
provided with a copy of their signed ICF. 
9.3 
Patient’s Diary Card 
The patient’s diary card will be reviewed by clinical study personnel at all study treatment visits for 
confirmation of medication dosage and any rescue medication received.  The study personnel are 
responsible for (i) ensuring that patients and/or caregivers are properly collecting data and recording it 
into the diaries; and (ii) transcribing the diary recordings into the eCRF.  The diary will be collected at all 
study visits after Baseline.  The originals of all diaries will be maintained at the site as source documents.  
9.4 
Electronic Case Report Forms 
For each patient enrolled who has given informed consent, an eCRF must be completed and electronically 
signed by the investigator to certify that the data within each eCRF are complete and correct.  This also 


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applies to those patients who fail to complete the study.  If a patient is withdrawn from the study because 
of a treatment-limiting AE, thorough efforts should be made to document the outcome.  
Any site personnel delegated responsibility for data entry, query resolution, or eCRF approval must 
complete training prior to accessing the eCRF.  The electronic data capture (EDC) vendor will provide a 
username once training completion has been confirmed and the account has been approved by the 
sponsor.  Changes to the data once it has been initially saved will be tracked via audit trail and will require 
a reason for the change.  The audit trail will also include who made the change and a date/time stamp. 
The eCRFs will be reviewed by the study monitor at the study site.  Errors detected by subsequent in-
house data review may necessitate clarification or correction of errors.  All changes will be documented 
and approved by the investigator. 
The investigator will be provided with copies of the eCRFs for their site on a CD-ROM at the end of the 
study. 
9.5 
Quality Assurance 
9.5.1 
Documentation 
For each process, evaluation, or test that generates study data but is not described in the protocol or eCRF, 
a written description of the data generation procedures shall be retained in the quality assurance section of 
the study files.  In the case of routine clinical diagnostic procedures, only a copy of the relevant 
certification document is required. 
9.5.2 
Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the investigator.  
This will include telephone calls and on-site visits.  The study will be routinely monitored to ensure 
compliance with the study protocol and the overall quality of data collected.  During the on-site visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol.  As part of the data audit, source 
documents will be made available for review by the study monitor.  The study monitor may periodically 
request review of the investigator study file to assure the completeness of documentation in all respects of 
clinical study conduct. 
The study monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative and the caregiver for study procedures and for the release of medical 
records to the sponsor, FDA, other regulatory authorities, and the IRB.  The study monitor will also verify 
that assent was obtained for patients not capable of providing informed consent or that documentation is 
provided by the investigator explaining why the patient was unable to provide assent.  The investigator or 
appointed delegate will receive the study monitor during these on-site visits and will cooperate in 
providing the documents for inspection and respond to inquiries.  In addition, the investigator will permit 
inspection of the study files by authorized representatives of the regulatory agencies. 
On completion of the study, the study monitor will arrange for a final review of the study files after which 
the files should be secured for the appropriate time period. 


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9.6 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Avanir, the investigator agrees to keep 
records, including the identity of all participating patients (sufficient information to link records, e.g., 
CRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant correspondence 
(e.g., letters, meeting minutes, telephone calls reports).  The records should be retained by the investigator 
according to ICH, local regulations, or as specified in the Clinical Trial Agreement, whichever is longer. 
If the investigator is unable for any reason to continue to retain study records for the required period (e.g., 
retirement, relocation), Avanir should be prospectively notified.  The study records must be transferred to 
a designee acceptable by Avanir, such as another investigator, another institution, or to Avanir.  The 
investigator must obtain Avanir’s written permission before disposing of any records, even if retention 
requirements have been met. 
9.7 
Source Data 
The documents that will form the source data for the clinical study (e.g., patient charts, laboratory reports) 
must be defined and documented in the in-house study master file prior to the start of the study.  Data on 
the eCRFs which will be checked against source data during monitoring visits must also be defined and 
documented in the in-house study master file including the percentage of each of the source data to be 
verified and the percentage of patients’ eCRFs to be monitored. 
9.8 
Data Handling 
Data collected on the eCRFs will be entered into EDC system by trained site staff.  Any queries arising 
from data entry will be checked with the investigator and changes approved.  
9.9 
Laboratory Procedures 
Site laboratory will collect hematology and chemistry blood samples and urine samples for analysis.  
Blood samples will be collected for PK analysis at Visit 4 (Day 43) and Visit 8 (Day 99).  Instructions for 
shipping the laboratory samples for evaluation will be provided. 
9.10 
Guidelines for Good Clinical Practice 
Standards for GCP must be adhered to for all study-based procedures. 
9.11 
Conditions for Amending the Protocol 
Protocol modification to ongoing studies which could potentially adversely affect the safety of patients or 
which alter the scope of the investigation, the scientific quality of the study, the experimental design, 
dosages, duration of therapy, assessment variables, the number of patients treated, or patient selection 
criteria must be made only after appropriate consultation between an appropriate representative of Avanir 
and the investigator. 


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Protocol modifications must be prepared by a representative of Avanir or the investigator, and reviewed 
and approved by Avanir.   
All protocol modifications must be reviewed and approved by the appropriate IRB in accordance with 
local requirements, before the revised edition can be implemented.  Modifications which eliminate an 
apparent immediate hazard to patients do not require pre-approval by the IRB. 
9.12 
Conditions for Terminating the Study 
Both Avanir and the principal investigator reserve the right to terminate the study at the site at any time.  
Should this be necessary, the procedures to effect study termination will be arranged after review and 
consultation by both parties.  In terminating the study, Avanir and the investigator will assure that 
adequate consideration is given to the protection of the patient’s interests. 
9.13 
Confidentiality of Study Documents and Patient Records 
The investigator must assure that the patient’s anonymity will be maintained.  On eCRFs or other 
documents submitted to Avanir, patients should not be identified by their names but by an identification 
code. 
The investigator should keep a separate log of patient’s codes, names, and addresses.  Documents not for 
submission to Avanir, for example, patients’ signed ICFs, should be maintained by the investigator in 
strict confidence. 
9.14 
Reports 
At the completion of the study, the investigator shall provide the sponsor with an adequate report shortly 
after completion of the investigator's participation in the study as described in the Code of Federal 
Regulations (CFR) Title 21, Part 312.64. 
9.15 
Publications 
It is anticipated that a report of this study will be published in the scientific literature by the sponsor.  The 
investigator will not seek to arrange for publication of any of the information or results from the study in 
any scientific journal, or other publication or by way of lecture without Avanir’s prior review and written 
consent.  
9.16 
Audits/Inspections 
The investigator should understand that source documents for this study should be made available to 
appropriately qualified personnel or designee(s) from Avanir or to health authority inspectors after 
appropriate notification.  The verification of the eCRF data may be by direct inspection of source 
documents (where permitted by law) or through an interview exchange. 
The inspector from the regulatory authority will be especially interested in the following items: 
 
Visits from the sponsor’s representatives 


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 
IRB approval(s) 
 
Study medication accountability 
 
Study protocol and amendments 
 
ICFs of the patient (if capable of providing ICF, according to the investigator) or patient’s 
authorized representatives and caregivers 
 
Assent of the patients (if capable of providing assent, according to the investigator) 
 
Medical records supportive of eCRF data 
 
Reports to the IRB and the sponsor 
 
Record retention 
The sponsor will be available to help investigators prepare for an inspection. 


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10 
REFERENCES 


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11 
APPENDICES 
Appendix 15: 
Investigator Responsibilities 
Appendix 16: 
World Medical Association Declaration of Helsinki 


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Guidance for Industry
E6 Good Clinical Practice:
Consolidated Guidance
ICH
April 1996


Guidance for Industry
E6  Good Clinical Practice: 
Consolidated Guidance
Additional copies are available from:
 the Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research (CDER),
5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication,
Training, and Manufacturers Assistance (HFM-40)
Center for Biologics Evaluation and Research (CBER)
1401 Rockville Pike, Rockville, MD 20852-1448,
http://www.fda.gov/cber/guidelines.htm
(Fax) 888-CBERFAX or 301-827-3844
(Voice Information) 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
April 1996
ICH


13
(b) Changes increasing the risk to subjects and/or affecting significantly the
conduct of the trial (see section 4.10.2). 
(c) All adverse drug reactions (ADRs) that are both serious and
unexpected. 
(d)  New information that may affect adversely the safety of the subjects or
the conduct of the trial.
3.3.9  Ensuring that the IRB/IEC promptly notify in writing the
investigator/institution concerning:
(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.
3.4
Records
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists,
lists of occupations/affiliations of members, submitted documents, minutes of meetings,
and correspondence) for a period of at least 3 years after completion of the trial and make
them available upon request from the regulatory authority(ies).
The IRB/IEC may be asked by investigators, sponsors, or regulatory authorities to provide
copies of its written procedures and membership lists.
4.
INVESTIGATOR
4.1
Investigator's Qualifications and Agreements
4.1.1  The investigator(s) should be qualified by education, training, and
experience to assume responsibility for the proper conduct of the trial, should meet
all the qualifications specified by the applicable regulatory requirement(s), and
should provide evidence of such qualifications through up-to-date curriculum vitae
and/or other relevant documentation requested by the sponsor, the IRB/IEC,
and/or the regulatory authority(ies).
4.1.2  The investigator should be thoroughly familiar with the appropriate use of
the investigational product(s), as described in the protocol, in the current
Investigator's Brochure, in the product information, and in other information
sources provided by the sponsor.


14
4.1.3  The investigator should be aware of, and should comply with, GCP and the
applicable regulatory requirements.
4.1.4  The investigator/institution should permit monitoring and auditing by the
sponsor, and inspection by the appropriate regulatory authority(ies).
4.1.5  The investigator should maintain a list of appropriately qualified persons to
whom the investigator has delegated significant trial-related duties.
4.2
Adequate Resources
4.2.1  The investigator should be able to demonstrate (e.g., based on retrospective
data) a potential for recruiting the required number of suitable subjects within the
agreed recruitment period.
4.2.2  The investigator should have sufficient time to properly conduct and
complete the trial within the agreed trial period.
4.2.3  The investigator should have available an adequate number of qualified staff
and adequate facilities for the foreseen duration of the trial to conduct the trial
properly and safely.
4.2.4  The investigator should ensure that all persons assisting with the trial are
adequately informed about the protocol, the investigational product(s), and their
trial-related duties and functions.
4.3
Medical Care of Trial Subjects
4.3.1  A qualified physician (or dentist, when appropriate), who is an investigator
or a subinvestigator for the trial, should be responsible for all trial-related medical
(or dental) decisions. 
4.3.2  During and following a subject's participation in a  trial, the
investigator/institution should ensure that adequate medical care is provided to a
subject for any adverse events, including clinically significant laboratory values,
related to the trial. The investigator/institution should inform a subject when
medical care is needed for intercurrent illness(es) of which the investigator
becomes aware. 
4.3.3  It is recommended that the investigator inform the subject's primary
physician about the subject's participation in the trial if the subject has a primary
physician and if the subject agrees to the primary physician being informed.


15
4.3.4  Although a subject is not obliged to give his/her reason(s) for withdrawing
prematurely from a trial, the investigator should make a reasonable effort to
ascertain the reason(s), while fully respecting the subject's rights.
4.4
Communication with IRB/IEC
4.4.1  Before initiating a trial, the investigator/institution should have written and
dated approval/favorable opinion from the IRB/IEC for the trial protocol, written
informed consent form, consent form updates, subject recruitment procedures
(e.g., advertisements), and any other written information to be provided to
subjects. 
4.4.2  As part of the investigator's/institution’s written application to the IRB/IEC,
the investigator/institution should provide the IRB/IEC with a current copy of the
Investigator's Brochure.  If the Investigator's Brochure is updated during the trial,
the investigator/institution should supply a copy of the updated Investigator’s
Brochure to the IRB/IEC.
4.4.3  During the trial the investigator/institution should provide to the IRB/IEC all
documents subject to its review.  
4.5
Compliance with Protocol
4.5.1  The investigator/institution should conduct the trial in compliance with the
protocol agreed to by the sponsor and, if required, by the regulatory authority(ies),
and which was given approval/favorable opinion by the IRB/IEC.  The
investigator/institution and the sponsor should sign the protocol, or an alternative
contract, to confirm their agreement.
4.5.2  The investigator should not implement any deviation from, or changes of,
the protocol without agreement by the sponsor and prior review and documented
approval/favorable opinion from the IRB/IEC of an amendment, except where
necessary to eliminate an immediate hazard(s) to trial subjects, or when the
change(s)  involves only logistical or administrative aspects of the trial (e.g.,
change of monitor(s), change of telephone number(s)).
4.5.3  The investigator, or person designated by the investigator, should document
and explain any deviation from the approved protocol.
4.5.4  The investigator may implement a deviation from, or a change in, the
protocol to eliminate an immediate hazard(s) to trial subjects without prior
IRB/IEC approval/favorable opinion.  As soon as possible, the implemented


16
 deviation or change, the reasons for it, and, if appropriate, the proposed protocol
amendment(s) should be submitted:
(a)  To the IRB/IEC for review and approval/favorable opinion;
(b)  To the sponsor for agreement and, if required; 
(c)  To the regulatory authority(ies).
4.6
Investigational Product(s)
4.6.1  Responsibility for investigational product(s) accountability at the trial site(s)
rests with the investigator/institution.
4.6.2  Where allowed/required, the investigator/institution may/should assign some
or all of the investigator's/institution’s duties for investigational product(s)
accountability at the trial site(s) to an appropriate pharmacist or another
appropriate individual who is under the supervision of the investigator/institution.
4.6.3  The investigator/institution and/or a pharmacist or other appropriate
individual, who is designated by the investigator/institution, should maintain
records of the product's delivery to the trial site, the inventory at the site, the use
by each subject, and the return to the sponsor or alternative disposition of unused
product(s).  These records should include dates, quantities, batch/serial numbers,
expiration dates (if applicable), and the unique code numbers assigned to the
investigational product(s) and trial subjects. Investigators should maintain records
that document adequately that the subjects were provided the doses specified by
the protocol and reconcile all investigational product(s) received from the sponsor.
4.6.4  The investigational product(s) should be stored as specified by the sponsor
(see sections 5.13.2 and 5.14.3) and in accordance with applicable regulatory
requirement(s).
4.6.5  The investigator should ensure that the investigational product(s) are used
only in accordance with the approved protocol.
4.6.6  The investigator, or a person designated by the investigator/institution,
should explain the correct use of the investigational product(s) to each subject and
should check, at intervals appropriate for the trial, that each subject is following
the instructions properly.
4.7
Randomization Procedures and Unblinding
The investigator should follow the trial's randomization procedures, if any, and should
ensure that the code is broken only in accordance with the protocol.  If the trial is blinded,


17
the investigator should promptly document and explain to the sponsor any premature
unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the
investigational product(s).
4.8
Informed Consent of Trial Subjects
4.8.1  In obtaining and documenting informed consent, the investigator should
comply with the applicable regulatory requirement(s), and should adhere to GCP
and to the ethical principles that have their origin in the Declaration of Helsinki. 
Prior to the beginning of the trial, the investigator should have the IRB/IEC's
written approval/favorable opinion of the written informed consent form and any
other written information to be provided to subjects.
4.8.2  The written informed consent form and any other written information to be
provided to subjects should be revised whenever important new information
becomes available that may be relevant to the subject’s consent.  Any revised
written informed consent form, and written information should receive the
IRB/IEC's approval/favorable opinion in advance of use.  The subject or the
subject’s legally acceptable representative should be informed in a timely manner if
new information becomes available that may be relevant to the subject’s
willingness to continue participation in the trial.  The communication of this
information should be documented.
4.8.3  Neither the investigator, nor the trial staff, should coerce or unduly influence
a subject to participate or to continue to participate in a trial.
4.8.4  None of the oral and written information concerning the trial, including the
written informed consent form, should contain any language that causes the subject
or the subject's legally acceptable representative to waive or to appear to waive
any legal rights, or that releases or appears to release the investigator, the
institution, the sponsor, or their agents from liability for negligence.
4.8.5  The investigator, or a person designated by the investigator, should fully
inform the subject or, if the subject is unable to provide informed consent, the
subject's legally acceptable representative, of all pertinent aspects of the trial
including the written information given approval/favorable opinion by the
IRB/IEC.
4.8.6  The language used in the oral and written information about the trial,
including the written informed consent form, should be as nontechnical as practical
and should be understandable to the subject or the subject's legally acceptable
representative and the impartial witness, where applicable. 


18
4.8.7  Before informed consent may be obtained, the investigator, or a person
designated by the investigator, should provide the subject or the subject's legally
acceptable representative ample time and opportunity to inquire about details of
the trial and to decide whether or not to participate in the trial.  All questions
about the trial should be answered to the satisfaction of the subject or the subject's
legally acceptable representative.
4.8.8  Prior to a subject’s participation in the trial, the written informed consent
form should be signed and personally dated by the subject or by the subject's
legally acceptable representative, and by the person who conducted the informed
consent discussion. 
4.8.9  If a subject is unable to read or if a legally acceptable representative is
unable to read, an impartial witness should be present during the entire informed
consent discussion.  After the written informed consent form and any other written
information to be provided to subjects is read and explained to the subject or the
subject’s legally acceptable representative, and after the subject or the subject’s
legally acceptable representative has orally consented to the subject’s participation
in the trial, and, if capable of doing so, has signed and personally dated the
informed consent form, the witness should sign and personally date the consent
form.  By signing the consent form, the witness attests that the information in the
consent form and any other written information was accurately explained to, and
apparently understood by, the subject or the subject's legally acceptable
representative, and that informed consent was freely given by the subject or the
subject’s legally acceptable representative.
4.8.10  Both the informed consent discussion and the written informed consent
form and any other written information to be provided to subjects should include
explanations of the following:
(a)  That the trial involves research.
(b)  The purpose of the trial.
(c)  The trial treatment(s) and the probability for random assignment to
each treatment.
(d)  The trial procedures to be followed, including all invasive procedures.
(e)  The subject's responsibilities.
(f)  Those aspects of the trial that are experimental.


19
(g)  The reasonably foreseeable risks or inconveniences to the subject and,
when applicable, to an embryo, fetus, or nursing infant.
(h)  The reasonably expected benefits.  When there is no intended clinical
benefit to the subject, the subject should be made aware of this. 
(i)  The alternative procedure(s) or course(s) of treatment that may be
available to the subject, and their important potential benefits and risks. 
(j)  The compensation and/or treatment available to the subject in the event
of trial-related injury. 
(k)  The anticipated prorated payment, if any, to the subject for
participating in the trial.
(l)  The anticipated expenses, if any, to the subject for participating in the
trial.
(m)  That the subject's participation in the trial is voluntary and that the
subject may refuse to participate or withdraw from the trial, at any time,
without penalty or loss of  benefits to which the subject is otherwise
entitled. 
(n)  That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory
authority(ies) will be granted direct access to the subject's original medical
records for verification of clinical trial procedures and/or data, without
violating the confidentiality of the subject, to the extent permitted by the
applicable laws and regulations and that, by signing a written informed
consent form, the subject or the subject's legally acceptable representative
is authorizing such access.
(o)  That records identifying the subject will be kept confidential and, to the
extent permitted by the applicable laws and/or regulations, will not be made
publicly available.  If the results of the trial are published, the subject’s
identity will remain confidential. 
(p)  That the subject or the subject's legally acceptable representative will
be informed in a timely manner if information becomes available that may
be relevant to the subject's willingness to continue participation in the trial. 
(q)  The person(s) to contact for further information regarding the trial and
the rights of trial subjects, and whom to contact in the event of trial-related
injury. 


20
(r)  The foreseeable circumstances and/or reasons under which the subject's
participation in the trial may be terminated. 
(s)  The expected duration of the subject's participation in the trial.
(t)  The approximate number of subjects involved in the trial. 
4.8.11  Prior to participation in the trial, the subject or the subject's legally
acceptable representative should receive a copy of the signed and dated written
informed consent form and any other written information provided to the subjects. 
During a subject’s participation in the trial, the subject or the subject’s legally
acceptable representative should receive a copy of the signed and dated consent
form updates and a copy of any amendments to the written information provided
to subjects.
4.8.12  When a clinical trial (therapeutic or nontherapeutic) includes subjects who
can only be enrolled in the trial with the consent of the subject’s legally acceptable
representative (e.g., minors, or patients with severe dementia), the subject should
be informed about the trial to the extent compatible with the subject’s
understanding and, if capable, the subject should assent, sign and personally date
the written informed consent.
4.8.13  Except as described in 4.8.14, a nontherapeutic trial (i.e., a trial in which
there is no anticipated direct clinical benefit to the subject) should be conducted in
subjects who personally give consent and who sign and date the written informed
consent form.
4.8.14  Nontherapeutic trials may be conducted in subjects with consent of a
legally acceptable representative provided the following conditions are fulfilled:
(a)  The objectives of the trial cannot be met by means of a trial in subjects
who can give informed consent personally.
(b)  The foreseeable risks to the subjects are low.
(c)  The negative impact on the subject’s well-being is minimized and low.
(d)  The trial is not prohibited by law.
(e)  The approval/favorable opinion of the IRB/IEC is expressly sought on
the inclusion of such subjects, and the written approval/favorable opinion
covers this aspect. 


21
Such trials, unless an exception is justified, should be conducted in patients having
a disease or condition for which the investigational product is intended.  Subjects
in these trials should be particularly closely monitored and should be withdrawn if
they appear to be unduly distressed.
4.8.15  In emergency situations, when prior consent of the subject is not possible,
the consent of the subject's legally acceptable representative, if present, should be
requested.  When prior consent of the subject is not possible, and the subject’s
legally acceptable representative is not available, enrollment of the subject should
require measures described in the protocol and/or elsewhere, with documented
approval/favorable opinion by the IRB/IEC, to protect the rights, safety, and well-
being of the subject and to ensure compliance with applicable regulatory
requirements.  The subject or the subject's legally acceptable representative should
be informed about the trial as soon as possible and consent to continue and other
consent as appropriate (see section 4.8.10) should be requested.
4.9
Records and Reports
4.9.1  The investigator should ensure the accuracy, completeness, legibility, and
timeliness of the data reported to the sponsor in the CRFs and in all required
reports.
4.9.2  Data reported on the CRF, which are derived from source documents,
should be consistent with the source documents or the discrepancies should be
explained.
4.9.3  Any change or correction to a CRF should be dated, initialed, and explained
(if necessary) and should not obscure the original entry (i.e., an audit trail should
be maintained); this applies to both written and electronic changes or corrections
(see section 5.18.4(n)).  Sponsors should provide guidance to investigators and/or
the investigators' designated representatives on making such corrections.  Sponsors
should have written procedures to assure that changes or corrections in CRFs
made by sponsor's designated representatives are documented, are necessary, and
are endorsed by the investigator.  The investigator should retain records of the
changes and corrections.
4.9.4  The investigator/institution should maintain the trial documents as specified
in Essential Documents for the Conduct of a Clinical Trial (see section 8.) and as
required by the applicable regulatory requirement(s).  The investigator/institution
should take measures to prevent accidental or premature destruction of these
documents.


22
4.9.5  Essential documents should be retained until at least 2 years after the last
approval of a marketing application in an ICH region and until there are no
pending or contemplated marketing applications in an ICH region or at least 2
years have elapsed since the formal discontinuation of clinical development of the
investigational product.  These documents should be retained for a longer period,
however, if required by the applicable regulatory requirements or by an agreement
with the sponsor.  It is the responsibility of the sponsor to inform the
investigator/institution as to when these documents no longer need to be retained
(see section 5.5.12).
4.9.6  The financial aspects of the trial should be documented in an agreement
between the sponsor and the investigator/institution.
4.9.7  Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
investigator/institution should make available for direct access all requested trial-
related records. 
4.10
Progress Reports
4.10.1  Where required by the applicable regulatory requirements, the investigator
should submit written summaries of the trial’s status to the institution.  The
investigator/institution should submit written summaries of the status of the trial to
the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.
4.10.2  The investigator should promptly provide written reports to the sponsor,
the IRB/IEC (see section 3.3.8), and, where required by the applicable regulatory
requirements, the institution on any changes significantly affecting the conduct of
the trial, and/or increasing the risk to subjects.
4.11
Safety Reporting
4.11.1  All serious adverse events (SAEs) should be reported immediately to the
sponsor except for those SAEs that the protocol or other document (e.g.,
Investigator's Brochure) identifies as not needing immediate reporting.  The
immediate reports should be followed promptly by detailed, written reports.  The
immediate and follow-up reports should identify subjects by unique code numbers
assigned to the trial subjects rather than by  the subjects' names, personal
identification numbers, and/or addresses.  The investigator should also comply
with the applicable regulatory requirement(s) related to the reporting of
unexpected serious adverse drug reactions to the regulatory authority(ies) and the
IRB/IEC.


23
4.11.2  Adverse events and/or laboratory abnormalities identified in the protocol as
critical to safety evaluations should be reported to the sponsor according to the
reporting requirements and within the time periods specified by the sponsor in the
protocol.
4.11.3  For reported deaths, the investigator should supply the sponsor and the
IRB/IEC with any additional requested information (e.g., autopsy reports and
terminal medical reports).
4.12
Premature Termination or Suspension of a Trial
If the trial is terminated prematurely or suspended for any reason, the
investigator/institution should promptly inform the trial subjects, should assure appropriate
therapy and follow-up for the subjects, and, where required by the applicable regulatory
requirement(s), should inform the regulatory authority(ies).  In addition:
4.12.1  If the investigator terminates or suspends a trial without prior agreement of
the sponsor, the investigator should inform the institution, where required by the
applicable regulatory requirements, and the investigator/institution should
promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and
the IRB/IEC a detailed written explanation of the termination or suspension.
4.12.2  If the sponsor terminates or suspends a trial (see section 5.21), the
investigator should promptly inform the institution, where required by the
applicable regulatory requirements, and the investigator/institution should
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written
explanation of the termination or suspension.
4.12.3  If the IRB/IEC terminates or suspends its approval/favorable opinion of a
trial (see sections 3.1.2 and 3.3.9), the investigator should inform the institution,
where required by the applicable regulatory requirements, and the
investigator/institution should promptly notify the sponsor and provide the sponsor
with a detailed written explanation of the termination or suspension.
4.13
Final Report(s) by Investigator/Institution
Upon completion of the trial, the investigator should, where required by the applicable
regulatory requirements, inform the institution, and the investigator/institution should
provide the sponsor with all required reports, the IRB/IEC with a summary of the trial’s
outcome, and the regulatory authority(ies) with any report(s) they require of the
investigator/institution.


CONFIDENTIAL AND PROPRIETARY 
AVANIR PHARMACEUTICALS, INC 
Protocol 15-AVP-786-203 
Version 1.0 
Appendix 16: 
World Medical Association Declaration of Helsinki 
Page 128


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World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
Clinical Review & Education
Special Communication
jama.com
JAMA
November 27, 2013
Volume 310, Number 20
2191
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13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2192
JAMA
November 27, 2013
Volume 310, Number 20
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
jama.com
JAMA
November 27, 2013
Volume 310, Number 20
2193
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icianmustseekinformedconsentfrom
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epresentative.Theseindividualsmustno
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he benefits, risks,
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
JAMA
November 27, 2013
Volume 310, Number 20
jama.com
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