Clinical trial NCT05845398
Conditions: Alcohol Use Disorder
Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Start date: 2023-01-29; Completion date: 2023-08-22
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to test the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of of repeat doses of DCR-AUD in adult healthy volunteers who are social drinkers.

The main questions it aims to answer are:

* Are repeat doses of DCR-AUD safe and well-tolerated in healthy adults who are social drinkers?
* How does the drug behave inside the human body and how it is removed from the human body?
* What are the symptoms the drug may cause with alcohol consumption?

Participants will:

* Receive multiple doses of DCR-AUD.
* Have assessment visits through Week 24.
* Participate in up to 10 Ethanol Interaction Assessments (EIAs) to see how the body is affected by DCR-AUD.

Researchers will compare the groups of participates who receive study drug with the group of participants who receive placebo to see if the study drug is safe and tolerable and whether the study drug has any real effect.

Detailed description:

Arms: arm 1: Multiple doses of DCR-AUD. Subcutaneous administration of of DCR-AUD. arm 2: Multiple doses of placebo comparator. Subcutaneous administration of Placebo for DCR-AUD, volume to match active single dose
Interventions: intervention 1: DCR-AUD intervention 2: Placebo
Intervention descriptions: intervention 1: DCR-A1203, the drug substance of DCR-AUD, is a synthetic double-stranded (hybridized duplex) RNA oligonucleotide conjugated to GalNAc ligands that enable specific hepatic access and update after subcutaneous administration. DCR-AUD is a sterile solution of DCR-A1203 at a concentration of 160 mg/mL in water for injection (WFI). intervention 2: 0.9% saline for injection.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
'LFHUQD3KDUPDFHXWLFDOV, Inc. 
NCT number 
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Sponsor trial ID: 
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Official title of study: 
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Document date*: 
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*Document date refers to the date on which the document was most recently updated.








Dicerna Protocol DCR-AUD-102 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 1 
17-Jan-2023 
Original Protocol 
06-Dec-2022 
 
Amendment 1 (17-Jan-2023) 
Overall Rationale for the Amendment: 
The protocol was amended in response to queries from the US Food and Drug Administration. 
Additional updates and clarifications were also included. A summary of all changes follows in 
the table below.  
Description of Change 
Brief Rationale 
Section # and Name 
Clarified that, following an SAE, 
additional EIAs will not be 
performed if the SAE may have been 
related to study intervention and that 
repeat EIAs may pose a recurrent risk 
to the participant. 
To enhance participant safety and 
allow for PI discretion in the conduct 
of EIAs following an SAE. 
7.3.1  Serious Adverse Event 
Decrease from 3 to 2 the number of 
participants experiencing a Grade 3 
CTCAE event that would trigger a 
study stopping rule. 
To enhance participant safety.  
7.4. 
Study Stopping Rules 
Require that participants remain in 
clinic until the 24-hour postdose PK 
blood sample is collected (increases 
in-clinic admission by one night). 
Also results in change of timing for 
distribution of alcohol use symptom 
diary. 
To simplify clinical operations and 
reduce the likelihood of missed 
sample collection. 
1.3. 
Schedule of Activities 
Changed pre-admission alcohol 
testing from urine to breath. 
Breath-alcohol testing provides a 
more accurate assessment of recent 
alcohol intake than does urine 
testing. 
1.3. 
Schedule of Activities 
5.3. 
Lifestyle Considerations 
8.6.1. Ethanol Interaction 
Assessments 
10.2. Clinical Laboratory Tests 
Added that a positive urine drug 
VFUHHQRQ'D\í(in addition to at 
Screening) will result in study 
exclusion. 
To ensure that participants are not 
users of illicit drugs. 
1.3. 
Schedule of Activities 
5.2. 
Exclusion Criteria 
Updated text in Exclusion Criterion 
#3 (history of suicidal ideation or 
behavior). 
To provide clarification on the 
timeframe during which positive 
answers in the C-SSRS would result 
in study exclusion. 
5.2. 
Exclusion Criteria 
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Dicerna Protocol DCR-AUD-102 
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Description of Change 
Brief Rationale 
Section # and Name 
Added that metabolites of 
DCR-AUD may also be analyzed 
To provide for a more complete PK 
profile of DCR-AUD 
8.5 
Pharmacokinetics 
Changed sampling times for blood 
draws for ADA detection from 
Days 29 and 57 to Days 42 and 70. 
To provide for ADA sample 
collection 14 days after each dose 
administration. 
1.3. 
Schedule of Activities 
Changed timing of ALDH2 
genotyping from Screening to 
Day í 
To allow that only eligible 
participants undergo genotyping. 
1.3. 
Schedule of Activities 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
MEDICAL MONITOR AND PHARMACOVIGILANCE CONTACT INFORMATION ............3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.1.1. 
Rationale .....................................................................................................................11 
1.1.2. 
Objectives and Endpoints ...........................................................................................12 
1.1.3. 
Overall Design ............................................................................................................12 
1.2. 
Overall Study Schema ................................................................................................14 
1.3. 
Schedule of Activities (SoA) ......................................................................................15 
2. 
INTRODUCTION ......................................................................................................21 
2.1. 
Study Rationale ...........................................................................................................21 
2.1.1. 
Overview of Alcohol Use Disorder ............................................................................21 
2.1.2. 
Nonclinical Overview of DCR-AUD .........................................................................22 
2.2. 
Benefit/Risk Assessment ............................................................................................23 
2.2.1. 
Risks Related to DCR-AUD Mechanism of Action ...................................................23 
2.2.2. 
Risk Assessment .........................................................................................................25 
2.2.3. 
Benefit Assessment .....................................................................................................26 
2.2.4. 
Overall Benefit:Risk Conclusion ................................................................................26 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................27 
4. 
STUDY DESIGN .......................................................................................................28 
4.1. 
Overall Design ............................................................................................................28 
4.2. 
Scientific Rationale for Study Design ........................................................................28 
4.3. 
Justification for Dose ..................................................................................................29 
4.4. 
End of Study Definition ..............................................................................................29 
5. 
STUDY POPULATION .............................................................................................30 
5.1. 
Inclusion Criteria ........................................................................................................30 
5.2. 
Exclusion Criteria .......................................................................................................31 
5.3. 
Lifestyle Considerations .............................................................................................33 
5.4. 
Screen Failures ............................................................................................................34 
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6. 
STUDY INTERVENTION ........................................................................................35 
6.1. 
Study Intervention(s) Administered ...........................................................................35 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................35 
6.2.1. 
Handling and Accountability ......................................................................................35 
6.2.2. 
Storage ........................................................................................................................36 
6.2.3. 
Preparation and Administration ..................................................................................36 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................36 
6.4. 
Study Intervention Compliance ..................................................................................37 
6.5. 
Dose Modification ......................................................................................................37 
6.6. 
Continued Access to Study Intervention after the End of the Study. .........................37 
6.7. 
Concomitant Therapy .................................................................................................37 
6.7.1. 
Rescue Medicine .........................................................................................................38 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................38 
7.1. 
Participant Discontinuation/Withdrawal from the Study ...........................................38 
7.2. 
Lost to Follow Up .......................................................................................................38 
7.3. 
Individual Participant Stopping Rules ........................................................................39 
7.3.1. 
Serious Adverse Event ................................................................................................39 
7.3.2. 
Abnormal Liver Function Tests ..................................................................................39 
7.3.3. 
Electrocardiogram Findings ........................................................................................39 
7.3.4. 
Significant Negative Reaction to Alcohol Ingestion ..................................................39 
7.4. 
Study Stopping Rules .................................................................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
8.1. 
Efficacy Assessments .................................................................................................40 
8.1.1. 
Alcohol Consumption via Timeline Follow Back ......................................................41 
8.1.2. 
Blood Phosphatidylethanol Levels .............................................................................41 
8.2. 
Safety Assessments .....................................................................................................41 
8.2.1. 
Screening Tests ...........................................................................................................42 
8.2.1.1. 
Mini-International Neuropsychiatric Interview ..........................................................42 
8.2.1.2. 
Laboratory Tests to Determine Eligibility ..................................................................42 
8.2.2. 
Physical Examinations ................................................................................................42 
8.2.3. 
Vital Signs ..................................................................................................................42 
8.2.4. 
Electrocardiograms .....................................................................................................43 
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8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................43 
8.2.5.1. 
Columbia-Suicide Severity Rating Scale ....................................................................43 
8.2.6. 
Clinical Safety Laboratory Assessments ....................................................................44 
8.2.7. 
Pregnancy Testing ......................................................................................................44 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................44 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event Information ....................45 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................45 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................45 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................45 
8.3.5. 
Pregnancy ...................................................................................................................46 
8.4. 
Treatment of Overdose ...............................................................................................46 
8.5. 
Pharmacokinetics ........................................................................................................46 
8.6. 
Pharmacodynamics .....................................................................................................47 
8.6.1. 
Ethanol Interaction Assessments ................................................................................47 
8.6.1.1. 
EIA Blood Biomarkers ...............................................................................................48 
8.6.1.2. 
EIA Physiologic Signs and Symptoms .......................................................................48 
8.6.1.3. 
Stopping Rules for an EIA ..........................................................................................48 
8.6.1.4. 
Follow-up of Participants Who Continue to have Positive Ethanol Reaction 
Symptoms at Day 168 (Conditional Follow-up) ........................................................49 
8.6.2. 
Presence of Physiologic Symptoms Associated with Consumption of Ethanol 
Outside of EIAs ..........................................................................................................49 
8.7. 
Genetics ......................................................................................................................49 
8.8. 
Immunogenicity Assessments ....................................................................................49 
8.9. 
Health Economics .......................................................................................................50 
9. 
STATISTICAL CONSIDERATIONS .......................................................................50 
9.1. 
Statistical Hypotheses .................................................................................................50 
9.2. 
Sample Size Determination ........................................................................................50 
9.3. 
Populations for Analyses ............................................................................................51 
9.4. 
Statistical Analyses .....................................................................................................51 
9.4.1. 
General Considerations ...............................................................................................51 
9.4.2. 
Primary Endpoint(s) ....................................................................................................52 
9.4.3. 
Secondary Endpoints ..................................................................................................52 
9.4.3.1. 
EIA Composite Score .................................................................................................52 
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9.4.3.2. 
Blood Biomarkers .......................................................................................................53 
9.4.3.3. 
Pharmacokinetics ........................................................................................................53 
9.4.4. 
Exploratory Endpoint(s) .............................................................................................53 
9.5. 
Interim Analysis ..........................................................................................................53 
9.6. 
Safety Review Committee and Data Safety Monitoring Committee..........................53 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................56 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................56 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................56 
10.1.2. 
Financial Disclosure ...................................................................................................56 
10.1.3. 
Informed Consent Process ..........................................................................................56 
10.1.4. 
Data Protection ...........................................................................................................57 
10.1.5. 
Committees Structure .................................................................................................57 
10.1.5.1. 
Safety Review Committee ..........................................................................................57 
10.1.5.2. 
Data Safety Monitoring Committee ............................................................................57 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................58 
10.1.7. 
Data Quality Assurance ..............................................................................................58 
10.1.8. 
Study and Site Start and Closure ................................................................................59 
10.1.9. 
Publication Policy .......................................................................................................60 
10.2. 
Clinical Laboratory Tests ...........................................................................................60 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................62 
10.3.1. 
Definition of Adverse Event .......................................................................................62 
10.3.2. 
Definition of Serious Adverse Event ..........................................................................62 
10.3.3. 
Definition of Adverse Events of Special Interest .......................................................63 
10.3.4. 
Recording and Follow-up of AEs and/or SAEs ..........................................................64 
10.3.4.1. 
AE and SAE Recording ..............................................................................................64 
10.3.4.2. 
Assessment of Intensity ..............................................................................................65 
10.3.4.3. 
Assessment of Causality .............................................................................................65 
10.3.4.4. 
Follow-up of AEs and SAEs .......................................................................................66 
10.3.5. 
Reporting of SAEs ......................................................................................................66 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................66 
10.4.1. 
Definitions ..................................................................................................................66 
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10.4.2. 
Contraception Guidance .............................................................................................67 
10.4.3. 
Collection of Pregnancy Information .........................................................................68 
10.4.3.1. 
Male Participants with Partners Who Become Pregnant ............................................68 
10.4.3.2. 
Participants Who Become Pregnant ...........................................................................69 
10.5. 
Genetics ......................................................................................................................69 
10.6. 
Liver Safety: Suggested Actions and Follow-up Assessments ...................................70 
10.7. 
Abbreviations ..............................................................................................................72 
10.8. 
Protocol Amendment History .....................................................................................76 
10.9. 
Investigator Signature Page ........................................................................................77 
11. 
REFERENCES ...........................................................................................................78 
 
Table of Tables 
Table 1: 
Schedule of Activities – Screening, Dosing, EOS, and CFU Visits (see 
Table 2 for non-dosing visits) .....................................................................................15 
Table 2: 
Schedule of Activities – Non-dosing Visits (see Table 1 for Screening, 
Dosing, and EOS Visits) .............................................................................................18 
Table 3: 
Schedule of Activities - 4-Hour Ethanol Interaction Assessments .............................20 
Table 4: 
Study Intervention Administered ................................................................................35 
Table 5: 
Minimal Timing of the Safety Review Committee Data Reviews .............................55 
Table 6: 
Protocol-Required Safety Laboratory Assessments ...................................................61 
Table 7: 
Grading of Injection Site Reactions, CTCAE v 5.0 ....................................................64 
Table 8: 
Highly Effective Contraceptive Methods ...................................................................68 
 
Table of Figures 
Figure 1: 
Study Schematic for DCR-AUD-102 .........................................................................14 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1b, Double-blind, Placebo-controlled, Repeat-dose, Safety, 
Tolerability, Pharmacokinetic, and Pharmacodynamic Study of DCR-AUD in Healthy 
Volunteers  
Short Title: Phase 1b Repeat Dose Study of DCR-AUD in Healthy Volunteers  
1.1.1. 
Rationale 
DCR-AUD is being developed for the treatment of alcohol use disorder (AUD) in adults using an 
RNA interference (RNAi) technology platform. DCR-A1203, the drug substance of DCR-AUD, 
is a synthetic double-stranded (annealed duplex) RNA oligonucleotide conjugated to GalNAc 
ligands that enable subcutaneous delivery of stable, highly specific, and long-acting knockdown 
of mRNA in the liver via hepatic GalNAc carbohydrate receptors. The target of DCR-AUD is 
aldehyde dehydrogenase 2 (ALDH2), one of the primary enzymes required for alcohol 
metabolism. Alcohol metabolism occurs predominantly in the liver via a 2-step process in which 
alcohol is first converted to acetaldehyde via alcohol dehydrogenase and then to acetic acid by 
ALDH2. ALDH2 enzyme inhibition can result in unpleasant symptoms after alcohol 
consumption such as flushing, headache, lightheadedness, palpitations, nausea, and vomiting, as 
a result of unmetabolized acetaldehyde accumulation. Unpleasant reactions to alcohol 
consumption in humans with naturally occurring ALDH2 mutations are thought to be protective 
against AUD and account for its low prevalence in individuals who are heterozygous or 
homozygous for ALDH2 allele mutations causing slower metabolism of acetaldehyde. The 
magnitude and duration of acetaldehyde accumulation is proportional to both the degree of 
ALDH2 enzyme inhibition (e.g., partial vs total) and the amount of alcohol consumed. 
DCR-AUD is designed to selectively reduce ALDH2 mRNA and ALDH2 activity in the liver, 
and thereby decrease the conversion of acetaldehyde to acetic acid after ethanol ingestion. In 
cynomolgus monkeys, a single SC dose of 3 mg/kg DCR-AUD resulted in reduction of 
ALDH2 mRNA expression in liver up to 112 days postdose, with maximum reduction observed 
at 4 weeks postdose.  
This repeat-dose study is being conducted to characterize the safety and tolerability and PK 
profiles of DCR-AUD when administered monthly, and to determine if a PD effect (resulting 
from cumulative ALDH2 mRNA knock down) can be observed during Ethanol Interaction 
Assessments (EIA) in a population of social drinkers after repeat doses of DCR-AUD.  
 
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Intervention Groups and Duration: 
Participants will be randomized 3 to 1 to DCR-AUD or placebo, administered at a dose of 
480 mg once every 4 weeks at Days 1, 29, and 57. 
Individual participants will be screened for a period of up to 4 weeks. Randomization and 
administration of the first dose of study intervention will occur on Day 1. Participants will return 
to the site for safety, tolerability, PK, and PD monitoring at specified time points as per the 
Schedule of Activities. Participants will be followed for approximately 24 weeks after the first 
injection of study intervention.  
Study Population Key Criteria: 
x Overtly healthy men and women aged 21 to 65 years. 
x No diagnosis of AUD within the preceding 12 months per Diagnostic and Statistical 
Manual of Mental Disorders (DSM-5). 
x Social drinkers who consume, on average, 5 to 20 drinks per week for men or 5 to 
14 drinks per week for women over the 4 weeks prior to screening, and not more than 
8 drinks in a single day.  
x No evidence of overt or sub-clinical hepatic pathology, as manifest by serologic tests 
demonstrating hepatic inflammation or compromised hepatic synthetic function. 
x No history of substance use disorder (SUD) or illicit drug use (excluding cannabis) 
within the preceding 12 months. 
x No history of alcohol withdrawal symptoms including delirium tremens or alcohol-
related seizures. 
Treatment Blinding:  
Participants and site study staff will be blinded to the randomization. Some members of the 
Sponsor team will be unblinded. Complete details will be presented in the Study Blinding Plan.  
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Page 14 
1.2. 
Overall Study Schema 
Figure 1: 
Study Schematic for DCR-AUD-102 
 
 
 
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1.3. 
Schedule of Activities (SoA) 
Table 1: 
Schedule of Activities – Screening, Dosing, EOS, and CFU Visits (see Table 2 for non-dosing visits) 
 
Screen 
Dosing Visits 
EOS/ET a 
CFUb 
Study Week 
 
— 
4 
8 
24 
28 
Study Day íWRí 
í 
1 
2 
4 
28 
29 
30 
32 
56 
57 
58 
168 
169 
197 
Window (days) c  
 
– 
– 
– 
– 
– 
±2 
– 
– 
– 
±2 
– 
– 
±7 
±7 
Procedure/Assessment 
 
 
Pre 
Post 
 
 
 
Pre 
Post 
 
 
 
Pre 
Post 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychological history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug testing d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening laboratory testing e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALDH2 genotyping f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS g 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Alcohol TLFB h 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Pregnancy test i 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
SARS-CoV-2 test j 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Drug/alcohol screen k 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Clinic site admission l 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
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Table 1: 
Schedule of Activities – Screening, Dosing, EOS, and CFU Visits (see Table 2 for non-dosing visits) (Continued) 
 
Screen 
Dosing Visits 
EOS/ET a 
CFUb 
Study Week 
 
— 
4 
8 
24 
28 
Study Day íWRí 
í 
1 
2 
4 
28 
29 
30 
32 
56 
57 
58 
168 
169 
197 
Window (days) c  
 
– 
– 
– 
– 
– 
±2 
– 
– 
– 
±2 
– 
– 
±7 
±7 
Procedure/Assessment 
 
 
Pre 
Post 
 
 
 
Pre 
Post 
 
 
 
Pre 
Post 
 
 
 
 
Clinic site discharge m 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
EIA n 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Randomize 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study intervention 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
12-lead ECG o 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
 
 
X 
 
Vital signs 
X p 
 
X 
X q 
 
 
 
X 
X q 
 
 
 
X 
X q 
 
 
X 
 
Physical examination r 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Blood sample for PEth s 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Hematology, chemistry, UA t 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Coagulation panel u 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Complement panel v 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Blood sample for ADA w 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Blood sample for PK x 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Alcohol use symptom diary y 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
Record AEs & SAEs z 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record concomitant meds 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA=antidrug antibody; AE=adverse event; ALDH2=aldehyde dehydrogenase 2 gene; CBC=complete blood count; CFU=conditional follow-up visit; 
C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EIA=ethanol interaction assessment; EOS=end of study; ET=early termination; 
FSH=follicle-stimulating hormone; HbA1c=hemoglobin A1c; ICF=informed consent form; MINI=Mini-International Neuropsychiatric Interview; PEth=phosphatidylethanol; 
PK=pharmacokinetic; RBC=red blood cell; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SIB=suicidal ideation or behavior; 
TLFB=Timeline Follow Back; UA=urinalysis 
a At the time of discontinuation for the study, an early termination (ET) visit should be conducted, if possible. 
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b Participants with significant symptoms at the Day 168 EIA will be followed for an additional 4 weeks at the discretion of the Investigator. 
c Visits without a specified window are to be conducted relative to the associated scheduled visit. For example, Day 28 will always be the day prior to the Day 29 visit, regardless 
of where Day 29 falls within the ± 2-day visit window 
d Screening tests positive for cannabis are not exclusionary. 
e To include hematology (CBC with differential and RBC indices), clinical chemistry, coagulation panel, urinalysis, viral serology, HbA1c, and FSH (as indicated). See 
Section 10.2 for a complete list of parameters. 
f Baseline genetic testing for ALDH2 mutations. Participation is optional; participants who do not wish to undergo genotyping may still participate in the study. 
g The Baseline version will be administered at Screening and at subsequent visits the “C-SSRS Since Last Visit” version will be administered. Participants who exhibit signs of 
Suicidal Ideation or Behavior (SIB) should undergo a risk assessment. All factors contributing to SIB should be evaluated and consideration should be given to discontinuation 
of study intervention.  
h TLFB will be completed for the 2-week period that precedes each study visit, including Screening. 
i Pregnancy testing required only in female participants. If a urine pregnancy test is positive, confirm with serum pregnancy test. Local laboratory may be used. Female 
participants must have a negative pregnancy test prior to overnight admission. 
j Testing to be performed at the site upon admission. Participants with a positive SARS-CoV-2 test will not be admitted to clinic and will not receive study intervention or undergo 
EIA. Other assessments not requiring clinic admission (i.e., safety assessments) will be performed. Testing will be performed per site standard processes. 
k Study participants are to refrain from drinking alcohol and using cannabis for 24 hours prior to each EIA. Participants with a positive urine-drug or breath-alcohol test will not be 
admitted to clinic and will not undergo EIA. Participants with a positive urine drug test on Day í1 will be excluded from the study. 
l Participants must be fasting for at least 3 hours prior to admission to the clinic. 
m Participants may be discharged from clinic following collection of the 24-hour postdose PK sample. Participants will return to clinic for collection of PK samples at  72 hours 
postdose on Days 4 and 32. 
n EIA will be conducted on the first day of the visit once all other assessments for that day have been completed. A total of 10 EIAs will be conducted. The timing of assessments 
and ethanol administration are detailed in Table 3.  
o On dosing days, ECGs will be conducted approximately 30 minutes predose and 15-to-30 minutes postdose. If multiple assessments are due, the order of assessment should be 
ECG, vitals, PK, and then other assessments; with PK sample collection occurring at the nominal time. At Screening and EOS, one ECG will be performed. Screening ECGs 
may be repeated one time for determination of eligibility. 
p Blood pressure, if out of range at Screening, may be repeated one time for determination of eligibility. 
q Blood pressure and pulse rate to be recorded 15 (±5) minutes postdose. 
r Height will be measured and recorded at Screening. Weight will be measured and recorded at every visit. 
s Sample to be collected prior to ethanol administration. 
t Hematology to include complete blood count with differential and RBC indices. See Section 10.2 for a complete list of parameters. 
u See Section 10.2 for a complete list of parameters. 
v Blood samples for complement testing to be collected predose and 2, 8, and 24 hours postdose on Day 1 and Day 57. 
w Blood sample for ADA testing to be drawn at same time as predose PK sample on Day 1. 
x Plasma samples for PK analysis to be collected predose and at 1, 2, 4, 6, 8, 24, and 72 hours postdose (exception: no 72-hour PK sample is required at Day 57). A single sample 
will be collected on Day 168. If multiple assessments are due, the order of testing should be ECG, vitals, PK, and then other assessments, with the PK sampling performed 
preferably at the nominal time point. A ±15-minute window will be allowed for collections at 1, 2, 4, 6, and 8 hours postdose. A ±30-minute window will be allowed for 
collection at 24 hours postdose. A ±60-minute window will be allowed for collection at 72 hours postdose. 
y Participants to record any symptoms associated with use of alcohol outside of in-clinic EIAs. Diary to be issued at time of discharge from clinic and collected and reviewed upon 
return to clinic. 
z AEs and SAEs will be recorded from time ICF is signed. SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up.  
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Table 2: 
Schedule of Activities – Non-dosing Visits (see Table 1 for Screening, Dosing, and EOS Visits) 
Week 
2 
6 
10 
12 
16 
20 
Study Day 
14 
15 
42 
43 
70 
71 
84 
85 
112 
113 
140 
141 
Visit Window (days) a 
– 
±2 
– 
±2 
– 
±3 
– 
±5 
– 
±7 
– 
±7 
Procedure/Assessment 
 
Drug/alcohol screen b c 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy test d 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
SARS-CoV-2 test e c 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Clinical site admission f 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical examination g 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
C-SSRS h 
 
 
 
 
 
 
X 
 
 
 
 
 
Hematology, chemistry, UA i j 
 
 
 
 
 
 
X 
 
 
 
 
 
Coagulation panel j 
 
 
 
 
 
 
X 
 
 
 
 
 
Blood sample for ADA k 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Blood sample for PK k 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Blood sample for PEth k 
 
 
 
 
 
 
 
 
X 
 
 
 
EIA l 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Alcohol TLFB m 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Alcohol use symptom diary n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs and SAEs o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record concomitant meds  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical site discharge p 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Abbreviations: ADA=antidrug antibody; AE=adverse event; C-SSRS=Columbia-Suicide Severity Rating Scale; EIA=ethanol interaction assessment; 
PEth=phosphatidylethanol; PK=pharmacokinetics; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SIB=suicidal ideation or 
behavior; TLFB=Timeline Follow Back; UA=urinalysis 
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a Visits without a specified window are to be conducted relative to the associated scheduled visit. For example, Day 14 will always be the day prior to the Day 15 
visit, regardless of where Day 15 falls within the ± 2-day visit window. 
b Study participants are to refrain from drinking alcohol and using cannabis for 24 hours prior to each EIA. Participants with a positive urine-drug or breath-
alcohol test will not be admitted to clinic and will not undergo EIA. Other assessments not requiring clinic admission (i.e., safety assessments) should be 
performed. 
c Other assessments not requiring clinic admission (i.e., safety assessments) should be performed. 
d Pregnancy testing required only in female participants. If a urine pregnancy test is positive, confirm with serum pregnancy test. Local laboratory may be used. 
Female participants must have a negative pregnancy test prior to overnight admission. 
e Participants with a positive SARS-CoV-2 test will not be admitted to clinic and will not undergo EIA. Testing will be performed per site standard processes. 
f Participants must be fasting for at least 3 hours prior to admission to the clinic. 
g Weight will be measured and recorded at each visit. 
h The “C-SSRS Since Last Visit” version will be administered. Participants who exhibit signs of SIB should undergo a risk assessment.  
i Hematology to include complete blood count.  
j See Section 10.2 for complete list of testing parameters. 
k Sample to be collected prior to ethanol administration for EIA. 
l EIA will be conducted once all other assessments for that day have been completed. The timing of assessments and ethanol administration are detailed in 
Table 3. 
m TLFB will be completed for the 2-week period that precedes each study visit. 
n Participants to record any symptoms associated with use of alcohol outside of in-clinic EIAs. Diary to be issued at time of discharge from clinic and collected 
and reviewed upon return to clinic. 
o AEs and SAEs will be recorded from time ICF is signed. SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up.  
p Participants will be discharged in the morning when the PI deems it medically appropriate to do so. 
 
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Table 3: 
Schedule of Activities - 4-Hour Ethanol Interaction Assessments  
 
Pre-EIA 
EIA Test Period 
Time (minutes) 
-50 
-20 
0 a 
20 
30 
40 
60 
90 
120 
150 
180 
210 
240 
Window (minutes) 
 
 
- 
±5 
±5 
±5 
±10 
±10 
±10 
±10 
±10 
±10 
±10 
Procedure: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard meal b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Venous catheter placement c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG d 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Vital signs d e  
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Plasma biomarker sample d f 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
Questionnaire of 6 EIA symptoms d g 
 
 
X 
 
X 
 
X d 
 
X 
 
X 
 
 
Ethanol consumption h 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
EIA AEs i 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; ECG=electrocardiogram; EIA=ethanol interaction assessment; PK=pharmacokinetics  
a “Time 0” is immediately before the first sip of ethanol is consumed. All Time 0 assessments must be performed prior to initiation of alcohol intake. 
b Participants will arrive at the site after a minimum 3-hour fast, then will be provided a standardized meal before receiving the first drink. Participants will be given 30 minutes 
to consume the meal. 
c 
Catheter placement may be performed earlier in the day if preferred, but participants must be given at least a 20-minute rest period following placement of the venous access 
catheter prior to recording predose vital signs and ECG. For EIAs conducted prior to a dosing day, the venous catheter will be left in place for PK sample collections. 
d If multiple assessments are due at the same timepoint, the order of assessments should be ECG, vitals, blood draw, then any other assessments. The 60-minute symptom 
assessment should be conducted before the start of the 4th drink. 
e 
To include pulse rate and blood pressure. 
f 
Blood samples will be collected via venous access device. To include acetaldehyde, acetate, and ethanol. 
g Participants will be questioned by site staff to assess the 6 symptoms (flushing, headache, lightheadedness, palpitations, nausea, and vomiting) associated with increased blood 
acetaldehyde levels. 
h Ethanol will be consumed in 4 aliquots over an 80-minute period (20 minutes for each aliquot). Time windows do not apply to ethanol consumption. The ethanol will be mixed 
in a liquid that has no other alcohol, no caffeine, and is low in sugar. The dose of ethanol will be 0.8 g/kg (to a maximum of 56 g) for men and 0.68 g/kg (to a maximum of 
48 g) for women. See Section 8.6.1.3 of the protocol for ethanol administration stopping rules. 
i 
AEs associated with administration of ethanol will include events spontaneously reported by participants beginning with the first sip of ethanol (symptoms elicited under direct 
questioning [footnote g] are not considered AEs).  
 
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2. 
INTRODUCTION 
2.1. 
Study Rationale 
DCR-AUD is being developed for the treatment of AUD in adults using an RNAi technology 
platform. DCR-A1203, the drug substance of DCR-AUD, is a synthetic double-stranded 
(annealed duplex) RNA oligonucleotide conjugated to GalNAc ligands that enable specific 
hepatic access and uptake after subcutaneous (SC) administration. Once inside the hepatocyte, 
the antisense sequence of DCR-AUD is designed to target and reduce the expression of 
ALDH2 mRNA in the liver. 
The target of DCR-AUD is ALDH2, one of the primary enzymes required for alcohol 
metabolism. Alcohol metabolism occurs predominantly in the liver via a 2-step process in which 
alcohol is first converted to acetaldehyde via alcohol dehydrogenase and then to acetic acid by 
ALDH2. DCR-AUD is designed to selectively reduce ALDH2 mRNA and ALDH2 activity in the 
liver, and thereby decrease the conversion of acetaldehyde to acetic acid after ethanol ingestion. 
ALDH2 enzyme inhibition can result in unpleasant symptoms after alcohol consumption such as 
flushing, headache, lightheadedness, palpitations, nausea, and vomiting as a result of 
unmetabolized acetaldehyde accumulation. Unpleasant reactions to alcohol consumption in 
humans with naturally occurring ALDH2 mutations are thought to be protective against AUD 
and account for its low prevalence in individuals who are heterozygous or homozygous for 
ALDH2 allele mutations. The magnitude and duration of acetaldehyde accumulation is 
proportional to both the degree of ALDH2 enzyme inhibition (e.g., partial vs total) and the 
amount of alcohol consumed. 
Interim results of the ongoing Study DCR-AUD-101, which was the first study of DCR-AUD in 
humans, have shown DCR-AUD to be safe and well tolerated at doses ranging from 80 to 
960 mg, but no PD effects (sufficient elevation of plasma acetaldehyde levels or clinical 
symptoms) have been observed.  
The aims of this repeat-dose study are to characterize the safety and tolerability and PK profiles 
of DCR-AUD when administered monthly, and to determine if a PD effect (resulting from 
cumulative ALDH2 mRNA knock down) can be observed during EIAs in a population of social 
drinkers after repeat doses of DCR-AUD.  
2.1.1. 
Overview of Alcohol Use Disorder 
Alcohol use disorder is a chronic condition characterized by compulsive alcohol use, loss of 
control over alcohol use, and a negative emotional state when not using alcohol. A range of 
medical, psychological, social, economic, and personal problems are associated with AUD. 
'LDJQRVLVLVGHILQHGDVPHHWLQJ 2 of 11 criteria in the Diagnostic and Statistical Manual of 
Mental Disorders-5 (DSM 5) during the same 12-month period. A survey of over 36,000 adults 
found AUD had a 12-month prevalence of 13.9% adults in the US in 2013 (Grant et al., 2015). 
AUD often goes untreated, possibly due to the lack of adequate treatment options. It is estimated 
that < 10% of US adults with AUD seek help or treatment, and that similarly low percentages of 
those treated receive pharmacotherapy (Grant et al., 2015; SAMHSA, 2014; Litten et al., 2014; 
Han et al., 2015; Knudsen et al., 2011).  
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There are 3 FDA-approved medications for AUD: disulfiram, oral and long-acting injectable 
naltrexone, and acamprosate. However, many individuals show limited or no response to these 
drugs, with poor compliance a factor (EMA, 2010; Gastfriend, 2014; Chick et al., 1992; 
Jørgensen et al., 2011; Bryson et al., 2011). Thus, there remains an unmet need for an effective 
AUD treatment. 
2.1.2. 
Nonclinical Overview of DCR-AUD 
The pharmacology of DCR-A1203 was characterized in in vivo studies in mice and monkeys to 
demonstrate the ability to reduce levels of the hepatic ALDH2 mRNA. The potential for off-
target gene silencing was assessed using in silico evaluation of the human transcriptome. The 
sequence is conserved in mouse, monkey, and human, but not rabbit. Therefore, DCR-A1203 is 
active in both general toxicology species evaluated, mouse and monkey. In addition, a stand-
alone comprehensive safety pharmacology study in cynomolgus monkeys was conducted.  
Overall, the data support the hypothesis that DCR-AUD has potential to yield meaningful and 
robust clinical responses across the AUD patient population based upon the following:  
x A single SC dose of up to 100 mg/kg in mice resulted in a dose-dependent decrease in 
Aldh2 mRNA expression in liver, persistent for 14 days postdose, followed by dose-
dependent recovery. 
x Following a single 3 mg/kg SC dose of DCR-A1203, liver ALDH2 mRNA expression 
levels were reduced by > 75% in cynomolgus monkeys, with the nadir at 28 days 
postdose, and > 50% reduction in ALDH2 mRNA expression up to 112 days postdose. 
x Repeat SC administration of DCR-A1203 at 30 to 300 mg/kg resulted in significant 
reduction of hepatic Aldh2 mRNA in mice (> 97%) and hepatic ALDH2 in monkeys 
(> 86%) at all dose levels evaluated. 
x Based on in silico analysis, potential off-target complementarities with 3 or fewer 
mismatches and a full seed-region match, were completely absent from the human 
transcripts analyzed, demonstrating that DCR-A1203 has a high degree of specificity for 
hepatic ALDH2 mRNA.  
The safety of DCR-A1203 has been characterized in a program of nonclinical studies. 
Subcutaneous repeat-dose toxicity studies have been conducted at doses up to 300 mg/kg for up 
to 6 months in mice and 9 months in monkeys. DCR-A1203 has been evaluated for potential 
genotoxicity in a bacterial reverse mutation assay and in vitro and in vivo micronucleus studies. 
In addition, preliminary reproductive toxicity studies were conducted in mice and rabbits.  
x DCR-A1203 administration had no adverse effects on cardiovascular, respiratory, or 
central nervous system function in conscious, radiotelemetry-implanted cynomolgus 
monkeys following a single SC injection of up to 300 mg/kg. 
x The administration of DCR-A1203 in repeat-dose studies for up to 6 months in mice and 
9 months in monkeys resulted in no DCR-A1203-related, adverse findings. The NOAEL 
in the mouse and monkey repeat-dose toxicity studies was considered to be 300 mg/kg, 
the highest dose level administered.  
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x In a preliminary embryofetal development (EFD) study in mice with daily SC dosing, no 
DCR-A1203-related toxicity was observed at dose levels up to 1000 mg/kg (highest dose 
administered). In a preliminary EFD study in rabbits with daily SC dosing (dose levels 
from 2 to 50 mg/kg), maternal toxicity (lower body weight gains and lower food 
consumption) in dams and embryofetal effects (higher post implantation loss and lower 
mean fetal weights) were observed at all DCR-A1203 dose levels. The human relevance 
of these contradictory observations in mice and rabbits is unclear, as DCR-A1203 is not 
pharmacologically active in rabbits and no such observations were noted in the EFD 
study in the pharmacological responsive mouse with DCR-A1203.  
x DCR-A1203 was not genotoxic in the bacterial reverse mutation or in vitro and in vivo 
micronucleus assays. 
Overall, the nonclinical safety program of DCR-A1203 did not identify any major safety issues. 
The human relevance of preliminary nonclinical reproductive studies is unclear, and participants 
will follow contraception guidance. A detailed description of the chemistry and pharmacology of 
DCR-AUD is provided in the Investigator’s Brochure.  
2.2. 
Benefit/Risk Assessment 
The summary of potential risks provided below is based on results of the ongoing FIH study 
(DCR-AUD-101) and on in-depth review of literature relating to the proposed approach and 
insights from the nonclinical pharmacology and toxicology studies. 
The antisense sequence of DCR-AUD is designed to target and reduce the expression of ALDH2 
mRNA in the liver. Potential off-target complementarities at the level of a single mismatch were 
completely absent from the human transcripts analyzed in in-silico studies. These findings 
demonstrate that DCR-AUD has a high degree of specificity for the ALDH2 mRNA. The 
sequence is conserved in mouse, monkey, and human, and therefore, DCR-AUD is active in all 
nonclinical general toxicology species evaluated. To date, DCR-A1203 has been associated with 
no adverse effects in nonclinical studies.  
Clinical experience with the Dicerna GalXC™ siRNA platform in more than 200 patients and 
HVs suggests a favorable safety profile with little-to-no evidence of systemic immune 
stimulation or toxicities. Mild, self-limiting injection site reactions have been reported (Dicerna 
data on file). In addition, in the on-going DCR-AUD-101 trial, single doses of DCR-AUD 
(range: 80 to 960 mg) administered to 24 participants have shown good tolerability. Specifically, 
no SAEs have been observed, and the vast majority of AEs in the trial have been mild in 
severity. 
As part of the study’s planned mitigation strategy, all study participants will be monitored for 
signs or symptoms of systemic toxicity, decline in liver or kidney function, abnormalities in 
hematologic parameters (including platelets and coagulation parameters), and abnormalities in 
vital signs, ECGs, complement activation, or other relevant safety parameters. 
2.2.1. 
Risks Related to DCR-AUD Mechanism of Action 
DCR-AUD, at the proposed dose, is designed to induce mild symptoms resulting from 
substantial alcohol consumption (e.g.,  4 drinks/occasion) by selective reduction of ALDH2 
mRNA and ALDH2 activity in the liver, and thereby a decrease in the conversion of 
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acetaldehyde to acetic acid after ethanol ingestion. In sufficient amounts, acetaldehyde 
accumulation is associated with unpleasant effects, potentially including flushing, headache, 
lightheadedness, palpitations, nausea, and vomiting. More severe reactions to acetaldehyde 
accumulation can include copious vomiting, sweating, chest pain, palpitation, dyspnea, 
hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. The 
intensity of the reaction varies with each individual but is generally proportional to the amounts 
of alcohol ingested and the degree of ALDH2 inhibition. The duration of the reaction varies from 
30 to 60 minutes and up to several hours in the more severe cases if there is prolonged alcohol 
exposure in the blood. Symptoms are typically self-limited and managed with watchful 
observation and supportive care. More severe acetaldehyde reactions have been documented with 
disulfiram treatment and in individuals who are homozygous for ALDH2-gene–inactivating 
mutations compared with ALDH2 mutation heterozygotes, proportional to the magnitude of 
systemic ALDH2 inactivation. 
Study participants will be clearly informed of these potential risks. Symptoms that develop with 
concomitant alcohol consumption are expected to be self-limited and manageable with 
supportive care and can be avoided by limiting or eliminating alcohol consumption. 
In the absence of direct measurement of ALDH2 activity in the liver (e.g., via liver biopsy), EIAs 
are necessary to evaluate and confirm DCR-AUD PD activity. The EIAs in this protocol 
(4 standard drinks [approximately 56 g for men and 48 g for women] administered over an 
80-minute window) are designed to reflect a plausible level of consumption for frequent drinkers 
and patients with AUD. Possible signs and symptoms of alcohol intolerance will be recorded in 
the clinic under close observation and controlled conditions.  
 
 
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2.2.2. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
 
 
 
Study Intervention: DCR-AUD 
Injection site reactions  
Subcutaneous administration of the 
study intervention may cause a 
specific local reaction originating 
around the injection site, such as 
erythema, itching, discomfort, and 
pain. 
Most ISRs are mild and self-limiting. 
Participants will be monitored for the 
development of ISRs (Section 10.3.3) 
Potential reproductive effects 
In a preliminary EFD study in 
rabbits with daily SC dosing, 
maternal toxicity in dams and 
embryofetal effects were observed 
at all dose levels. The human 
relevance of these preliminary 
nonclinical reproductive studies is 
unclear. 
All participants of childbearing 
potential are required to practice 
highly effective contraception 
consistently throughout the study and 
for 24 weeks after the last dose of 
study intervention (Section 10.4). 
Severe symptoms associated 
with acetaldehyde accumulation 
following consumption of 
alcohol 
In sufficient amounts, acetaldehyde 
accumulation is associated with 
unpleasant effects, including 
flushing, headache, 
lightheadedness, palpitations, 
nausea, and vomiting. More severe 
reactions to acetaldehyde 
accumulation can include copious 
vomiting, sweating, chest pain, 
palpitation, dyspnea, hypotension, 
syncope, marked uneasiness, 
weakness, vertigo, blurred vision, 
and confusion. 
If significant or severe adverse 
V\PSWRPVRFFXULQparticipants 
treated with DCR-AUD during the 
trial, additional DCR-AUD dosing (if 
scheduled) and subsequent EIAs will 
be discontinued. In the event this 
occurs, all study participants will be 
advised to avoid alcohol for the entire 
study observation period.  
Suicidal ideation or behavior 
(SIB) 
Patients diagnosed with AUD may 
be at risk for SIB. Because 
DCR-AUD is being developed for 
the treatment of AUD, HV will be 
screened and monitored for the 
presence or emergence of SIB 
while on study. 
There is no evidence to suggest that 
HV exposed to DCR-AUD are at risk 
for SIB, however, all participants will 
be monitored for the emergence of SIB 
via the C-SSRS at regular intervals 
throughout the study (Section 8.2.5.1). 
Study Procedures 
EIA: alcohol administration may 
cause intoxication and is 
expected to cause mild, 
unpleasant effects in participants 
receiving DCR-AUD 
 
Required to assess and confirm 
DCR-AUD PD activity, including 
magnitude and duration of effects 
associated with concomitant 
alcohol interaction 
During EIAs, alcohol to be 
administered as one standard drink 
every 20 minutes for 4 drinks (i.e., 
over 80 minutes) in a Phase 1 unit 
clinical setting under close 
observation.  
Eligible participants will have drinking 
histories suggesting tolerability to the 
amount of ethanol to be administered 
in the EIAs.  
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Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
 
 
 
Blood sampling, including 
cannulation. Risks include acute 
pain, bleeding, vessel injury, 
and, in rare instances, arterial 
vessel blockage, potentially 
leading to infection. 
Blood sampling is required to 
assess the safety, PK, and PD of 
DCR-AUD. 
The total volume of blood to be 
withdrawn for research purposes has 
been limited to the minimum required 
for a complete assessment. 
Other 
Prolonged PD activity of 
DCR-AUD may cause alcohol 
intolerance for up to 3 months or 
more after last dose in study 
participants. Adverse effects are 
not expected but potentially 
possible with concomitant small 
or incidental amounts of alcohol 
during DCR-AUD treatment. 
Adverse effect(s) resulting from 
high levels of alcohol intake during 
DCR-AUD treatment is an 
intentional design element of the 
DCR-AUD target product profile 
and predicted based on the core 
RNAi/GalXC drug platform.  
The clinical significance is 
expected to be limited to high or 
very high alcohol consumption, but 
adverse effects may occur at lower 
ingested amounts. 
Ensure risks related to DCR-AUD 
potential PD effects and duration are 
clearly communicated in the informed 
consent. 
Adverse effects related to alcohol 
consumption are self-limited, 
reversible, and avoidable. 
 
2.2.3. 
Benefit Assessment 
There is no expected benefit for HV participants in the study. Data generated in this study will 
contribute to the development of a potential new therapy for AUD, an area of significant unmet 
medical need, and FDA-approved treatment options. 
The siRNA-mediated reduction of ALDH2 via DCR-AUD is designed to offer significant safety 
advantages relative to agents such as disulfiram, which inhibits multiple aldehyde 
dehydrogenases as well as other enzymes (Koppaka et al., 2012). siRNA-mediated reduction will 
only target ALDH2 in the liver, leaving other aldehyde dehydrogenases able to function. Further, 
DCR-AUD reduction of ALDH2 will be liver-specific, leaving non-liver ALDH2 unaffected.  
2.2.4. 
Overall Benefit:Risk Conclusion 
With the measures planned to minimize participant risk in this study, the potential risks 
identified in association with DCR-AUD are justified by possible future benefits that may be 
afforded to patients with AUD. 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a double-blind, randomized, placebo-controlled study of DCR-AUD to evaluate the 
safety, tolerability, PK, and PD of repeat doses of DCR-AUD in adult HVs.  
Each participant will be screened for up to 28 days. Participants may undergo rescreening one 
time at the discretion of the Investigator or Sponsor. Screening assessments will include a 
psychological history and a history of alcohol consumption using the TLFB method to identify 
participants who are HVs and who meet the minimum inclusion/exclusion alcohol consumption 
requirements. TLFB is a validated method to retrospectively assess drinking behavior history. 
Randomization and administration of the first dose of study intervention will occur on Day 1. 
Repeated doses of 480 mg study intervention will be administered to 16 adult HVs (12 active and 
4 placebo). Each participant will receive 3 SC doses of study intervention (on Day 1, Day 29, 
and Day 57). Up to 10 EIAs will be conducted over the 24-week period to characterize the PD of 
DCR-AUD.  
All participants will be given a diary to track AEs and drinking history for the study duration. 
Quantitative drinking history will be captured by TLFB questionnaire completed every 2 weeks. 
Participants will be trained on the use of the diary prior to discharge from the clinic and will 
report on the diary at each visit. 
At the discretion of the Investigator, participants who present with increasing positive ethanol 
reaction symptoms at the Day 168 EIA (e.g., flushing, headache, lightheadedness, palpitations, 
nausea, or vomiting) will be followed for an additional 4 weeks (through Day 197). 
4.2. 
Scientific Rationale for Study Design 
DCR-AUD is designed to selectively reduce ALDH2 mRNA and ALDH2 activity in the liver, 
and thereby decrease the conversion of acetaldehyde to acetic acid after ethanol ingestion. In 
cynomolgus monkeys, a single SC dose of 3 mg/kg DCR-AUD resulted in reduction of 
ALDH2 mRNA expression in liver up to 112 days postdose, with maximum reduction observed 
at 4 weeks postdose.  
Study DCR-AUD-101 was designed to evaluate the safety, tolerability, PK, and PD of single 
ascending doses of DCR-AUD in healthy adult volunteers who abstained from drinking alcohol 
during the study (outside of the study-mandated EIAs). In that first-in-human (FIH) study, 
DCR-AUD, at doses ranging from 80 to 960 mg, was found to be safe and well tolerated. 
However, while the plasma PK was well characterized, no clear pattern of plasma biomarkers or 
physiologic symptoms during EIAs indicative of target engagement was established at any dose.  
In addition to further characterizing the safety and tolerability and PK profiles of DCR-AUD 
when administered monthly, this repeat-dose study is being conducted to determine if a PD 
effect (resulting from cumulative ALDH2 mRNA knock down) can be observed in a population 
of social drinkers. Knockdown of ALDH2 activity by DCR-AUD that is sufficient to increase 
plasma acetaldehyde levels and induce symptoms may require both repeat doses and several 
months to be manifest, supporting the 24-week follow-up observation period in this trial.  
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The up-to-10 EIAs will permit evaluation of the onset of DCR-AUD effect and when this effect 
wanes or extinguishes. The amount of ethanol administered during EIAs in this study is double 
that given during Study DCR-AUD-101. The 4 drinks over 80 minutes were included to reflect 
the drinking patterns experienced by patients with AUD.  
4.3. 
Justification for Dose 
The dose level of 480 mg was selected following evaluation of nonclinical PK/PD and safety 
data and based on results of the on-going DCR-AUD-101 study evaluating single ascending 
doses up to 960 mg. 
Administration of DCR-A1203 in the repeat-dose studies for up to 6 months in mice and 9 
months in monkeys resulted in no adverse findings related to DCR-A1203. The NOAEL in the 
mouse and monkey chronic repeat-dose toxicity studies was considered to be 300 mg/kg, the 
highest dose level administered.  
Interim results from DCR-AUD-101 have shown single doses of DCR-AUD to be safe and well 
tolerated at doses ranging from 80 to 960 mg. No clear pattern of plasma biomarkers or 
physiologic symptoms indicative of target engagement was established at any dose. 
See the DCR-AUD IB for an overview of safety margins. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all of the 
Day 169 EOS assessments, as shown in the SoA (Section 1.3). The conditional follow-up visit is 
not required of all participants and is conducted only at the discretion of the Investigator, based 
on the occurrence of substantial symptoms during the Day 169 EIA, or a reported adverse event 
profile reported at that visit that warrants further follow-up. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
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5. 
STUDY POPULATION 
Sixteen participants are planned to be enrolled in this study: 12 will receive DCR-AUD and 
4 will receive placebo. 
Protocol waivers or exemptions are not allowed. Participants may undergo rescreening one time 
at the discretion of the Investigator or Sponsor (Section 5.4)  
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply.  
Age 
1. 
21 to 65 years, inclusive, at the time of signing informed consent. 
Type of Participant and Disease Characteristics 
2. 
Overtly healthy volunteers, as determined by medical evaluation including medical 
history, physical examination, and laboratory testing. 
3. 
No diagnosis of AUD within the preceding 12 months per Diagnostic and Statistical 
Manual of Mental Disorders (DSM-5). 
4. 
Social drinkers who consume, on average, 5 to 20 drinks per week for men or 5 to 
14 drinks per week for women over the 4 weeks prior to Screening, and not more than 
8 drinks in a single day.  
5. 
No evidence of overt or sub-clinical hepatic pathology, as manifest by serologic tests 
demonstrating hepatic inflammation or compromised hepatic synthetic function 
(i.e., AST, ALT, GGT, total bilirubin < 1.5 times the ULN at Screening and 'D\í).  
6. 
eGFR  60 mL/min/1.73 m2 at Screening. 
7. 
No history of significant adverse reaction(s) to alcohol. Participant should be expected to 
tolerate the amount of alcohol administered during EIAs. 
8. 
Willing to participate in up to 10 EIAs. 
9. 
Has a negative test for SARS-CoV-LQIHFWLRQRQ'D\í. 
10. Systolic BP in the range of 80 to 140 mmHg and diastolic BP in the range of 50 to 
95 mmHg at Screening. If out of range, BP may be repeated once at the discretion of the 
Investigator. 
Sex and Contraceptive Requirements 
11. Male or female  
• 
Male participants with partners of childbearing potential must agree to use 
contraception from Screening through at least 24 weeks after the last dose of study 
intervention and refrain from donating sperm during this period (see Section 10.4).  
• 
Female participants may not be pregnant or breastfeeding, and at least one of the 
following conditions must apply:  
í Is not a woman of childbearing potential (WOCBP) or  
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í If a WOCBP, must agree to follow the contraceptive guidance (see Section 10.4), 
beginning at consent and the first Screening visit and for at least 24 weeks after 
the last dose of study intervention. 
Weight  
12. BMI within the range 18.0 to 32.0 kg/m2 (inclusive).  
Informed Consent  
13. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply. 
Medical Conditions 
1. 
History of any medical condition that may interfere with the metabolism of study 
intervention or with the clinical and laboratory assessments in this study.  
2. 
History of serious, persistent medical conditions, including liver, gastrointestinal, 
pulmonary, renal, or cardiovascular abnormalities.  
3. 
History of suicidal attempt at any time or an answer of “yes” on any of the following 
items in the C-SSRS at Screening:  
a. Items 1 or 2 of the Suicidal Ideation section, if ideation occurred in the previous 
12 months.  
b. Items 4 or 5 of the Suicidal Ideation section, in lifetime.  
c. Any item of the Suicidal Behavior section of the C-SSRS, in lifetime. 
4. 
Any history of severe or recent clinically significant depression, anxiety, bipolar disorder, 
schizophrenia, or other neuropsychiatric disorder that, in the judgement of the 
Investigator, represents a safety risk to the participant were they to participate in the trial, 
as informed by the participant’s medical history and/or responses to the MINI Screen 
Questionnaire. 
5. 
History of substance use disorder (SUD) or illicit drug use (excluding cannabis) within 
the preceding 12 months. 
6. 
History of alcohol withdrawal symptoms including delirium tremens or alcohol-related 
seizures. 
7. 
Any condition that, in the opinion of the Investigator, would make the participant 
unsuitable for participation or could interfere with participation in or completion of the 
study, including: 
a. Poorly controlled or unstable hypertension. 
b. Diabetes mellitus treated with insulin or hypoglycemic agents (including metformin) 
or HbA1C > 7%. 
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c. Asthma requiring hospital admission within the preceding 12 months. NOTE: Persons 
with clinically stable asthma who have not been hospitalized in the prior year and are 
treated only with orally inhaled medications are not excluded. 
d. Currently poorly controlled endocrine conditions, except for hypothyroidism that is 
stable (no treatment change in prior 6 months). 
e. Significant infection or known systemic inflammatory process ongoing at Screening. 
f. History of chronic or recurrent UTI, or UTI within 1 month prior to Screening. 
8. 
History of malignancy within the preceding 5 years requiring treatment, with the 
exception of excised low grade basal cell skin neoplasms.  
9. 
History of any concomitant medical condition for which alcohol consumption is 
prohibited or advised against by the participant’s physician or health care provider.  
10. SARS-CoV-2 infection in the 14 days prior to randomization.  
11. Clinically significant illness within the 7 days prior to the first administration of study 
intervention. 
Prior/Concomitant Therapy  
12. History of multiple drug allergies or a history of allergic reaction to an oligonucleotide-
based therapy.  
13. Use of prescription medications (except for hormonal replacement/contraceptive 
medication for women and inhaled medication for treatment of clinically stable asthma) 
within 14 days or 5 half-lives (whichever is longer) prior to administration of study 
intervention. Participants being treated for hypothyroid disease must be on stable 
treatment (no treatment changes in the preceding 6 months).  
14. Receipt of any vaccine (including COVID-19) within 14 days prior to the first 
administration of study intervention.  
15. Regular use of OTC medications, including NSAID (periodic or occasional NSAID use 
to control temporary pain is not exclusionary).  
Prior/Concurrent Clinical Study Experience  
16. Previously participated in Dicerna Study DCR-AUD-101. 
17. Has received an investigational agent within 30 days or 5 half-lives (whichever is longer) 
prior to dosing or is in follow-up of another clinical study prior to initial dosing with the 
study intervention. 
Diagnostic Assessments  
18. Clinically significant abnormalities in vital signs at Screening: pulse rate (< 40 bpm or 
> 90 bpm), respiratory rate, or temperature. 
19. Clinically significant abnormalities in 12-lead ECG at Screening or predose on Day 1, 
including QTcF > 470 msec in females and > 450 msec in males.  
20. Positive urine drug test at Screening RU'D\í1. Tests positive for cannabis are not 
exclusionary. 
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21. Seropositive for antibodies to HIV, HBV, or HCV at Screening (historical testing may be 
used if performed within the 3 months prior to screening). NOTE: In participants with 
previous treatment for hepatitis C with direct-acting HCV medication and seropositivity 
for HCV, or in participants with prior infection and spontaneous resolution, HCV RNA 
must be undetectable (at least 2 negative HCV RNA tests at least 12 weeks apart), and 
the HCV infection must have been resolved or cured > 3 years prior to initial dosing with 
the investigational medication.  
22. Safety laboratory test result at Screening considered clinically unacceptable for study 
participation by the Investigator. 
Other Exclusions  
23. History of intolerance to SC injection(s) or significant abdominal scarring that could 
potentially hinder study intervention administration or evaluation of local injection site 
tolerability.  
24. Scheduled for an elective surgical procedure during the conduct of this study.  
25. Donation of > 500 mL of blood within the 2 months prior to administration of study 
intervention or donation of plasma within 7 days prior to Screening. 
5.3. 
Lifestyle Considerations 
Alcohol, Tobacco, and Cannabis 
1. 
Study participants are to refrain from drinking alcohol for 24 hours prior to each EIA and 
must have a negative breath-alcohol test on the day of the study visit.  
2. 
Study participants will be advised to avoid consuming more than 4 drinks during any 
drinking session outside of in-clinic EIAs.  
3. 
Study participants will be instructed to stop drinking at the onset of any ethanol reaction 
symptoms during outside drinking sessions. 
4. 
Tobacco/nicotine use is not restricted. 
5. 
Study participants are to refrain from using cannabis for 24 hours prior to each EIA and 
must have a negative urine-drug test on the day of the study visit.  
Activity 
1. 
Study participants should abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities (e.g., walking at a pace < 3 miles per hour, shopping, watering plants) in that 
24-hour time period. 
Meals and Dietary Restrictions 
1. 
For each EIA study visit, participants will be required to fast for at least 3 hours and then 
will be fed a standardized meal in the clinic prior to administration of ETOH for the EIA. 
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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Participants may undergo rescreening one time at the discretion of the Investigator or 
Sponsor. Among blood tests, only pregnancy, hematology, chemistry, and coagulation tests may 
be repeated. Blood pressure, heart rate, and ECG may be repeated for participants who have 
abnormal readings but who are otherwise healthy, and, in the opinion of the Investigator, the 
abnormal values reflect a transient departure from the range permitted for eligibility.  
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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), including placebo, intended 
to be administered to a study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
The clinical dose is expressed in terms of the weight of the DCR-AUD free acid, rather than that 
of the sodium salt (Table 4). 
Table 4: 
Study Intervention Administered  
Arm Name 
Active  
Placebo 
Intervention Name 
DCR-AUD 
Physiologic saline (0.9% aqueous 
sodium chloride) for injection 
Intervention Type 
Drug 
Drug 
Dose Formulation 
solution for injection 
n/a 
Unit Dose Strength 
160 mg/mL  
n/a 
Dose Level(s) and Frequency 
480 mg Q4W × 3 
Volume to match active, Q4W × 3 
Route of Administration 
SC injection (thigh or abdomen) 
SC injection (thigh or abdomen) 
Use 
Experimental 
Placebo comparator 
IMP or NIMP 
IMP 
n/a 
Sourcing 
Provided centrally by the Sponsor or 
designee 
Provided locally by the study site 
(Pharmacy staff is not blinded) 
Packaging and Labeling 
DCR-AUD will be provided in vials. 
Each vial will be labeled as required 
per country. 
n/a 
Abbreviations: IMP: investigational medicinal product; n/a: not applicable; NIMP: non-investigational medicinal product; 
Q4W: once every 4 weeks; SC: subcutaneous 
 
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Handling and Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and that any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply or administer study intervention.  
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Pharmacy Manual. 
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6.2.2. 
Storage 
DCR-AUD is to be stored at or below 30°C (inclusive). Do not freeze.  
All study intervention must be stored in a secure, environmentally controlled and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with access 
limited to the Investigator and authorized site staff. 
The placebo comparator should be stored in accordance with the product labeling. 
6.2.3. 
Preparation and Administration 
Study intervention will be prepared by the unblinded pharmacist or designee. A second 
medically qualified person must check the dose preparation prior to administration to be sure the 
correct dose has been prepared.  
If stored at 2°C to 8°C, DCR-AUD should be allowed to warm to room temperature for 
approximately 1 hour before administration.  
DCR-AUD is administered as a SC injection into the thigh or abdomen. The maximum volume 
of a single SC injection should not exceed 1.5 mL; the total dose will be administered as 2 SC 
injections of equal volume at separate injection sites, preferably in separate quadrants.  
Placebo will be administered as an SC injection of physiologic saline (0.9% aqueous sodium 
chloride) in the thigh or abdomen at a volume equal to that of DCR-AUD.  
All used DCR-AUD vials will be retained and quarantined in the pharmacy. Once drug 
accountability is recorded to be accurate, the vials will be destroyed on site per clinic SOP. 
Complete details will be provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a randomized, placebo-controlled, double-blind study, where the Investigators, study site 
personnel (excluding pharmacy staff), CRO staff, and study participants will be blinded for the 
duration of the study. Some members of the Sponsor team will be unblinded for the duration of 
the study. This enables the Sponsor to immediately and comprehensively evaluate the safety of 
the study participants. Complete details will be presented in the Study Blinding Plan.  
The overall DCR-AUD to placebo ratio is 3:1. All participants will be centrally assigned to 
randomized study intervention using an Interactive Voice/Web Response System (IVRS/IWRS). 
Before the study is initiated, the telephone number and call-in directions for the IVRS and/or the 
log in information and directions for the IWRS will be provided to each site. To maintain the 
study blind, the unblinded site pharmacy staff will be responsible for the preparation and 
dispensing of all study intervention. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.  
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an emergency, 
the Investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, the 
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Investigator should make every effort to contact the Medical Monitor prior to unblinding a 
participant’s treatment assignment, unless this could delay emergency treatment of the 
participant. If a participant’s treatment assignment is unblinded, the Medical Monitor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation and case report form, as applicable.  
Potentially unblinded study results will not be shared with blinded study participants or site 
personnel. 
6.4. 
Study Intervention Compliance 
At the site, study intervention will be administered by the Investigator or designee. The date and 
time of each dose administered in the clinic will be recorded in the source documents and 
recorded in the eCRF. The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention. 
6.5. 
Dose Modification 
Not applicable. See Section 7.3 for individual participant stopping rules. 
6.6. 
Continued Access to Study Intervention after the End of the Study. 
Not applicable. 
6.7. 
Concomitant Therapy 
Study participants must abstain from taking prescription or nonprescription drugs within 14 days 
or 5 half-lives (whichever is longer) prior to the first administration of study intervention until 
EOS, with the following exceptions: 
x Regular use of vitamins is acceptable. 
x Hormonal replacement/contraceptive medication for women is acceptable. 
x Inhaled medication for treatment of clinically stable asthma is acceptable.  
x Participants being treated for hypothyroid disease must be on stable treatment (no 
treatment changes in the preceding 6 months).  
x Occasional use of NSAIDs for pain management is acceptable. Regular use of OTC 
medications (including NSAIDs) is not allowed. 
x Participants must not receive any vaccine from Day í14 through Day 71 of the study.  
Any medication or vaccine (including OTC or prescription medicines, recreational drugs [with 
the exception of cannabis], vitamins, and herbal supplements) that the participant is receiving at 
the time of enrollment or receives during the study must be recorded along with:  
1. 
Reason for use.  
2. 
Dates of administration, including start and end dates. 
3. 
Dosage information, including dose and frequency. 
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6.7.1. 
Rescue Medicine 
Not applicable. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons.  
If a participant has a significant adverse reaction to alcohol at the Day –1 visit (before 
administration of DCR-AUD), the participant will be discontinued from the study. The 
participant will be replaced.  
If possible, at the time of discontinuing from the study, an early termination (ET) visit should be 
conducted, as shown in the SoA (Table 1).  
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records.  
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
eCRF. Participants who sign the ICF and are randomized but do not receive the study 
intervention may be replaced. Participants who sign the ICF, are randomized and do receive the 
study intervention and subsequently withdraw or are withdrawn or discontinued from the study 
may be replaced at the discretion of the Sponsor. 
7.2. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site despite multiple attempts.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:  
x The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.  
x Before a participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.  
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x Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
7.3. 
Individual Participant Stopping Rules 
7.3.1. 
Serious Adverse Event 
If a participant experiences an SAE (Section 10.3.2), unless it is clearly the result of a non-study-
related event, further dosing of the participant will be paused while the SRC reviews the event. 
Based on this review, a decision will be made as to whether the participant may continue to 
receive doses of study intervention. In participants who have completed dosing, continued 
follow-up with protocol-specified assessments, including subsequent EIAs, will be pursued if the 
participant is willing and the PI determines it is safe to do so. Additional EIAs will not be 
performed if, in the clinical judgment of the PI and/or SRC, the SAE could be related to study 
intervention and that repeat EIAs pose a recurrent risk to the participant, or if the participant 
declines these additional assessments. Participants will continue to be followed for other study 
procedures as detailed in the SoA. 
7.3.2. 
Abnormal Liver Function Tests 
Discontinuation of study intervention is required when a participant meets one of the conditions 
outlined in Section 10.6. Discontinuation of study intervention may also be considered in the 
presence of other abnormal liver function tests, if the Investigator believes that it is in best 
interest of the participant. 
7.3.3. 
Electrocardiogram Findings 
If a clinically significant finding is identified (including, but not limited to, the QTcF findings 
below) after enrollment, the Investigator or qualified designee will determine if the participant 
can continue in the study and if any change in participant management is needed. This review of 
the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE.  
x Absolute QTcF > 500 msec and/or  
x QTcF change of > 60 msec from baseline and >450 msec.  
x New and clinically significant arrhythmia or rhythm abnormality. 
7.3.4. 
Significant Negative Reaction to Alcohol Ingestion 
Any participant who experiences a significant negative reaction to alcohol ingestion that includes 
severe or serial vomiting or hemodynamic instability (syncope or significant pre-syncope, or BP 
decline of more than 25 mmHg from Baseline with some lightheaded symptoms, or HR increases 
to  110 bpm with some symptoms during an EIA) will be discontinued from additional dosing 
and will be advised to not drink outside of the clinic for the duration of the study. The participant 
will continue to be followed in the study for other protocol-specified procedures. The PI will 
determine if additional/subsequent protocol-specified EIAs will be conducted, based on the 
nature and severity of symptoms observed. 
See Section 8.6.1.3 regarding full details on stopping rules for conduct of an EIA. 
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7.4. 
Study Stopping Rules 
All further dosing in the study will be stopped if any of the following conditions occur AND the 
SRC recommends stopping the study:  
x 2 participants develop a Grade 3 CTCAE event, unless it is clearly the result of a non-
study-related event.  
x SDUWLFLSDQWGHYHORSVD*UDGH&7&$(HYHQW, unless it is clearly the result of a 
non-study-related event. 
All further DCR-AUD dosing and subsequent EIAs will be stopped if the following occurs AND 
the SRC recommends stopping the study: 
x 3 participants treated with DCR-AUD experience significant or severe adverse 
symptoms associated with alcohol ingestion. In the event this occurs, all study 
participants will be advised to avoid alcohol for the remainder of the study period. 
In the event a study stopping rule is triggered and the SRC calls a halt on dosing, the SRC may 
request that an external, independent, unblinded DSMC be convened to review the decision and 
make a recommendation to the SRC as to whether the study should stop or continue with no 
changes or continue with appropriate modifications to address the safety concern (see 
Section 10.1.5). Should the DSMC recommend stopping the study, all ongoing participants will 
continue to be followed for safety assessments as indicated in the schedule of activities.  
The Sponsor will promptly notify the site if study stopping rules are triggered. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Section 1.3. Adherence to the study design 
requirements, including those specified in Table 1, Table 2, and Table 3 (Section 1.3) is essential 
and required for study conduct.  
Protocol waivers or exemptions are not allowed. Participants may undergo rescreening one time 
at the discretion of the Investigator or Sponsor (Section 5.4). 
Urgent safety concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness.  
Participants will be given a diary to track AEs associated with alcohol intake for the study 
duration. Participants will be trained on the use of the diary prior to discharge from the clinic for 
Week 1 and will report on the diary at each visit.  
If multiple assessments are due, the order of priority should be ECG, vitals, blood draws, and 
then other assessments.  
The maximum amount of blood drawn from each participant (including PK, biomarker, and 
safety laboratory testing) will not exceed 550 mL over an 8-week period. 
8.1. 
Efficacy Assessments 
This is a Phase 1 study with the primary objective of evaluating safety. Pharmacokinetic and PD 
assessments are detailed in Section 8.5 and Section 8.6, respectively.  
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As the study participants are HV not diagnosed with AUD, no true assessment of efficacy can be 
made. However, study participants may be inclined to change their alcohol intake should they 
experience physiologic symptoms associated with increased acetaldehyde while drinking. As 
such, 2 assessments of alcohol intake, TLFB and PEth, will be considered in exploratory 
analyses. 
8.1.1. 
Alcohol Consumption via Timeline Follow Back 
Participants will complete the TLFB at screening and throughout the study period to capture any 
change in drinking behavior. At every visit, the TLFB will be used to assess each participant’s 
alcohol consumption for the 2-week period that precedes the study visit.  
The TLFB was developed as a procedure to aid recall of past drinking (Sobell & Sobell, 1992). 
Currently, self-reports are the only viable method for retrospectively measuring drinking with 
any precision. Alternative methods exist, but they are either impractical (e.g., continuous direct 
observation), fraught with problems (e.g., alcohol sweat patches), or they only measure very 
recent drinking (e.g., blood alcohol tests). TLFB stands as the most exhaustively evaluated 
method that can be used to retrospectively assess drinking behavior over time. 
8.1.2. 
Blood Phosphatidylethanol Levels 
Hepatic ethanol oxidation is the prevalent route of human ethanol metabolism, eliminating more 
than 90% of ingested ethanol. Several nonoxidative routes of ethanol metabolism that result in 
the enzymatic conjugation of ethanol to endogenous metabolites have also been described. Due 
to slower elimination rates, these nonoxidative ethanol metabolites persist in body fluids and 
tissues for much longer than ethanol itself, thus enabling the retrospective assessment of ethanol 
intake even when ethanol itself is no longer present in the body. 
Phosphatidylethanol (PEth) is a phospholipid produced in erythrocyte membranes after alcohol 
exposure, first described by Alling et al. (1983). In drinking experiments, PEth production began 
as soon as ethanol was consumed and peaked 1 to 3 hours after alcohol consumption 
(Gnann et al., 2012; Heier et al., 2016). With frequent alcohol consumption, and a half-life of 
approximately 5 days, PEth accumulates in whole blood (Javors et al., 2016). Because PEth can 
be detected in blood for up to one month after one-time alcohol intake, it can be used as a 
biomarker to determine both current and recent consumption (Kummer et al., 2016).  
Ulwelling & Smith (2018) proposed 3 ranges of PEth values likely to describe a person’s 
average recent alcohol consumption/drinking behavior:  
x <20 ng/mL  
Abstinence or light drinking (0 to <2 drinks/day) 
x 20 – 199 ng/mL 
Moderate drinking (2 to 4 drinks/day for several days a week) 
x > 200 ng/mL 
Heavy drinking (at least 4 drinks/day for several days a week) 
Thus, PEth may be used to identify and/or monitor individuals with chronic excessive drinking 
behavior (Viel et al., 2012). 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). Safety 
assessments will be conducted in all participants at every study visit unless otherwise specified. 
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Site personnel will be provided training in the use of all study-specific instruments (see the Study 
Reference Manual). 
8.2.1. 
Screening Tests 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.2.1.1. 
Mini-International Neuropsychiatric Interview 
The MINI Screen is a brief structured diagnostic interview to meet the need for a short but 
accurate structured psychiatric interview for multicenter clinical trials (Sheehan et al., 1998). 
This validated tool can be administered in a short period of time (approximately 15 minutes) and 
will be administered at screening to exclude participants with major psychiatric disorders. The 
MINI Screen will be administered by a Health Care Provider. 
8.2.1.2. 
Laboratory Tests to Determine Eligibility 
In addition to the hematology, clinical chemistry, coagulation, and urinalysis panels indicated in 
Table 6, the following tests will be performed during screening: 
x Follicle-stimulating hormone (as needed to confirm menopausal status) 
x Viral serology (human immunodeficiency virus antibody, hepatitis B surface antigen, 
and hepatitis C virus antibody) 
x Hemoglobin A1c 
x Urine drug screen (to include, at a minimum, amphetamines, barbiturates, cocaine, 
opiates, and benzodiazepines) 
8.2.2. 
Physical Examinations 
Complete physical examinations will be conducted at every visit. Physical examinations will 
include, at a minimum, assessments of the Cardiovascular, Respiratory, Gastrointestinal, 
Neurological, and Skin systems. Height will be measured and recorded at Screening. Weight will 
be measured and recorded at every visit.  
x Investigators should pay special attention to clinical signs related to previous serious 
illnesses or AEs. 
x All physical examinations should include inspection of the injection site. 
8.2.3. 
Vital Signs 
Temperature by skin refraction, pulse rate, respiratory rate, and blood pressure will be assessed, 
unless otherwise indicated in the SoA.  
Blood pressure and pulse measurements will be assessed in the seated position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
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Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).  
Temperature will be obtained in degrees Celsius (°C), pulse rate will be counted for a full minute 
and recorded in beats per minute, and respirations will be counted for a full minute and recorded 
in breaths per minute.  
Note: In addition to standard vital sign measurements for safety, vital signs will be recorded as 
part of the EIA and results will be identified as such (e.g., HR for EIA) in the eCRF 
8.2.4. 
Electrocardiograms 
Standard 12-lead ECGs will be performed in the supine position after the participant has rested 
comfortably for 5 minutes. ECGs will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and corrected QT interval (QTcF, Fridericia 
correction). Refer to Section 7.3.3 for QTc withdrawal criteria and any additional readings that 
may be necessary. Screening ECGs may not be repeated for determination of eligibility. 
The Investigator or designee is responsible for reviewing the ECGs to assess whether the results 
are within normal limits and to determine the clinical significance of the results. These 
assessments will be recorded on the CRF.  
ECGs also will be conducted for EIA assessments. These ECG results will be recorded as part of 
the EIA and will be identified as such (e.g., ECG for EIA) in the CRF. 
Note: If multiple assessments are due, the order of priority should be ECG, vitals, blood draws, 
and then other assessments, with the PK sampling being performed preferably at the nominal 
time point.  
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Patients diagnosed with AUD may be at risk for SIB. Because DCR-AUD is being developed for 
the treatment of AUD, HV will be screened and monitored for the presence or emergence of SIB 
while on study. Consideration should be given to discontinuing study intervention in participants 
who experience signs of SIB, following a risk assessment.  
8.2.5.1. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a suicidal ideation rating scale created by researchers at Columbia University 
(Posner et al., 2011). It rates an individual's degree of suicidal ideation on a scale, ranging from 
“wish to be dead” to “active suicidal ideation with specific plan and intent.”  
The scale identifies behaviors that may be indicative of an individual's intent to commit suicide. 
The C-SSRS is used extensively across primary care, clinical practice, surveillance, research, and 
institutional settings and is part of a national and international public health initiative involving 
the assessment of suicidal ideation and behavior. The C-SSRS requires no mental health or 
medical training to administer it. The C-SSRS will be administered by site personnel who are 
trained in its administration. 
The Baseline version will be administered at Screening and at subsequent visits the “C-SSRS 
Since Last Visit” version will be administered. 
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8.2.6. 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoAs 
(Section 1.3) for the timing and frequency.  
The Investigator must review the laboratory report, document this review in the eCRF, and 
record any clinically relevant changes occurring during the study in the AE section of the eCRF. 
The laboratory reports must be filed with the source documents. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated (central laboratory) until the values return to normal or stabilize 
at a level no longer considered clinically significant by the Investigator or Medical Monitor.  
x If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified.  
x All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the Laboratory Manual and the SoA (Section 1.3).  
x If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE), then the results 
must be recorded in the eCRF. 
8.2.7. 
Pregnancy Testing 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test. If a urine test is positive, it must be confirmed with a 
serum test. See Section 8.3.5 for reporting of pregnancy in a study participant or the partner of a 
male participant. 
Additional pregnancy testing should be performed as indicated in SoA (Section 1.3). 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected.  
Pregnancy testing with a sensitivity of at least 25 mIU/mL will be performed. 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs, SAEs, and adverse events of special interest (AESI) can be found in 
Section 10.3.1, Section 10.3.2, and Section 10.3.3, respectively.  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are severe or serious, and considered related to the study intervention or study 
procedures, or that caused the participant to discontinue study intervention or the study. 
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8.3.1. 
Time Period and Frequency for Collecting Adverse Event Information 
All AEs and SAEs will be collected from the time the ICF is signed through the last follow-up 
visit at the time points specified in the SoAs (Section 1.3).  
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 10.3.5. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available.  
Investigators are not obligated to actively seek AE or SAE after conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
Injection sites will be examined by study staff for assessment of ISRs (Section 10.3.3). 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AESIs (as defined in Section 10.3.3), will 
be followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.2). Further information on follow-up procedures is 
provided in Section 10.3.4. If symptoms related to ethanol ingestion that the Investigator 
considers relevant are present at the end of study, the Sponsor may request continued contact 
with participants in order to collect further data. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRBs/IECs, and Investigators.  
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
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it with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate, according to local 
requirements. 
8.3.5. 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until 24 weeks after the last dose.  
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4.3.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.  
The participant or pregnant partner will be followed to determine the outcome of the pregnancy. 
The Investigator will collect follow-up information on the participant or pregnant partner and the 
neonate, and the information will be forwarded to the Sponsor.  
Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
8.4. 
Treatment of Overdose 
For this study, any dose of DCR-AUD greater than 960 mg will be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose.  
In the event of an overdose, the Investigator should:  
x Keep the participant under observation at least overnight. The Investigator will use 
his or her judgment to determine if it is safe for the participant to undergo the EIA 
scheduled for that visit. 
x Closely monitor the participant for any AEs or laboratory abnormalities until 
DCR-AUD PD effects can no longer be detected.  
x Contact the CRO Medical Monitor immediately.  
x Document the quantity of the excess dose. 
It should be noted that an overdose is not an AE, in and of itself. See Section 10.3.1 for details. 
8.5. 
Pharmacokinetics 
Blood samples (2 mL) will be collected for measurement of plasma concentrations of DCR-AUD 
and its metabolites as specified in the SoAs (see Section 1.3).  
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in the Laboratory Manual and the Laboratory Specification document. The actual date 
and time (24-hour clock time) of each sample will be recorded.  
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Each plasma sample will be divided into 2 aliquots (one for PK and one backup). Samples 
collected for analyses of plasma concentrations of DCR-AUD and its metabolites may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the study.  
Pharmacokinetic parameters to be determined may include area under the concentration curve 
(AUC), minimum observed concentration (Cmin), maximum observed concentration (Cmax), time 
to maximum concentration (Tmax), terminal elimination half-life (t1/2), apparent clearance (CL/F), 
and apparent volume of distribution (Vd/F). Additional parameters may be estimated if deemed 
appropriate.  
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files but will not constitute a protocol amendment. The IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF.  
Drug concentration information that may be unblinding will not be reported to investigative sites 
or blinded personnel until the study has been unblinded. 
8.6. 
Pharmacodynamics 
DCR-AUD is designed to selectively reduce ALDH2 activity in the liver and the conversion of 
acetaldehyde to acetic acid after alcohol consumption. The build-up of acetaldehyde causes 
unpleasant effects after drinking (e.g., flushing, headache, lightheadedness, palpitations, nausea, 
or vomiting). As such, the PD activity of DCR-AUD will be assessed during EIAs via these 
6 symptoms, blood biomarkers (ethanol, acetaldehyde, and acetate), and heart rate.  
Published literature consistently demonstrate that administration of low/moderate alcohol intake 
(0.1 to 0.8 g/kg) in human ALDH2 mutation homo- or heterozygotes results in clearly 
differentiated increases in blood acetaldehyde and heart rate compared with ALDH2 normal 
alleotypic controls (Bae et al., 2012; Peng et al., 1999; Peng et al., 2007; Nishimura et al., 2002; 
Enomoto et al., 1991).  
8.6.1. 
Ethanol Interaction Assessments 
Serial EIAs will be performed to assess the indirect PD effects of ALDH2 reduction 
(acetaldehyde increase). EIAs will be conducted in accordance with the SoA in Section 1.3. 
Should an EIA be missed, due to COVID-19 or other circumstances, the missed EIA may be 
conducted at an unscheduled visit at the discretion of the Investigator and the Sponsor.  
Participants will be required to be fasted for at least 3 hours prior to administration of a 
standardized meal and must have a negative breath alcohol test on the day of the study visit prior 
to the EIA. Prior to each EIA, venous catheters will be placed at least 20 minutes before the first 
EIA vital signs are assessed at time 0. For EIAs conducted prior to a dosing day, the venous 
catheter will be left in place for PK sample collections. 
Participants will consume a fixed dose of ethanol mixed in a liquid that has no additional 
alcohol, no caffeine, and is low in sugar. The ethanol dose will be 0.8 g/kg (to a maximum of 
56 g) for male participants and 0.68 g/kg (to a maximum of 48 g) for female participants. 
Ethanol will be consumed in 4 equal aliquots over an 80-minute period (20 minutes for each 
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aliquot). During the EIA, participants will receive nothing by mouth (remain NPO) except water 
ad libitum. Assessments will be made over an estimated 4-hour period, as detailed in Table 3.  
Participants will remain in the Phase 1 unit for over-night observation. The Investigator will not 
discharge any participant experiencing ongoing effects of ethanol administration and will not do 
so until it is deemed medically safe to do so. 
8.6.1.1. 
EIA Blood Biomarkers 
Blood biomarkers to be assessed include measurement of acetaldehyde, acetate, and ethanol. 
Blood samples (2 mL) will be collected via a venous access device at the times indicated in 
Table 3. Additional details regarding blood sample collection and processing will be detailed in 
the Laboratory Manual. 
As plasma biomarker data may be unblinding, results will not be reported to investigative sites or 
blinded personnel until the study has been unblinded. 
8.6.1.2. 
EIA Physiologic Signs and Symptoms 
EIA assessments will include the direct questioning of participants as to the presence of ethanol 
reaction symptoms (flushing, headache, lightheadedness, palpitations, nausea, and vomiting) at 
the times indicated in Table 3. Note: the presence of these ethanol reaction symptoms will not be 
considered AEs. 
A composite 6-symptom score for each participant during each EIA will be determined as 
follows: 
x At each of the timepoints during the EIA, each symptom will be given a numeric 
score of 0 (not present) to 3 (present and severe), with the exception of vomiting, 
which will be given a score of 3. 
x The composite symptom score for each of the EIA timepoints will be the summed 
value for each of the 6 symptoms at that timepoint (range 0 – 18). 
x The Peak score for a given day's EIA will be the participant’s highest post-alcohol 
ingestion timepoint score minus the participant’s pre-alcohol score. 
Vital signs (BP and heart rate) and standard 12-lead ECGs will be recorded at the times indicated 
in Table 3.  
8.6.1.3. 
Stopping Rules for an EIA 
During the conduct of an EIA, administration of alcohol to a participant may be stopped for the 
following physiologic responses, though follow-up EIA assessments will be conducted:  
x Any vomiting or severe nausea (as judged by Investigator)  
x Systolic blood pressure increase of > 25 mmHg (or to a level > 160 mmHg) or 
decrease of > 15 mmHg to < 70 mmHg or any decline accompanied by symptomatic 
hypotension (pre-syncope, syncope, lightheadedness) 
x Diastolic blood pressure decrease to < 50 mmHg or any decline accompanied by 
symptomatic hypotension (pre-syncope, syncope, lightheadedness)  
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x HR increase of > 20 beats per minute and to a level > 100 beats per minute  
x Temperature increase of > 1°Celsius  
x Any clinically meaningful change in affect or clinical status, per Investigator or 
supervising designee’s clinical judgment 
8.6.1.4. 
Follow-up of Participants Who Continue to have Positive Ethanol Reaction 
Symptoms at Day 168 (Conditional Follow-up) 
All participants who have ethanol reaction symptoms during the Day 168 EIA will be instructed 
to continue limit drinking to 4 drinks or less during any drinking session.  
Participants who present clinically significant positive ethanol reaction symptoms at the Day 168 
EIA (flushing, headache, lightheadedness, palpitations, nausea, or vomiting) that the PI considers 
severe and/or warranting further follow-up, will be followed for an additional 4 weeks (through 
Day 197; see Table 1). If symptoms related to ethanol ingestion that the Investigator considers 
relevant are present at Day 197, the Sponsor may request continued contact with participants in 
order to collect further data.  
8.6.2. 
Presence of Physiologic Symptoms Associated with Consumption of Ethanol 
Outside of EIAs 
Participants will be allowed to continue drinking alcohol in the windows between study visits, 
but will be advised not to drink more than 4 drinks in any one drinking session. Participants will 
be given a diary to report the occurrence and severity of any physical symptoms that occur with 
alcohol consumption outside of the in-clinic EIAs.  
Participants will be instructed to stop drinking at the onset of any symptoms during outside 
drinking sessions. 
8.7. 
Genetics 
Unpleasant reactions to alcohol consumption in humans with naturally occurring ALDH2 
mutations are thought to be protective against AUD and account for its low prevalence in 
individuals who are heterozygous or homozygous for ALDH2 allele mutations. A 6 mL sample 
of whole blood for DNA isolation will be collected from participants who have consented to 
ALDH2 genotyping. Participation is optional; participants who do not wish to undergo 
genotyping may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample, 
unless it was included in the original consent.  
See Section 10.5 for information regarding the use of DNA samples. Details on processes for 
collection and shipment and destruction of these samples can be found in the Laboratory Manual. 
8.8. 
Immunogenicity Assessments 
Serum samples for the detection and characterization of antibodies to DCR-AUD will be stored 
until a validated assay method is available.  
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Serum samples will be collected at times specified in the SoA (Section 1.3). Additionally, serum 
samples should also be collected at the final visit from participants who discontinued study 
intervention or were withdrawn from the study.  
Serum samples will be screened for antibodies binding to DCR-AUD, and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to DCR-AUD and/or further characterize the immunogenicity of DCR-AUD.  
Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
activity of DCR-AUD.  
8.9. 
Health Economics 
Health Economics parameters are not planned for this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
Statistics will be descriptive. No tests of statistical inference are planned. 
9.2. 
Sample Size Determination 
No formal sample size estimations were performed. The sample size of 16 participants (12 active 
and 4 placebo) was considered sufficient to provide an initial assessment of the safety profile of 
DCR-AUD in HVs, and adequate for the purpose of describing PK/PD data in HVs. 
The sample size is based on clinical rather than statistical considerations. 
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9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined. 
Population 
Description 
Enrolled 
All participants who sign the ICF. 
Randomized 
All participants who sign the ICF and who are randomized to 
study intervention. 
Pharmacokinetic 
All participants randomized to study intervention and who receive 
at least 1 dose of DCR-AUD and have at least 1 postdose PK 
assessment. 
Pharmacodynamic 
All participants randomized to study intervention and who receive 
at least 1 dose of DCR-AUD or placebo and have at least 
1 postdose PD assessment 
Safety 
All participants randomized to study intervention and who receive 
at least 1 dose of DCR-AUD or placebo. Participants will be 
analyzed according to the initial dose received.  
 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock. The SAP will include 
a more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.4.1. 
General Considerations 
In general, summary statistics (n, mean, SD, median, minimum, and maximum for continuous 
variables, and number and percentage of participants in each category for categorical variables) 
will be provided for all variables.  
Baseline is defined as the last non-missing measurement prior to the date and time of the dose of 
study intervention. 
All analyses will be based on observed data without imputation for missing values. Except for 
outlier analyses, measurements collected from unscheduled visits will not be included in the 
summary tables or figures but will be included in the participant listings. Source data for the 
summary tables and statistical analyses will be presented as participant data listings. 
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9.4.2. 
Primary Endpoint(s) 
The primary endpoints of the study are the assessment of the incidence and severity of AEs and 
SAEs, and the changes from baseline in vital signs, 12-lead ECG, clinical laboratory tests, and 
physical examination findings. 
All safety analyses will be performed on the Safety Population. Adverse events will be defined 
as treatment-emergent AEs if they have a start date on or after the administration of study 
intervention during the treatment period. Frequency and percentages by treatment group will be 
used to summarize AEs, SAEs, AEs of special interest, and AEs by relationship.  
Descriptive statistics and changes from baseline will be provided for vital signs, 12-lead ECG, 
clinical laboratory tests, and physical examination findings by treatment group and visit. 
Laboratory parameter shifts from baseline to abnormal post-baseline values will be presented by 
treatment group. Mean laboratory values over time will be plotted by dose group. 
By-participant listings will be provided for all the safety parameters. 
9.4.3. 
Secondary Endpoints 
PD analyses will be performed on the Pharmacodynamic Population, and PK analyses will be 
performed on Pharmacokinetic Population. Actual sampling times will be used for all parameter 
estimations. The principal secondary endpoint of interest will be the change from baseline in the 
composite 6-symptom score after EIAs (as described in Section 8.6.1.2).  
9.4.3.1. 
EIA Composite Score 
EIAs will include an active assessment of the 6 key symptoms (flushing, headache, palpitations, 
lightheadedness, nausea, and vomiting) that DCR-AUD may elicit, in order to determine if the 
protocol-specified DCR-AUD dose regimen gives the proper constellation of these symptoms. 
These symptoms will be collected by active questioning of each participant at different time 
points during each EIA.  
The following symptom scoring framework would be described as an arbitrary point system, 
where: 
Symptom 
No Symptom 
Mild symptom 
Moderate symptom 
Severe symptom 
Score 
0 
1 
2 
3 
Each participant at each timepoint in an EIA after alcohol administration will be given a 
composite score for that timepoint as sum of all 6 symptom scores.  
Baseline is defined as last non-missing value prior to alcohol administration. 
Descriptive statistics of EIA composite score (n, mean, median, IQR [Inter Quartile Range], 
minimum and maximum) for absolute values and changes from baseline will be presented by 
treatment, placebo, visit, and time point.  
Descriptive statistics of Peak EIA composite score (n, mean, median, IQR, minimum and 
maximum) for absolute values and changes from baseline will be presented by treatment, 
placebo, and visit (Days). The Peak EIA composite score is defined as maximum composite 
score at each visit. 
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9.4.3.2. 
Blood Biomarkers 
Descriptive statistics and change from baseline will be provided for blood PD assessments, 
including acetaldehyde accumulation (absolute values and AUC) during the EIAs, where 
applicable.  
9.4.3.3. 
Pharmacokinetics 
Plasma concentrations and PK parameters will be listed and summarized by group and by time 
point with descriptive statistics. The arithmetic mean, SD, CV%, geometric mean, geometric 
CV%, minimum, median, and maximum will be presented.  
Additional PK parameters may be estimated if deemed appropriate. Details will be provided in 
the PK Analysis Plan. Analysis of PK parameters may be reported in a supplement to the CSR.  
PK analyses will be conducted with noncompartmental and/or compartmental models to 
determine PK parameter estimates. Population PK and Population PK-PD analyses may be 
performed and will be reported in a separate report. 
9.4.4. 
Exploratory Endpoint(s) 
The exploratory endpoint of change in drinking amounts will be assessed using the TLFB and by 
analysis of blood levels of phosphatidylethanol.  
Average daily drinking amounts over each 2-week period after the start of dosing will be 
compared to the amount during the 2-week period before first dose. Change in drinking amounts 
for each postdose period will be evaluated in connection with changes in EIA-induced peak 
symptoms and plasma acetaldehyde levels during the preceding EIA. 
Other exploratory analyses will be conducted as deemed appropriate and will be detailed in the 
SAP.  
9.5. 
Interim Analysis 
In order to enable decision making for the future clinical development of DCR-AUD, an interim 
analysis may be conducted after all participants have received all 3 doses of study intervention.  
Variables to be analyzed may include assessments of safety (AEs, laboratory testing, physical 
findings), pharmacokinetics, and pharmacodynamics (blood biomarkers and physiologic signs 
and symptoms). Should the interim analysis be conducted, complete details will be provided in 
the SAP. 
9.6. 
Safety Review Committee and Data Safety Monitoring Committee 
An SRC will conduct periodic reviews and will review all cumulative safety, tolerability, and 
available PD data on participants. Participant safety will be continuously monitored by the SRC 
by ongoing review of AEs, laboratory results, and other protocol-specified assessments, to allow 
safety signal detection throughout the study.  
Table 5 shows the minimal required timing of reviews by the SRC, as well as the decisions that 
the SRC may undertake with respect to the possible occurrence of study stopping rules (see 
Section 7.4).  
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At its discretion, and based on clinical judgment, the SRC may suspend DCR-AUD dosing or 
EIAs during the study at any time, even for reasons not explicitly stated elsewhere, and refer to 
the DSMC for any potential concern regarding participant safety or wellbeing. In addition, the 
DSMC will be convened on an ad hoc basis if an AE does trigger a stopping rule. The DSMC 
will review data and advise on whether the study should be stopped to ensure the safety of study 
participants. 
Complete details on the responsibilities of the Safety Committees will be detailed in the 
committee charters. For additional details on the composition of the SRC and DSMC, refer to 
Section 10.1.5. 
 
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Table 5: 
Minimal Timing of the Safety Review Committee Data Reviews 
Occurrence of a 
significant or severe 
adverse symptom 
Upon the occurrence of a significant or severe adverse symptom (see Section 7.3), 
all dosing and enrollment into the study will be interrupted until safety data can be 
reviewed by the SRC. The SRC will review the events associated with the 
significant or severe adverse symptom as well as the cumulative safety data 
collected on all participants previously dosed. The SRC will determine whether 
dosing, enrollment, and subsequent EIAs may resume. 
Occurrence of a safety 
issue that, in the SRC’s 
clinical judgment, could 
affect participant safety 
or study conduct  
Upon the occurrence of a situation or safety question that could affect participant 
safety or study conduct, the SRC will meet to discuss the issue. Actions to be taken 
include, but are not limited to: 
x Discontinuation of an individual participant 
x Discontinuation of dosing  
x Discontinuation of additional EIAs 
x Referral to the DSMC for review and recommendation, should a pattern of 
AEs of concern be identified, regardless of severity 
Occurrence of a 
potential study stopping 
rule 
Upon the occurrence of a potential study stopping rule (see Section 7.4), all dosing 
and enrollment will be interrupted until safety data can be reviewed by the SRC. 
The SRC will review the events associated with the triggering of the stopping rule 
as well as the cumulative safety data collected on all participants previously dosed. 
The SRC will determine whether dosing and enrollment may resume. The SRC may 
elect to refer the issue that triggered the study interruption to the DSMC for an 
independent review and recommendation regarding study resumption.  
Abbreviations: AE: adverse event; AUD: alcohol use disorder; DSMC: Data Safety Monitoring Committee; EIA: ethanol 
interaction assessment; SRC: Safety Review Committee  
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following:  
x Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines  
x Applicable ICH Good Clinical Practice (GCP) Guidelines  
x Applicable laws and regulations  
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
The Investigator will be responsible for the following:  
x Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC  
x Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
x Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
Each interested prospective participant (or legally authorized representative) will receive an 
informed consent document that contains study information and be given ample time to read the 
information and consider participation. The Investigator or his/her representative will explain the 
nature of the study and its risks and potential benefits to the prospective participant or his/her 
legally authorized representative and answer all questions regarding the study. 
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Prospective participants must be informed that the study involves research, their participation is 
voluntary, and that the choice not to participate or to discontinue the study at any time will 
involve no penalty or loss of benefits to which the individual is otherwise entitled. Consenting 
participants, or their legally authorized representatives, will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study, and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.  
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.  
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participants, who will be required to give consent for their data to be used as 
described in the informed consent  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
10.1.5.1. Safety Review Committee 
The SRC will comprise the PI and/or sub-Investigator, the Sponsor Medical Monitor, and the 
CRO Medical Monitor.  
See Section 9.5 for further details regarding the SRC. 
10.1.5.2. Data Safety Monitoring Committee 
The independent DSMC will comprise appropriately qualified clinicians who are not involved in 
the study. The DSMC will provide a comprehensive review of study safety and tolerability data 
on an ad hoc basis. Further operational details will be prespecified in the DSMC charter. 
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10.1.6. 
Dissemination of Clinical Study Data  
Data collected during the study will be shared with Investigators whose proposed use of the data 
has been approved by an independent review committee. A tabular summary of study results will 
be posted to www.ClinicalTrials.gov within 1 year of study completion. 
10.1.7. 
Data Quality Assurance 
 will use an electronic data capture system to completely collect all medical data during 
this trial. ClinBase™ is a software tool designed similarly to an electronic medical record for the 
documentation of e.g., medical history, demographics, vital signs, and AEs. Unlike a system 
(which is relying on data from other sources like paper records and is setup just to digitize these 
data for transmission), ClinBase ensures quality assurance and enables comprehensive capture of 
all relevant medical information gathered during clinical studies. Through a system provided 
workflow that includes barcode scanning and interfaces to medical equipment, trial operations 
performance is controlled and captured in real time. Thus, the system provides 100% 
transparency for monitors and is at any time accessible to the Investigators and clinical personnel 
for all medical documentation processes. 
ClinBase meets ICH GCP requirements as data are attributable, legible, contemporaneous, 
original, accurate, and complete (ALCOA-C). The system is fully Code of Federal Regulations 
(CFR) Title 21 Part 11 compliant. 
The Investigator will ensure the accuracy, completeness and timeliness of the data reported to the 
Sponsor. System supported data collection processes and procedures are validated to ensure 
completeness, accuracy, reliability, and consistency. A complete audit trail is maintained of all 
data changes. The Investigator or designee will cooperate with the Sponsor’s representative(s) 
for the periodic review of trial documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit. 
Electronic consistency checks (plausibility and completeness) will be used along with the 
Investigator review to identify any errors or inconsistencies in the data. Data clarification 
requests will be provided to the trial team by means of electronic or manual queries. 
During the trial setup, adequate and accurate clinical procedure forms are used to generate 
medical records, digital ECGs, AE and concomitant medication reporting, raw data collection 
forms, etc., which are designed as protocol to record all observations and other pertinent data for 
each subject receiving trial medication. The only regularly used paper-based trial document is the 
ICF because it requires wet-ink signatures. The ICFs will be archived in paper form at the end of 
the trial. Should additional paper forms be used, the recorded data must be transferred into 
ClinBase accurately and within due time. In pre-stabilized intervals or at the end of the trial, data 
will be exported from ClinBase data management systems for further processing. 
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors and the IRB to have direct access to all electronic records pertaining to the 
trial. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
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Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study, including quality 
checking of the data.  
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs).  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 5 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants.  
The first act of recruitment is site activation and will be the study start date.  
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.  
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.  
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:  
x Investigator noncompliance with the protocol, GCP, or regulatory requirements  
x Unsatisfactory enrollment with respect to quantity or quality  
x Incomplete data collection; inaccurate or knowingly false data submission  
x The PI is no longer capable of performing the tasks of the PI, and no replacement can 
be found.  
x The SRC determines that termination of the study is in the best interest of the 
research participants. 
x The Sponsor, Investigator or IRB/IEC determines that continuation of the study will 
not serve any scientific purpose.  
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x Circumstances beyond the control of the Sponsor or Investigator make it 
unreasonable to require the study’s continuation. 
x A request to discontinue the study by a regulatory or health authority.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participants and should assure appropriate participant 
therapy and/or follow-up. The complete set of stopping rules is detailed in Section 7. 
10.1.9. 
Publication Policy 
Publication of a summary of the results of the study is permissible according to the Sponsor and 
is not inconsistent with the preceding affirmation. Scientific dissemination of the results of this 
study is encouraged. Any formal publication of data collected as a result of the study will be 
considered a joint publication by the Investigator and the appropriate personnel of the Sponsor or 
their designees. Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
No submission of a manuscript may be made until the results from the study site have been 
received and analyzed by Sponsor, or the study has been terminated at all centers. A separate, 
individual publication of the results of the study will be delayed until initial publication of the 
results of the multi-center study, or a decision not to publish is made. Please refer to clinical 
study agreement for further details.  
For any publication or presentation, a manuscript of the paper or abstract must be received and 
approved by the Sponsor prior to outside submission. Whether or not there is a Sponsor author of 
the publications or presentations, a manuscript will be forwarded to the Sponsor for review and 
approval at least 30 days prior to submission of a journal publication, or at least 10 days prior to 
submission of an abstract.  
Note: Any language relating to these issues appearing in the clinical study agreement will 
supersede that which is outlined in this section. 
10.2. 
Clinical Laboratory Tests 
Table 6 summarizes the laboratory tests to be conducted. Full details for the testing are provided 
in the laboratory manual. Protocol-specific requirements for inclusion or exclusion of 
participants are detailed in Section 5.  
Additional tests may be performed during the study as determined necessary by the Investigator 
or required by local regulations.  
Investigators must document their review of each laboratory safety report.  
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
 
 
 
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10.3. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of study intervention.  
Events Meeting the AE Definition  
x Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator.  
x Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition.  
x New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.  
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.  
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.  
Events NOT Meeting the AE Definition  
x During the conduct of EIAs, participants will be questioned by site staff to assess the 
6 symptoms (flushing, headache, lightheadedness, palpitations, nausea, and vomiting) 
associated with increased blood acetaldehyde levels. These symptoms solicited via 
active questioning do not meet the AE definition. 
x Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.  
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).  
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.  
10.3.2. 
Definition of Serious Adverse Event  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 
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An SAE is defined as any untoward medical occurrence that, at any dose:  
x Results in death  
x Is life-threatening  
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.  
x Requires inpatient hospitalization or prolongation of existing hospitalization  
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.  
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. Pre-planned hospitalizations scheduled prior to signing the 
ICF, for an elective medical/surgical procedure do not meet this criterion.  
x Results in persistent disability/incapacity  
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.  
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.  
x Is a congenital anomaly/birth defect  
x Other situations:  
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.  
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
10.3.3. 
Definition of Adverse Events of Special Interest 
Per the Council for International Organizations of Medical Sciences Cumulative 
Pharmacovigilance Glossary (CIOMS VI, 2021), an AESI (serious or non-serious) is one of 
scientific and medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor may be appropriate. 
Such events may require further investigation in order to characterize and understand them.  
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Events Meeting the AESI Definition  
Injection Site Reaction  
An ISR is characterized by an intense adverse reaction (usually immunologic) developing at the 
site of an injection after 4 or more hours post-injection. Subcutaneous administration of the study 
intervention may cause a specific local reaction originating around the injection site, such as 
erythema, itching, discomfort and pain, and could include more severe manifestations such as 
ulceration or necrosis.  
Potential ISRs will be evaluated and recorded as follows:  
Individual signs or symptoms at the injection site with an onset of less than 4 hours from the time 
of study intervention administration will be recorded as individual AEs (bruising, itching, 
transient erythema, swelling, etc.) and not as ISRs.  
Signs or symptoms at the injection site with a time to onset of 4 or more hours post-injection will 
be recorded as an ISR if any of the CTCAE criteria for ISR detailed in Table 7 are met. Signs or 
V\PSWRPVDWWKHLQMHFWLRQVLWHWKDWRFFXUKRXUVSRVW-injection but are not specified in Table 7 
should be recorded as AEs. 
Table 7: 
Grading of Injection Site Reactions, CTCAE v 5.0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Tenderness with 
or without 
associated 
symptoms (e.g., 
warmth, 
erythema, itching) 
Pain, 
lipodystrophy; 
edema; phlebitis 
Ulceration or 
necrosis; severe 
tissue damage; 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
10.3.4. 
Recording and Follow-up of AEs and/or SAEs 
10.3.4.1. AE and SAE Recording 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, diagnostics reports) related to the event.  
The Investigator will then record all relevant AE/SAE information in the eCRF.  
It is not acceptable for the Investigator to send photocopies of the participant's medical records to 
the Sponsor in lieu of completion of the AE/SAE CRF page.  
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, will 
be redacted on the copies of the medical records before submission to the Sponsor.  
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
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10.3.4.2. Assessment of Intensity 
The Investigator will make an assessment of each AE and SAE reported during the study. The 
grade of each event will be determined using CTCAE v 5.0 criteria. 
10.3.4.3. Assessment of Causality 
The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.  
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.  
The Investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as concomitant therapy and other risk factors, as well as the temporal relationship of the 
event to study intervention administration will be considered and investigated. The Investigator 
will also consult the Investigator Brochure (IB) and/or Product Information (for marketed 
products) in his/her assessment.  
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality.  
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data to SAE Coordinator.  
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.  
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.  
The following definitions will be used in assessing causality:  
x Not Related: Event for which sufficient evidence exists to conclude that the etiology 
is unrelated to study intervention.  
x Possibly Related: There is some temporal relationship between the event and the 
administration of the study intervention, and the event is unlikely to be explained by 
the participant’s medical condition or other therapies.  
x Probably Related: The temporal relationship between the event and administration 
of the study intervention is suggestive and the event is unlikely explained by the 
participant’s medical condition or other therapies. 
x Definitely Related: The event follows reasonable temporal sequence from 
administration of the study intervention, follows a known or suspected response 
pattern to the study intervention, is confirmed by improvement upon stopping the 
study intervention, and reappears upon repeated exposure, if that occurs. 
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10.3.4.4. Follow-up of AEs and SAEs 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Sponsor with a copy of any post-mortem findings including 
histopathology.  
New or updated information will be recorded in the originally completed CRF.  
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information.  
10.3.5. 
Reporting of SAEs  
Facsimile or electronic transmission of the SAE Report Form is the preferred method to transmit 
this information to the SAE coordinator.  
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service.  
Initial notification via telephone does not replace the need for the Investigator to complete and 
sign the SAE Report Form within the designated reporting time frames.  
Contacts for SAE reporting can be found on the Medical Monitor and Pharmacovigilance 
Contact Information page. 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information  
10.4.1. 
Definitions  
Woman of Childbearing Potential (WOCBP)  
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).  
If fertility is unclear (e.g., amenorrhea in athletes) and a menstrual cycle cannot be confirmed 
before administration of study intervention, additional evaluation should be considered.  
Women in the following categories are not considered WOCBP  
1. 
Premenarchal  
2. 
Premenopausal with one of the following:  
a. Documented hysterectomy  
b. Documented bilateral salpingectomy  
c. Documented bilateral oophorectomy  
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For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., müllerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry.  
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.  
3. 
Postmenopausal  
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required.  
b. Participants on HRT and whose menopausal status is in doubt will be required 
to use one of the non-estrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
10.4.2. 
Contraception Guidance 
Male Participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following from Day 1 through the end of study (EOS) visit:  
x Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
x Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of < 1% per year as described in Table 8 when having penile-vaginal intercourse 
with a WOCBP who is not currently pregnant.  
Male participants must refrain from donating sperm for the duration of the study and following 
the last dose of study intervention for at least 24 weeks.  
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame.  
Female Participants  
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 8. 
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Table 8: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
(Failure rate of <1% per year when used consistently and correctly) 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation  
x 
Oral  
x 
Intravaginal  
x 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
x 
Oral  
x 
Injectable  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
Highly Effective Methods That Are User Independent a 
x 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation  
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS) 
x 
Bilateral tubal occlusion 
x 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP, and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
10.4.3. 
Collection of Pregnancy Information 
10.4.3.1. Male Participants with Partners Who Become Pregnant 
The Investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive DCR-AUD.  
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
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Dicerna Protocol DCR-AUD-102 
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Page 69 
child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 10 
weeks following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
10.4.3.2. Participants Who Become Pregnant 
The Investigator will collect pregnancy information on any participant who becomes pregnant 
while participating in this study. The initial Information will be recorded on the appropriate form 
and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy.  
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
10 weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. A 
spontaneous abortion (occurring at < 22 weeks gestational age) or still birth (occurring at 
> 22 weeks gestational age) is always considered to be an SAE and will be reported as such. Any 
post-study pregnancy-related SAE considered reasonably related to the study intervention by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the Investigator 
is not obligated to actively seek this information in former study participants, he or she may learn 
of an SAE through spontaneous reporting.  
Any participant who becomes pregnant while participating in the study will discontinue study 
intervention. 
10.5. 
Genetics 
Use/Analysis of DNA  
x DNA samples will be analyzed for ALDH2 genotyping. Additional exploratory 
analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data.  
x The results of genetic analyses may be reported in the CSR or in a separate study 
summary.  
x The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
x The samples will be retained while research on DCR-AUD continues, but no longer 
than 5 years or other period as per local requirements. 
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Dicerna Protocol DCR-AUD-102 
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Page 70 
10.6. 
Liver Safety: Suggested Actions and Follow-up Assessments 
Phase 1 liver chemistry stopping criteria are designed to ensure participant safety and to evaluate 
liver event etiology: 
Liver Chemistry Stopping Criteria  
(Applies both to additional DCR-AUD dosing and further EIAs) 
ALT/AST-
absolute 
ALT or AST increases to ×ULN 
,I$/7RU$67increases to >2×ULN AND total bilirubin t 2×ULN (> 35% 
direct bilirubin) or INR > 1.5, report to Sponsor in expedited manner.a, b 
See additional actions and follow-up assessments below 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
LPPHGLDWHO\DYDLODEOHGLVFRQWLQXHVWXG\LQWHUYHQWLRQLI$/7×8/1DQGWRWDOELOLUXELQ×ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable 
urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.  
b $OOHYHQWVRI$/7×8/1DQGWRWDOELOLUXELQ 2×ULN (> GLUHFWELOLUXELQRU$/7×ULN and 
INR > 1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to sponsor in an expedited 
manner and as an SAE if SAE criteria met (excluding studies of hepatic impairment or cirrhosis).  
 
Required Actions, Monitoring, and Follow-up Assessments  
Actions: 
x 
Immediately discontinue study intervention 
x 
Report the event to the CRO Medical Monitor within 24 hours 
x 
Complete an SAE data collection tool if the event also met the criteria for an SAE b 
x 
Perform liver function follow-up assessments as described in the Follow Up Assessments 
below.  
x 
Do not restart or rechallenge participant with study intervention (neither IMP nor additional 
EIAs). 
x 
Monitor the participant until liver function test abnormalities resolve, stabilize, or return to 
baseline (as detailed below). 
Monitoring: 
If ALT or AST  3×ULN AND total bilirubin t2×ULN or INR > 1.5 
x 
Repeat liver function tests (include ALT, AST, alkaline phosphatase, total bilirubin, and INR) 
and perform liver function follow-up assessments within 24 hours. 
x 
Monitor participant twice weekly until liver function test abnormalities resolve, stabilize, or 
return to baseline. 
x 
A specialist or hepatology consultation is recommended. 
If ALT or AST  3×ULN AND total bilirubin < 2×8/1DQG,15 1.5: 
x 
Perform liver function tests (include ALT, AST, alkaline phosphatase, total bilirubin, and INR) 
and perform liver function follow-up assessments within 24 to 72 hours 
x 
Monitor participants weekly until liver function abnormalities resolve, stabilize, or return to 
baseline 
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Dicerna Protocol DCR-AUD-102 
Version 2.0, 17-Jan-2023 
 
Page 71 
Follow-Up Assessments: 
x 
Viral hepatitis serology (includes Hepatitis A IgM antibody; HBsAg and HBcAb; hepatitis C 
RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody [or if 
unavailable, heterophile antibody or monospot testing]; and hepatitis E IgM antibody)  
x 
Obtain serum CK, LDH, GGT, GLDH, and serum albumin 
x 
Fractionate bilirubin, if total bilirubin t 2×ULN 
x 
Obtain complete blood count with differential to assess eosinophilia 
x 
Record the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, 
on the eCRF 
x 
Record use of concomitant medications or ingestions (including wild mushrooms, 
acetaminophen, herbal remedies, recreational drugs, and other over-the-counter medications). 
Note any concomitant medications that have been recently initiated or for which doses have 
increased. 
x 
Record alcohol use on the eCRF 
 
If ALT or AST  3×ULN AND total bilirubin t2×ULN or INR > 1.5 obtain the following in 
addition to the assessments listed above: 
x 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulins 
x 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) and/or liver 
biopsy to evaluate liver disease  
x 
Liver biopsy may be considered and discussed with local specialists if available, for instance: 
 
When serology raises the possibility of autoimmune hepatitis (AIH) 
 
When suspected DILI progresses or fails to resolve on withdrawal of study intervention 
 
In participants with acute or chronic atypical presentation. 
 
 



Dicerna Protocol DCR-AUD-102 
Version 2.0, 17-Jan-2023 
 
Page 72 
10.7. 
Abbreviations 
Abbreviation 
Description 
ADA 
antidrug antibody(ies) 
AE 
adverse event 
AESI 
AE of special interest 
ALDH2 
aldehyde dehydrogenase 2 
ALDH2  
gene for aldehyde dehydrogenase 2 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUD 
alcohol use disorder 
BAC 
blood alcohol concentration 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
°C 
degrees Celsius 
CFR 
Code of Federal Regulations 
CFU 
conditional follow-up 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase (creatine phosphokinase) 
CL 
clearance 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
contract research organization 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
coefficient of variation (percent) 
DCR-A1203 
drug substance for this IMP 
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Dicerna Protocol DCR-AUD-102 
Version 2.0, 17-Jan-2023 
 
Page 73 
Abbreviation 
Description 
DS 
drug substance 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
e.g. 
for example (exempli gratia) 
EIA 
ethanol interaction assessment 
EOS 
end of study 
EOT 
end of treatment 
ETOH 
ethyl alcohol 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GABA 
gamma-aminobutyric acid 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIPPA 
Health Insurance Portability and Accountability Act 
hr 
hour(s) 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
HV 
healthy volunteer 
IA 
interim analysis  
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
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Dicerna Protocol DCR-AUD-102 
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Page 74 
Abbreviation 
Description 
i.e. 
that is (id est) 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
ITT 
Intent to treat 
IUD 
intrauterine device 
IVRS/IWRS 
Interactive Voice/Web Response System 
IUS 
intrauterine hormone-releasing system 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram(s) 
min 
minute(s) 
MINI 
Mini International Neuropsychiatric Interview 
mL 
milliliter(s) 
mRNA 
messenger ribonucleic acid 
NOAEL 
no observed adverse effect level 
NPO 
nothing by mouth 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over the counter 
PD 
pharmacodynamic(s) 
PEth 
phosphatidylethanol 
PK 
pharmacokinetic 
PI 
Principal Investigator 
QTcF 
QT interval (Fridericia correction) 
RNA 
ribonucleic acid 
RNAi 
RNA interference 



Dicerna Protocol DCR-AUD-102 
Version 2.0, 17-Jan-2023 
 
Page 75 
Abbreviation 
Description 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SIB 
suicidal ideation or behavior 
siRNA 
small interfering RNA 
SoA 
schedule of activities 
SRC 
Safety Review Committee 
SUD 
substance abuse disorder 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TBD 
to be determined 
TLFB 
Timeline Follow Back 
Tmax 
time to maximum observed concentration 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
Vd/F 
apparent volume of distribution 
WFI 
water for injection 
WOCBP 
woman(en) of childbearing potential 



Dicerna Protocol DCR-AUD-102 
Version 2.0, 17-Jan-2023 
 
Page 76 
10.8. 
Protocol Amendment History 
Amendment 1 (17-Jan-2023) 
Overall Rationale for the Amendment 
The protocol was amended in response to queries from the US Food and Drug Administration. 
Additional updates and clarifications were also included.  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
 



Dicerna Protocol DCR-AUD-102 
Version 2.0, 17-Jan-2023 
 
Page 77 
10.9. 
Investigator Signature Page 
 
A Phase 1b, Double-blind, Placebo-controlled, Repeat-dose, Safety, Tolerability, 
Pharmacokinetic, and Pharmacodynamic Study of DCR-AUD in Healthy Volunteers  
 
Protocol Number:  
DCR-AUD-102 
Version: 
2.0 
Date:  
17-Jan-2023 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with Good Clinical Practice (GCP) guidelines, the Declaration of 
Helsinki, and local regulations (as applicable). 
 
 
Signature: 
 
Date: 
Name: 
 
Title: 
Institution: 
 
Site Number: 
 
 



Dicerna Protocol DCR-AUD-102 
Version 2.0, 17-Jan-2023 
 
Page 78 
11. 
REFERENCES 
 
Alling C, Gustavsson L, Anggard E: An abnormal phospholipid in rat organs after ethanol 
treatment. FEBS Lett 1983; 152: 24–8. 
Bae KY, Kim SW, Shin HY, Kim JM, Shin IS, Kim SJ, et al. The acute effects of ethanol and 
acetaldehyde on physiological responses after ethanol ingestion in young healthy men with 
different ALDH2 genotypes. Clin Tox. 2012 Apr 1;50(4):242-9. 
Bryson WC, McConnell J, Korthuis PT, McCarty D. Extended-release naltrexone for alcohol 
dependence: persistence and healthcare costs and utilization. Am J Manag Care. 2011 Jun;17 
Suppl 8:S222-34.  
Chick J, Gough K, Falkowski W, Kershaw P, Hore B, Mehta B, et al. Disulfiram treatment of 
alcoholism. Br J Psychiatry. 1992 Jul;161:84-9.  
CIOMS Cumulative Pharmacovigilance Glossary, Geneva, Switzerland: Council for 
International Organizations of Medical Sciences (CIOMS), 2021.   
EMA/CHMP/EWP/20097/2008 (previously EMEA/CHMP/EWP/20097/2008). Committee for 
Medicinal Products for Human Use (CHMP). Guideline on the development of medicinal 
products for the treatment of alcohol dependence. 18 February 2010. 
Enomoto N, Takase S, Yasuhara M, Takada A. Acetaldehyde metabolism in different aldehyde 
dehydrogenase-2 genotypes. Alcohol Clin Exp Res. 1991;15(1):141-4. 
Gastfriend DR. A pharmaceutical industry perspective on the economics of treatments for 
alcohol and opioid use disorders. Ann NY Acad Sci. 2014 Oct;1327:112-30.  
Gnann H, Weinmann W, Thierauf A. Formation of phosphatidylethanol and its subsequent 
elimination during an extensive drinking experiment over 5 days. Alcohol Clin Exp Res. 2012 
Sep;36(9):1507-11. 
Grant BF, Goldstein RB, Saha TD, Chou SP, Jung J, Zhang H, et al. Epidemiology of DSM-5 
Alcohol Use Disorder: Results from the National Epidemiologic Survey on Alcohol and Related 
Conditions III. JAMA Psychiatry. 2015 Aug;72(8):757-66. 
Han B, Hedden SL, Lipari R, Copello EA, Kroutil LA. Receipt of services for behavioral health 
problems: Results from the 2014 National Survey on Drug Use and Health. Rockville, MD: 
Substance Abuse and Mental Health Services Administration. 2015 Sep. Available from: 
https://www.samhsa.gov/data/report/receipt-services-behavioral-health-problems-results-2014-
national-survey-drug-use-and-health. 
Heier C, Xie H, Zimmermann R: Nonoxidative ethanol metabolism—from biomarkers to 
bioactive lipids. Int Union Biochem Mol Biol 2016; 68:916–23. 
Javors 0$+LOOဨ.DSWXUF]DN15RDFKH-'.DUQVဨ:ULJKW7('RXJKHUW\'0&KDUDFWHUL]DWLRQ
of the pharmacokinetics of phosphatidylethanol 16: 0/18: 1 and 16: 0/18: 2 in human whole 
blood after alcohol consumption in a clinical laboratory study. Alcohol Clin Exp Res. 2016 
Jun;40(6):1228-34. 
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Dicerna Protocol DCR-AUD-102 
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Page 79 
Jørgensen CH, Pedersen B, Tønnesen H. The efficacy of disulfiram for the treatment of alcohol 
use disorder. Alcohol Clin Exp Res. 2011 Oct;35(10):1749-58.  
Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, et al. Aldehyde 
dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, 
substrate specificity, and clinical application. Pharmacol Rev. 2012 Jul;64(3):520-39. 
Knudsen HK, Abraham AJ, Roman PM. Adoption and implementation of medications in 
addiction treatment programs. J Addict Med. 2011 Mar;5(1):21-7.  
Kummer N, Ingels AS, Wille SM, Hanak C, Verbanck P, Lambert WE, et al. Quantification of 
phosphatidylethanol 18:0/18:1, 18:1/18:1, 16:0/16:0 in venous blood and venous and capillary 
dried blood spots from patients in alcohol withdrawal and control volunteers. Anal Bioanal 
Chem 2016; 408: 825–38. 
Litten RZ, Falk D, Ryan M, Fertig J. Research opportunities for medications to treat alcohol 
dependence: addressing stakeholders’ needs. Alcohol Clin Exp Res. 2014 Jan;38(1):27-32.  
Nishimura FT, Fukunaga T, Kajiura H, Umeno K, Takakura H, Ono T, Nishijo H. Effects of 
aldehyde dehydrogenase-2 genotype on cardiovascular and endocrine responses to alcohol in 
young Japanese subjects. Auton Neurosci. 2002;102:60-70. 
Peng G-S, Chen Y-C, Tsao T-P, Wang M-F, Yin S-J. Pharmacokinetic and pharmacodynamic 
basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 
gene allele. Pharmacogenet Genomics. 2007;17(10):845-55. 
Peng G-S, Wang M-F, Chen C-Y, Luu S-U, Chou H-C, Li T-K, Yin S-J. Involvement of 
acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of 
mitochondrial aldehyde dehydrogenase gene in Asians. Pharmacogenetics. 1999;9:463-76. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011; 168(12):1266-77. 
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-
International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a 
structured diagnostic psychiatric interview for DSN-IV and ICD-10. J Clin Psychiatry. 1998; 
59[Suppl 20]:22-33.  
Sobell LC, Sobell MB. Timeline follow-back: A technique for assessing self-reported alcohol 
consumption. In: Litten RZ, Allen JP, editors. Measuring alcohol consumption: psychosocial and 
biochemical methods. Washington DC: American Psychological Association.1992. pp. 41-72. 
Substance Abuse and Mental Health Services Administration, Results from the 2013 National 
Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS 
Publication No. (SMA) 14-4863. Rockville, MD: Substance Abuse and Mental Health Services 
Administration, 2014. Available from: https://www.samhsa.gov/data/sites/default/files/
NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.pdf. 
Ulwelling W, Smith K. The PEth blood test in the security environment: what it is; why it is 
important; and interpretative guidelines. J Forensic Sci. 2018 Nov;63(6):1634-40. 
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Viel G, Boscolo-Berto R, Cecchetto G, Fais P, Nalesso A, Ferrara S: Phosphatidylethanol in 
blood as a marker of chronic alcohol use: a systematic review and meta-analysis. Int J Mol Sci 
2012; 13:14788–812. 
 


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Cover Page for Statistical Analysis Plan 
Sponsor name: 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 1 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Dicerna Pharmaceuticals
DCR-AUD-102
A Phase 1b, Double-blind, Placebo-controlled, Repe t dose, Safety, Tolerability, Pharmacokinetic, and 
Pharmacodynamic Study of DCR-AUD in Healthy Volunteers
Statistical Analysis Plan
Version: 2.0
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DCR-AUD in H
UD
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 2 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
SPONSOR SIGNATURE PAGE
Approved by:
_________________________
_______________
Date
, Biostatistics
Biometrics & Clinical Data Management
Dicerna Pharmaceuticals, Inc. 
Approved by:
_________________________
_______________
Date
Medical Monitor
Dicerna Pharmaceuticals, nc. 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 4 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
TABLE OF CONTENTS
1
INTRODUCTION....................................................................................................................11
2
STUDY OBJECTIVES ............................................................................................................11
2.1
Primary Objective............................................................................................................11
2.2
Secondary Objective/Estimand(s) ...................................................................................11
2.3
Exploratory Objective(s) .................................................................................................11
3
INVESTIGATIONAL PLAN ..................................................................................................11
3.1
Overall Study Design and Plan........................................................................................11
3.2
Endpoints and Associated Variables ...............................................................................13
3.2.1
Primary Endpoints ......................................................................................................13
3.2.2
Secondary Endpoints ..................................................................................................13
3.2.3
Exploratory Endpoints................................................................................................13
3.2.4
Safety Variables.................................................... .....................................................13
3.2.5
Pharmacodynamic Variables .................................... ...............................................13
3.2.6
Immunogenicity Variables..................................... ......... ..........................................14
3.2.7
Pharmacokinetic Variables ...............................
....
.............................................15
4
STATISTICAL METHODS ................................. ....... ..........................................................17
4.1
Data Quality Assurance....................................... ...........................................................17
4.2
General Presentation Considerations.................
........................................................17
4.2.1
Treatment.................................................. ...............................................................17
4.2.2
Study Day ........................................... ......................................................................17
4.2.3
End of Study .................................. ............................................................................17
4.2.4
Baseline......................................
.....
....................................................................17
4.2.5
Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment.......................17
4.2.6
Summary and Representation of Data ........................................................................17
4.2.7
On-treatment assessment/event . ....... ........................................................................18
4.3
Software18
4.4
Study Participants........ .
... .... ..............................................................................18
4.4.1
Analysis Populations . . ..............................................................................................18
4.4.2
Disposition of Participants..........................................................................................19
4.4.3
Protocol Deviations ....................................................................................................19
4.4.3.1
Protocol Deviations with Non-PK Implications.........................................................19
4.4.3.2
Protocol Deviations with PK Implications .................................................................19
4.5
Demographics and Baseline Characteristics ...................................................................20
4.6
Medical History...............................................................................................................20
4.7
Prior and Concomitant Medications................................................................................20
4.8
Treatment Exposure and Compliance .............................................................................20
4.8.1
Treatment Exposure....................................................................................................20
4.8.2
Compliance.................................................................................................................20
4.9
Analysis Supporting Primary Objective(s)......................................................................21
4.10 Analysis Supporting Secondary Objective(s)..................................................................21
4.11 Efficacy Evaluation .........................................................................................................21
4.12 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis of 
Pharmacokinetic Parameters for Final Analysis..............................................................21
4.12.1
Pharmacokinetic Concentrations ................................................................................21
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 5 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.12.2
Pharmacokinetic Parameters.......................................................................................23
4.12.3
Statistical Analysis of Pharmacokinetic Parameters...................................................26
4.12.4
Pharmacodynamic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacodynamic Parameters ...............................................................................27
4.12.5
Pharmacodynamic Parameters....................................................................................28
4.13 Safety Evaluation.............................................................................................................31
4.13.1
Adverse Events ...........................................................................................................31
4.13.2
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................33
4.13.3
Clinical Laboratory Evaluation...................................................................................33
4.13.4
Vital Signs, .................................................................................................................34
4.13.5
ECG ............................................................................................................................35
4.13.6
Physical Examination .................................................................................................35
4.13.7
Other Analysis ............................................................................................................35
4.13.7.1 Columbia-Suicide Severity Rating Scale.............. .....................................................35
4.13.7.2 Exploratory Analyses...............................................
..............................................36
4.13.8
Daylight Saving Time (DST): ............................... ...................................................36
4.13.9
Safety Review Committee ................................
..... .............................................36
4.14 Cardio Dynamic Analyses..................................... ...... .................................................36
4.15 Biomarkers ......................................................... ............................................................36
4.16 Adjustments for Covariates ............................
.........................................................36
4.17 Handling of Dropouts or Missing Data ....
................................................................36
4.18 Subgroup Analysis................................... .......................................................................36
4.19 Planned Interim Analyses................................................................................................36
4.20 Determination of Sample Size................ ......................................................................37
4.21 Changes in the Conduct of the Study or Planned Analysis .............................................37
5
REFERENCES........................
..... .....................................................................................37
6
APPENDICES...................... .................................................................................................37
6.1
Schedule of Assessments............ ..................................................................................37
6.2
Imputation Rules for Partial Dates .. ...............................................................................48
6.3
Laboratory Test Parameters.............................................................................................53
List of Tables
Table 3-1
Plasma Pharmacodynamic Parameters ......................................................................14
Table 3-2
Plasma Pharmacokinetic Parameters After Each Dose Administration of Multiple 
Dose Study.................................................................................................................15
Table 4-1
Pharmacokinetic Parameter and Estimation ..............................................................23
Table 4-2 Pharmacodynamic Parameter and Estimation...................................................................27
Table 6-1
Schedule of Activities – Screening, Dosing, EOS, and CFU Visits (see Table 6-2 for 
non-dosing visits).......................................................................................................38
Table 6-2:
Schedule of Activities – Non-dosing Visits (see Error! Reference source not found.
for Screening, Dosing, and EOS Visits) ....................................................................43
Table 6-3:
Schedule of Activities - 4-Hour Ethanol Interaction Assessments............................46
Table 6-4
Algorithm for Treatment-Emergent Adverse Events:................................................50
Table 6-5
Algorithm for Prior/Concomitant Medications Categorization:................................52
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 6 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
List of Figures
Figure 3-1 Study Schematic for DCR AUD-102...............................................................................12
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 7 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
Final 1.0
28 Jun 2023
New document
Final 2.0
01 Sep 2023
Exploratory analysis updated
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 11 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
1
INTRODUCTION
This Statistical Analysis Plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of Study DCR AUD 102 A Phase 1b, Double-blind, Placebo-controlled, Repeat-dose, Safety,
Tolerability, Pharmacokinetic, and Pharmacodynamic Study of DCR-AUD in Healthy Volunteers.
This repeat-dose study is being conducted to characterize the safety and tolerability and PK profiles 
of DCR-AUD when administered monthly, and to determine if a PD effect (resulting from cumulative 
ALDH2 mRNA knock down) can be observed during Ethanol Interaction Assessments (EIA) in a 
population of social drinkers after repeat doses of DCR-AUD.
The content of this SAP is based on following study documents:
x
Study DCR AUD 102 protocol Version 2.0 17 Jan 2023.
x
Electronic Case Report Form (eCRF) Version 13.1.
This SAP will be finalized prior to database lock. Any changes after the finalization of this SAP will 
be documented in Statistical Method Modification Form.
2
STUDY OBJECTIVES
The objectives of the study are as follows:
2.1
Primary Objective
To evaluate the safety and tolerability of repeat doses of DCR AUD administered to adult HVs
2.2
Secondary Objective
x
To characterize the PD symptom profile of repeat doses of DCR-AUD in adult HVs
x
To characterize the plasma PD of repeat doses of DCR-AUD
x
To characterize the PK of repeat doses of DCR-AUD in adult HVs
2.3
Exploratory Objective(s)
To explore change in alcohol consumption following treatment with DCR-AUD in adult HVs.
3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This is a double-blind, randomized, placebo-controlled study of DCR-AUD to evaluate the safety, 
tolerability, PK, and PD of repeat doses of DCR-AUD in adult HVs. 
Participants will receive 3 injections of study intervention (Day 1, Day 29, and Day 57), and have 
assessment visits through Week 24. Up to 10 EIAs will be conducted over the 24-week period to
characterize the PD of DCR-AUD. For each EIA, participants will consume 4 standard drinks over 
the course of 80 minutes. Participants will be admitted to the clinic overnight for each EIA. At the 
discretion of the Investigator, participants who present with increasing positive ethanol reaction 
symptoms at the Day 169 EIA (flushing, headache, lightheadedness, palpitations, nausea, or
vomiting) will be followed for an additional 4 weeks (through Day 197).
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 12 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Figure 3-1 Study Schematic for DCR AUD-102
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 13 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
3.2
Endpoints and Associated Variables
The endpoints and variables are provided below.
3.2.1
Primary Endpoints
x
Incidence and severity of AEs and SAEs 
x
Changes from baseline in vital signs, 12-lead ECG, clinical laboratory tests, and physical 
examination findings.
3.2.2
Secondary Endpoints
x
Change in the occurrence and/or severity of 6 symptoms related to plasma acetaldehyde 
accumulation observed during in-clinic EIAs over the course of the study
x
Change in plasma PD biomarker assessments during serial EIA
o
acetaldehyde
o
acetate 
o
ethanol
x
Plasma PK parameters of DCR-AUD
3.2.3
Exploratory Endpoints
•
Change in alcohol consumption from baseline using Timeline Follow Back (TLFB)
•
Change from baseline in phosphatidylethanol (PEth) levels, reflecting cumulative recent 
alcohol ingestion. 
3.2.4
Safety Variables
•
Physical examinations
•
Vital signs (Temperature (by skin refraction), pulse rate, respiratory rate, and blood pressure)
•
12-lead electrocardiograms (ECG): Heart rate, PR interval, QRS interval, QT interval and QT 
interval using Fridericia’s correction [QTcF]
•
Columbia-Suicide Severity Rating Scale
•
Mini-International Neuropsychiatric Interview.
•
Clinical laboratory tests (hematology, clinical chemistry, coagulation and routine urinalysis 
parameters)
•
Adverse event (AE) assessments
•
Suicidal Ideation and Behavior Risk Monitoring
3.2.5
Pharmacodynamic Variables
DCR-AUD is designed to selectively reduce ALDH2 activity in the liver and the conversion of 
acetaldehyde to acetic acid after alcohol consumption. The build-up of acetaldehyde causes 
unpleasant effects after drinking (e.g., flushing, headache, lightheadedness, palpitations, nausea, or 
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the
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on from baseline u
rom base
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ture (by sk
ure (by s in refra
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ams (ECG
ia’s correcti
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 14 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
vomiting). As such, the PD activity of DCR-AUD will be assessed during EIAs via these 6 symptoms, 
and blood biomarkers (ethanol, acetaldehyde, and acetate) PD parameters to be estimated by Clinical 
Pharmacology, Modeling and Simulation (CPMS) group are provided in Table 3-1.
Table 3-1
Plasma Pharmacodynamic Parameters 
Protocol 
Parameter
WNL Name
Definition
tmax
Tmax
Time corresponding to occurrence of Cmax
(For acetaldehyde, acetate, and alcohol)
Cmax
Cmax
Maximum observed concentration (in the unit of 
μM and ng/mL) (For acetaldehyde, acetate, and 
alcohol) 
CmaxAbove
Cmax_Above_B
Maximum observed concentration that is above the 
baseline (in th  unit of μM and ng/mL) (For 
acetaldehyde)
baseline
Baseline
Response 
value 
just 
prior 
to 
treatment 
administration
AUCAbove
AUC_Above_B
Area under the curve that is above the baseline (for 
acetaldehyde)
AUCBelow
AUC_Below_B
Area under the curve that is below the baseline (for 
acetate)
AUC0-4h
AUCT
Observed partial area under the curve from time 0 
to 4 hours (for acetaldehyde, acetate, and alcohol) 
Cav
Cav
Average plasma concentration from time zero to 4 
hours
PD 
response 
change
PD_response_change
Changes in each biomarker level on each EIA day 
(i.e., D1,14,29,42, 57) compared to the basal level 
on Day -1
PD 
response % 
change
PD_response_%_change
Percent changes in each biomarker level on each 
EIA day (i.e., D1,14,29,42,57) compared to the 
basal level on Day -1
3.2.6
Immunogenicity Variables 
Immunogenicity testing (anti-drug DCR-AUD antibodies) using designated serum samples from each 
participant is planned to be conducted.
The ADA samples collected in this study will be stored and analyzed in the future
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 15 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
3.2.7
Pharmacokinetic Variables
Pharmacokinetic concentration data will be obtained at time point(s) described in the protocol version 
2.0 as follows:
PK concentrations of DCR-AUD will be determined at the following nominal times: 0 (pre-dose) 
and at 1, 2, 4, 6, 8, 24, and 72 hours post-dose on days 1, 29, 57 (exception: no 72-hour PK sample 
is required on Day 57). A single sample will be collected on Days 1, 14, 42, 70, and 168 along with 
the ADA samples. These single PK concentrations maybe used for deriving the PK parameters, if 
the concentrations are detectable.
Derivation of PK parameters will be the responsibility of CPMS group,
.
If calculable, the following PK parameters listed in Table 3-2 will be determined for DCR-AUD in 
plasma following single subcutaneous (SC) dose administration.
Table 3-2
Plasma Pharmacokinetic Parameters After Each Dose Administration of 
Multiple Dose Study
Parameter
WNL
Name
CDISC 
Name
Definition
Cmax
Cmax
CMAX
Maximum observed concentration
Clast
Clast
CLST
Last measurable concentration
Cmin
Cmin
CMIN
Minimum observed concentration in a 
dosing interval after last dose 
administration
tmax
Tmax
TMAX
Time corresponding to occurrence of 
Cmax
t½
HL_Lambda z
LAMZHL
Apparent terminal elimination half--life
λz
Lambda_z
LAMZ
Terminal elimination rate constant
AUC0-last
AUClast
AUCLST
Observed AUC from time zero to the last 
quantifiable concentration
AUC0-t
AUCT
AUCINT(0-
X)
Observed AUC from time zero to some 
fixed time t (i.e., AUC24 or AUC48)
AUC0-inf
AUCINF_obs
AUCIFO
AUC from time zero extrapolated to 
infinity
%AUCex
AUC_%Extrap_obs
AUCPEO
Percentage of AUC0-inf obtained by 
extrapolation beyond tlast
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 16 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Parameter
WNL
Name
CDISC 
Name
Definition
CL/F
Cl_F_obs
CLFO
Apparent clearance following SC 
administration
Vz/F
Vz_F_obs
VZFO
Apparent volume of distribution during 
terminal phase
Source: NCI EVS Terminology Resources website: 
http://www.cancer.gov/cancertopics/cancerlibrary/terminologyresources/cdisc.
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 17 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4
STATISTICAL METHODS
4.1
Data Quality Assurance
All tables, figures, and data listings to be included in the report will be independently checked for 
consistency, integrity, and in accordance with standard 
procedures.
4.2
General Presentation Considerations
This section is not applicable to PK data.
4.2.1
Treatment
480 mg of DCR-AUD and placebo in each arm.
4.2.2
Study Day
Study days will be numbered relative to the first day of study drug administration.
x
If the date of event is before the study drug administration, then:
Study day = (Date of measurement – Date of study drug administration [i.e. Day 1])
x
If the date of event is on or after the study drug administration, then:
Study day = (Date of measurement – Date of st dy drug administration [i.e. Day 1] ) + 1
4.2.3
End of Study
The end of the study is defined as the date of the last visit of the last participant in the study.
4.2.4
Baseline
Baseline is defined as the last non-missing measurement prior to the date and time of the dose of 
study intervention.
For the exploratory analysis using TLFB, baseline is the mean alcohol level as measured on Day -1.
No imputation will be done for missing baseline value for derivation of change from baseline or 
summary tables and shift tables.
4.2.5
Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment
Repeat, retest, and unscheduled assessment will not be considered for the calculation of summary 
statistics and figures, unless assessment qualifies as baseline.
Average of controlled and planned (scheduled) assessment will be considered for the calculation of 
summary statistics and figures, if more than one controlled/planned assessment will be performed at 
a specific time point. 
4.2.6
Summary and Representation of Data 
Continuous data will be summarized in terms of mean, standard deviation (SD), median, minimum, 
maximum, and number of observations, unless otherwise stated.
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 18 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Categorical data will be summarized in terms of the number of participants providing data at the 
relevant time point (n), frequency counts, and percentages.  
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean and median will be reported to one more decimal place than the 
raw data recorded in the database.  The SD will be reported to two more decimal places than the raw 
data recorded in the database.  In general, the maximum number of decimal places reported shall be 
four for any summary statistics.
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts.  
Percentages will be calculated using N as the denominator.  If sample sizes are small, the data displays 
will show the percentages, but any textual report will describe frequencies only. Percentage will be 
presented as whole number if count is 100.
If for any summary table, n is less than three then only n, minimum, and maximum should be 
presented, and other summary statistics will be left blank.
4.2.7
On-treatment assessment/event 
The overall observation period will be divided into three mutually exclusive segments: 
1. screening period: from day of participant’s informed consent to before date of first 
administration of study treatment
2. dosing period: from date of first administration of study treatment to 58 days after date of last 
administration of study treatment (including start and stop date)
3. follow-up period: starting at day 58+1 after last administration of study treatment.
4.3
Software
All report outputs will be produced using SAS® version 9.4 or later in a secure and validated 
environment.
The PK analyses will be conducted using Phoenix® WinNonlin (WNL) version 8.3 or later in a secure 
and validated environment. 
All report outputs will be provided to the Sponsor in RTF format.
4.4
Study Participants
4.4.1
Analysis Populations
Enrolled Population (ENR): All participants who sign the ICF.
Randomized Population (RP): All participants who sign the ICF and who are randomized to study 
intervention.
Safety Population (SP): All participants randomized to study intervention and who receive at least 1 
dose of DCR-AUD or placebo. Participants will be analyzed according to the initial dose received.
Pharmacokinetic Population (PKP): All participants randomized to study intervention and who 
receive at least 1 dose of DCR-AUD and have at least 1 postdose PK assessment.
Pharmacodynamic Population (PP): All participants randomized to study intervention and who 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 19 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
receive at least 1 dose of DCR-AUD or placebo and have at least 1 postdose PD assessment.
A summary table with the number of participants in each of the analysis population will be provided 
and this table will be displayed by treatment/sequence and overall, for ENR. A listing of participants
excluded from analysis populations will also be provided including reason of exclusion for ENR.
4.4.2
Disposition of Participants
A clear accounting of the disposition of all participants who enter the study will be provided from 
screening (excluding screen failure data) to study completion.
A summary of participant study completion status and reason for study withdrawal will be provided 
for the ENR. This display will show the number and percentage of participants who withdrew from 
the study, including primary reasons for study withdrawal.
A by-participant listing of study discontinuation will be presented for the ENR. The listing will 
include dose date and reasons for study discontinuation. 
A randomization listing will be presented and include the following: each participant’s randomization 
number, the treatment to which the participant has been randomized and replacement randomization 
number (if any) for the RP.
4.4.3
Protocol Deviations
All protocol deviations are predefined in the separat  document, Protocol Deviation Assessment Plan.
4.4.3.1
Protocol Deviations with Non-PK Implications
The defined protocol deviations will be collected during the study period by site monitor/clinical team
and programming team. All deviations related to study inclusion or exclusion criteria, conduct of the 
study, participant management or participant assessment, and handling of the participant’s rights will 
be described. 
A summary table of important proto ol deviations by study day, and treatment arm will also be 
provided for RP.
4.4.3.2
Protocol Deviations with PK Implications
Protocol deviations that may potentially impact PK parameter derivations include, but are not limited 
to:
x
SC administration deviations – interruption of administration, etc.
x
Missed PK samples that impact estimation of PK parameter(s)
x
Concomitant medications not authorized by protocol
x
PK samples obtained out of allowance window that may impact the estimation of PK 
parameter(s)
Protocol deviations (mentioned in Sections 4.4.3.1 and 4.4.3.2) and analysis populations will be 
reviewed in the blinded Data Review Report (DRR) Meeting to decide inclusion or exclusion of 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 20 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
participant(s) from analyses populations. Decisions regarding the exclusion of participants and/or 
participant data from analyses will be made prior to database lock and will be documented and 
approved.
A by-participant- listing of important and not-important protocol deviations will be provided 
including participant identifier; exclusion from specific analysis sets; and protocol deviation
classification, and protocol deviation description and exclusion from specific analysis populations.
Protocol Deviations related to COVID-19 will be listed separately.
4.5
Demographics and Baseline Characteristics
Demographic and anthropometric variables (age, sex, ethnicity, race, height, weight, and BMI) will 
be listed by participant. Demographic characteristics (age, sex, ethnicity, and race) and 
anthropometric characteristics (height, weight, and BMI) will be summarized by treatment, placebo, 
and overall, for the SP.
A by-participant listing for substance use will be provided for the SP.
4.6
Medical History
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA®),
Version 25.1 and assigned to a System Organ Class (SOC) and Preferred Term (PT).
Medical history data will be summarized by study day treatment, and overall for the SP and listed 
by participant including visit, description of the disease/procedure.
4.7
Prior and Concomitant Medication
Prior and Concomitant Medication:
Medications will be considered as prior if the start date of the medication is before the date of first 
administration of the study drug. 
Medications will be considered as concomitant if they are taken at least once in the treatment period 
starting with the first study administration and ending after the last study drug administration during 
the study. 
Medications starting prior to first administration of study drug and continuing during the study visit 
will be considered both prior and concomitant medication.
A summary table and by-participant listings of prior and concomitant medications will be provided
for the SP.
4.8
Treatment Exposure and Compliance
4.8.1
Treatment Exposure 
A by-participant listing of participant exposure to DCR-AUD will be generated. The listing will
include dose, date and time, unit, formulation, route, and frequency.
4.8.2
Compliance 
Compliance(%) = 100 × Total volume delivered (mL)/Total volume planned (mL)
A by-participant listing of treatment compliance will be provided.
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 21 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.9
Analysis Supporting Primary Objective(s)
Not Applicable.
4.10 Analysis Supporting Secondary Objective(s)
Not Applicable.
4.11 Efficacy Evaluation
Not applicable.
4.12 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacokinetic Parameters for Final Analysis
4.12.1 Pharmacokinetic Concentrations
Concentration Listings:
Pharmacokinetic concentration data for DCR-AUD, will be listed by study days, nominal and actual
timepoints and participant for the SP. Concentration listings will include nominal PK sampling time, 
actual sampling times relative to dose administration, deviation from nominal time, and percent 
deviation from nominal time, and concentrations
Plasma concentrations below the lower limit of 
quantification (LLOQ) will be presented as below the limit of quantification (BLQ) in the listings
and the LLOQ value presented as a footnote. Missing PK samples will be reported as no sample (NS) 
or not reportable (NR) as appropriate and conside ed excluded from PK analysis.
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, will be listed by 
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istings w
istration
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s below the limit 
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ote. Missing PK sa
Missing 
nd conside ed exc
onside ed 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 22 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Concentration Summary Tables:
Source data as reported from the laboratory will be used for calculation of concentration summary 
statistics.  Tabular summaries for concentration-time data will report N (number of participants who
received treatment), n (number of participants with non-missing values), and n(BLQ) (the number of 
participants with BLQ samples).
Concentration for DCR-AUD will be summarized by study days, and nominal timepoint for the PKP.
The following descriptive statistics will be presented for plasma concentrations obtained at each 
nominal time point: N, n, n(BLQ), arithmetic mean, SD, coefficient of variation (CV%), geometric 
mean, geometric CV% (calculated as: gCV% =SQRT(es²-1)*100; where s is the SD of the 
log-transformed values), median, minimum, and maximum values.
For summary tables, all BLQs will be considered zero, and the number of BLQs and non-BLQs at 
each scheduled time point will be reported.  Summary Statistics will not be calculated if non-BLQ 
concentrations at a scheduled time point is <3 and will be eported as NC.
The rules followed for calculation and presentation of concentration data with regards to the number 
of decimal places/significant digits for the listings of participant level concentrations and summary 
tables of concentration are as follows:
Concentration Listings and Tables
Rounding
Individual concentrations
n s.f. as supplied by bioanalytical laboratory
Minimum and Maximum
n s.f. at 3
Mean/SD/Median/Geomean
n s.f.  at 3
CV%/gCV%
n s.f. at 3
N/n
Whole number
s.f = significant figures, d.p. = decimal place
Concentration Figures:
For arithmetic mean linear/linear graphs, all BLQ values will be substituted with zero for calculation 
of arithmetic mean and for log/linear graphs the log transformed arithmetic mean will be displayed 
(this should not include zero).
For individual linear/linear and log/linear graphs all BLQ values will be substituted as follows:
x
BLQs at the beginning of a participant profile (i.e., before the first incidence of a measurable 
concentration) will be assigned to zero. When using log/linear scale, these timepoints will be 
considered missing.
x
BLQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing.
x
Single BLQs which fall between two measurable concentrations will be set to missing. 
x
Consecutive BLQs which fall between measurable concentrations will be set to missing. 
Measurable concentrations after consecutive BLQs will be set to missing.
To visualize participant-level concentrations and the comparison between study days, the descriptive 
PK graphs listed below will be generated Including LLOQ line in individual and summary plots.
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ear grap
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ine
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 23 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
x
Figure x.x.x: Individual participant profiles for DCR-AUD Plasma Concentration Time Data by 
Study Day – (Linear Scale and Semi-Logarithmic Scale) (SP)
x
Figure x.x.x : Overlaid individual participant profiles for DCR-AUD Plasma Concentration Time 
Data by Study Day – (Linear Scale and Semi-Logarithmic Scale) (SP)
x
Figure x.x.x : Mean (± SD) DCR-AUD Plasma Concentration Time Data by Study Day – (Linear 
Scale and Semi-Logarithmic Scale) (PKP)
Figures will be generated in color using unique line style and marker for each plot in the graph. For 
all PK concentration-time plots, linear scale will be used for x-axis (e.g., do not use an ordinal scale).
4.12.2 Pharmacokinetic Parameters
PK parameters will be provided by CPMS group. PK parameters will be calculated by NCA methods 
from the concentration-time data using Phoenix® WinNonlin® Version 8.3 or higher following these 
guidelines:
x
Actual time from SC dosing will be used in the calculation of all derived pharmacokinetic 
parameters. 
x
There will be no imputation of missing data. 
x
Handling of BLQ samples for derivation 
f plasma PK parameters after single dose 
administration
o
BLQs at the beginning of a participant profile (i.e., before the first incidence of a 
measurable concentration) will be assigned to zero.
o
BLQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing.
o
Single BLQs which fall between two measurable concentrations will be set to missing.
o
Consecutive BLQs which fall between measurable concentrations will be set to 
missing. Measurable concentrations after consecutive BLQs will also be set to 
missing.
x
Handling of BLQ samples for derivation of plasma PK parameters after multiple dose 
administration
o
BLQs for Day 1 at the beginning of a participant profile (i.e., before the first incidence of 
a measurable concentration) will be assigned to zero
o
BLQs on subsequent dosing days and not separated by a washout: pre-dose values, BLQs 
in the absorption phase, and BLQs between evaluable concentrations, will be substituted 
by LLOQ/2 before the calculation of the PK variables
o
Terminal BLQs (at the end of participant profile) will be set to missing.
Pharmacokinetic parameters will be estimated according to the guidelines presented in Table 4-1.
Table 4-1
Pharmacokinetic Parameter and Estimation
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BLQs which fa
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 24 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Parameter
Guideline for Derivation
Cmax, Cmin,
tmax, tmin,
Ctrough, Clast, 
Obtained directly from the observed concentration-time data
AUClast (or
AUC0-t)
The AUC from zero time (pre-dose) to the time of last quantifiable 
concentration will be calculated by a combination of linear and logarithmic 
trapezoidal methods. Unless specifically requested and justified, the linear 
up/log down trapezoidal method will be employed.
The AUC0-t is the sum of areas up to the time of the last quantifiable sample (no 
extrapolation will be applied):
AUC0-t=׬ ܥlast כ ݀ݐ
t
଴
AUC0-x
The AUC from zero time to the specific time x is the sum of areas up to the 
specific time x sample (no extrapolation will be applied):
AUC0-x =ܣܷܥ଴ି௫ൌ׬ ܥݔכ ݀ݔ
x
଴
AUC0-tau
The AUC over the dosing interval will be determined for multiple dose 
studies using the trapezoidal rule, as stated above. Calculated for days 1, 29 
and 57.
AUC0-inf
The area from zero time extrapolated to infinite time will be calculated as follows: 
AUC0-inf = AUC0-t+
஼last
ఒ೥
where Clast is the last observed quantifiable concentration. Calculated for days 1, 29, 
and 57.
%AUCex
The percentage of AUC0-in obtained by extrapolation will be calculated as follows: 
%AUCex =
AUC0- nf  ꟷ஺௎஼0-t
AUC0-inf
x100 . Unless otherwise determined by PK Scientist’s 
best knowledge and judgment, if the %AUCex is greater than 20% the value, 
%AUCex, and all dependent parameters (i.e., AUC0-inf, MRT, Vz and CL) will 
be flagged in listings and excluded from summary tables and statistical analysis 
of PK parameters. The reason for exclusion will be listed/footnoted in 
parameter listings.
λz and t½
1.
The apparent terminal phase rate-constant (λz) will be estimated by linear 
regression of concentration versus time data presented in a log-linear scale.
2.
Data are primarily monotonically decreasing in magnitude and are 
representative of the actual decline in the log concentration-time curve.
3.
Only those data points that are judged to describe the terminal log-linear 
decline will be used in the regression. 
4.
A minimum number of three data points in the terminal phase will be used in 
calculating λz with the line of regression starting at any post-Cmax data point (Cmax
should not be part of the regression slope). Unless otherwise determined by PK 
Scientist’s best knowledge and judgment or if instructed by the Sponsor, if the adjusted 
correlation coefficient (R2 adjusted) is <0.9, then λz and all the λz dependent 
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AUC0-infnf = AUC
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 25 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Parameter
Guideline for Derivation
parameters (i.e. t½, AUC0-inf, CL, MRT, and Vz) will be flagged in listings and 
excluded accordingly from summary tables and statistical analysis of PK parameters.
The reason for exclusion will be listed/footnoted in parameter listings.
5.
Unless otherwise determined by PK Scientist’s best knowledge and judgment, 
the interval used to determine λz should be equal or greater than 1.5-fold the estimated 
t½, and if less than 1.5-fold, λz will be flagged in listings and might be excluded from
summary tables and statistical analysis of PK parameters. All the derived parameters 
(i.e. t½, AUC0-inf, CL, MRT, and Vz) may also be flagged in listings and excluded 
from statistical analysis of PK parameters. The reason for exclusion will be 
listed/footnoted in parameter listings.
6.
The t½ will be calculated as follows: 
t½ =  ln2/λz = 0.693/ λz
7.
Data points may be dropped from the linear regression if the PK Scientist 
considers the reported values to be anomalous   Any data points so designated should 
remain in the listings with a footnote and be id ntified in the study report with a 
rationale for exclusion.
CL or CL/F
Apparent clearance (CL/F) following extravascular (e.g. SC) dosing will be 
calculated as:
CL/F = 
Dose
AUC0-ഓ/F
In the case of steady state administration AUC0-τ will be the denominator.
Vz/F
Volume of distribution at terminal phase following extravascular (SC) dosing may be 
calculated from:
Vz/F = 
Dos
λz×AUC0-ഓ/F=  (CL/F)/ Oz
Likewise, if derived for steady state administration AUC0-τ will be used.
Rac
Accumulation ratio, calculated from comparison of single dose and steady state data:
Racx = Steady state AUC0-τ
Single dose AUC0-τ
RacCmax = Steady state Cmax/ Single dose Cmax
Day 1 represents single dose and day 57 represents steady state.
PK Parameters Listings: 
PK parameters will be listed by participant for the SP. PK parameters that will be flagged and/or
excluded from summary tables and statistical analyses of PK parameters will be flagged and footnoted 
with the reason for flagging/exclusion. 
PK Parameter Summary Tables:
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SU
$
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RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 26 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Biostatistics group will consider the derived PK parameters as source data and will use this data 
without rounding for calculation of PK parameters summary statistics tables.  
PK parameters will be summarized by study day with descriptive statistics for the PKP.
Tabular summaries for PK parameters will report N (number of participants who received treatment)
and n (number of participants with non-missing values).
Descriptive statistics for calculated PK parameters will include N, n, arithmetic mean, SD, CV%, 
geometric mean, gCV%, median, minimum, and maximum values. For tmax, only N, n, median, 
minimum, and maximum values will be presented. No descriptive statistics will be determined when 
fewer than three individual PK parameters are available.
The rules followed for presentation of PK parameters data with regards to the number of decimal 
places/significant digits for the listings of participant level PK parameters and summary tables of PK 
parameters are as follows:
PK Parameter Listings and Tables
Rounding
Derived Individual parameters
3 s.f.
Directly Derived Individual parameters 
(Cmax, C12, C24)
n s.f. as supplied by the analytical laboratory
but not more than 3 s.f.
Minimum and Maximum
3 s.f.
Mean/SD/Median/Geomean
3 s.f.
CV%/gCV%
3 s.f.
Comparative estimates (e.g. ratios)
3 s.f.
CI and other percentages
2 d.p.
p-values
4 d.p.
N/n
Whole number
Exceptions for PK Tables
tmax individuals and min/max
3 s.f.
tmax median only
3 s.f.
s.f = significant figures, d.p. = decimal place
4.12.3 Statistical Analysis of Pharmacokinetic Parameters
We will use a one-way analysis of variance to compare the PK parameters of ALDH2 mutation. If 
there are 3 or more subjects with ALDH2 mutation, the PK parameters of these subjects as a group 
will be compared to those without ALDH2 mutation as another group. Otherwise, the PK parameters 
will be summarized with and without the individual(s) with ALDH2 mutation.
Sample SAS Code:
PROC MIXED DATA = DATA1 NOPRINT;
BY PARAMCD;
CLASS MUTATION;
MODEL LN_PK = MUTATION /DDFM = KR;
RUN;
WHERE, 
PARAMCD :short name of PK parameter
6HS'&5$8'6WDWLVWLFDO$QDO\VLV3ODQ_9970)_
Rou
Ro
G
3 s
G
f. as supplied by t
supplied 
but not m
but n
HG
YH
Y
RY
UR
UR
SU
SU
SU
SU
SU
S
SS
Tables
es
SS
SS
SS
SS
max
max
$S
$S
$
p. = decimal p
decim
arm
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 27 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
LN_PK; natural log transformed value of PK parameter
MUTATION: Group for the genetic mutation.
4.12.4 Pharmacodynamic Analysis, Concentration, and Parameter TFLs, and Statistical 
Analysis of Pharmacodynamic Parameters
Pharmacodynamic parameters will be estimated according to the guidelines presented in Table 4-2.
Table 4-2 Pharmacodynamic Parameter and Estimation
Parameter
Guidelines for Derivation
Cmax, tmax,
Obtained directly from the observed concentration-time data
Cav
The average concentration from time 0 to time 4 h:
AUC0-4/4 h
AUC0-4h-adjusted
The AUC adjusted from zero time to 4 h for Day X:
AUC0-4h (Day X) - AUC0-4h (Day -1)
Cav-adjusted
The Cav adjusted for Day X is time averaged concentration 
from zero time to 4 h:
Cav (Day X) - Cav (Day -1)
Cmax-adjusted
The Cmax adjusted for Day X is:
Cmax (Day X) - Cmax (Day -1)
AUC0-4h percent change
Percent change of AUC0-4h on Day X as compared to the 
basal level (Day -1): ((AUC0-4h (Day X) - AUC0-4h (Day-1)/ 
day -1)) X 100
Cav percent change
Percent change of Cav on Day X as compared to the basal 
level (Day -1): ((Cav (Day X) - Cav (Day-1)/ day -1)) X 100
Cmax percent change
Percent change of Cmax on Day X as compared to the basal 
level (Day -1): ((Cmax (Day X) - Cmax (Day-1)/ day -1)) X 
100
Individual participant’s biomarker (acetaldehyde, acetate, and ethanol) plasma concentration values 
(baseline unadjusted values only) will be provided by 
 Laboratories and 
. Baseline 
unadjusted and adjusted acetaldehyde, acetate, and ethanol concentration values will be listed by
study day, timepoint, ALDH2 mutation, and participant for the PP by 
. Concentration listings 
will include nominal biomarker sampling time, actual sampling times relative to dose administration, 
and percentage change from baseline. The corresponding baseline for each timepoint will be taken 
on Day -1.  For the biomarker concentration summary tables, descriptive statistics (N, n, arithmetic 
6HS'&5$8'6WDWLVWLFDO$QDO\VLV3ODQ_9970)_
$SSURYHG
The AUC adjusted fr
AUC adju
AUC
AUC0-4h (D
HG
R
The C
The Cav
av adjusted 
from zero time 
from zer
Cav (Day X)
(Da
RY
SUR
The Cm
The
SU
SU
SU
SSU
Pe
Pe
SS
SS
SS
SS
$
'RZQORDGHGE\
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 28 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
mean, SD, CV%, geometric mean, gCV%, median, IQR (inter quartile range), minimum, and 
maximum values) will be presented by study day, nominal timepoint, EIA days, and ALDH2 
mutation. For time variables only median, Tmin and Tmax will be presented. A by participant listing of 
ALDH2 mutation will be provided.
To visualize the comparison between study days the descriptive biomarker graphs will be generated.
x
Figure x.x.x: Individual Participant Profiles for acetaldehyde, acetate, and ethanol, Plasma
Concentration Time Data (Unadjusted and Adjusted for Baseline) by study day and EIA day (SP)
x
Figure x.x.x: Overlaid Individual Participant Profiles for acetaldehyde, acetate, and ethanol 
Plasma Concentration Time Data (Unadjusted and Adjusted for Baseline) by study day and EIA 
day (SP). The profiles for ALDH2 mutation will be plotted with dotted lines.
x
Figure x.x.x: Mean (± SD) baseline adjusted acetaldehyde, acetate, and ethanol Plasma
Concentration Time Data by study day and EIA day (PP)
x
Figure x.x.x: Mean (± SD) baseline adjusted acetaldehyde, acetate, and ethanol Plasma
Concentration without ALDH2 Mutant Time Data by study day and EIA day (PP)
x
Figure x.x.x: The Mean (± SD) baseline unadjusted acetaldehyde, acetate, and ethanol Plasma
Concentration Time profiles by study day and EIA days (PP)
x
Figure x.x.x: The Mean (± SD) baseline unadjusted acetaldehyde, acetate, and ethanol Plasma
Concentration without ALDH2 Mutant Time profiles by study day and EIA days (PP)
x
Figure x.x.x: The mean (± SD) Cmax (in the units of μM and ng/mL) and AUC0-4h (in the unit of 
ng*h/mL) of acetaldehyde, acetate  and ethanol following 4 Alcohol Drinks in 60 Minutes and 
Multiple Dose Administration of DCR AUD in Healthy Adults will be plotted with EIA days by 
study day (PP)
x
Figure x.x.x: The mean (± SD) Cmax (in the units of μM and ng/mL) and AUC0-4h (in the unit of 
ng*h/mL) without ALDH2 Mutant(s) of acetaldehyde, acetate, and ethanol following 4 Alcohol 
Drinks in 60 Minutes and Multiple Dose Administration of DCR AUD in Healthy Adults will be 
plotted with EIA days by study day (PP)
For each figure, participants belonging to each category will be shown on the same plot with separate 
figures for each treatment arm.  Participant level figures will use actual time, while mean plots will 
use planned time, except for pre-dose time point(s), where time 0 will be used rather than actual time.
4.12.5 Pharmacodynamic Parameters
DCR-AUD is designed to selectively reduce ALDH2 levels in the liver and the conversion of 
acetaldehyde to acetic acid. The build-up of acetaldehyde causes unpleasant effects after drinking 
(e.g., headache, facial flushing, tachycardia, nausea, vomiting). As such, the PD activity of DCR 
AUD will be assessed during EIAs using blood biomarkers (alcohol, acetaldehyde, and acetate), 
assessment of 6 symptoms and their severity induced during EIAs, and objective physiological 
biomarkers (heart rate and facial skin temperature). Participants’ subjective experience of the effects 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 29 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
of alcohol will be assessed. Instructions for the collection and handling of biological samples will be 
provided by the Sponsor in the Laboratory Manual and the Laboratory Specification document.
PD parameters will be calculated using drug effect model from the biomarker time data using 
Phoenix® WinNonlin® 8.3 or higher.  The biomarker parameters alcohol, acetaldehyde, and acetate 
unadjusted and adjusted for baseline will be estimated for treatment, nominal point, EIA days, and 
ALDH2 status. The Phoenix WinNonlin project file including all settings and analysis input file will 
be transferred to Dicerna when the biomarker PD analyses are completed.
The unadjusted and adjusted biomarker parameters will all be listed, and unadjusted parameters will 
be summarized by time point and treatment.  Descriptive statistics (number, arithmetic mean, SD, 
CV%, geometric mean, gCV%, minimum, median, and maximum) will be presented by nominal 
points, treatment, ALDH2 status, and EIA days for absolute, and percentage change from the 
biomarker baseline, where appropriate.  For time variables Tmin and Tmax, only median will be 
presented.
One way ANOVA model will be used to compare the unadjusted Biomarker parameters for DCR-
AUD and Placebo for PP.
To visualize the comparison between treatment and placebo following alcohol consumption the 
following descriptive PD parameter graphs will be generated:
The mean (± SD) Cmax and AUC0-4h of acetaldehyde, acetate, and ethanol will be plotted with EIA 
days . Two mean Cmax figures will be prepared: one in μM and another in ng/mL units.
4.12.1.1
Ethanol Interaction Assessments
EIAs will include an active assessment of the six key symptoms (flushing, headache, palpitations, 
lightheadedness, nausea, and vomiting) that DCR-AUD may induce, in order to determine what dose 
of DCR-AUD gives the proper constellation of these symptoms.
These symptoms will be collected by active questioning of each participant at different time points 
during each EIA i.e.  before alcohol administration, at 0 minutes, 15minutes, 30 minutes, 45 minutes, 
60 minutes, 90minutes, 120 minutes and 150 minutes after study drug administration. Should an EIA 
be missed, due to COVID-19 or other circumstances, the missed EIA may be conducted at the next 
scheduled visit or at an unscheduled visit at the discretion of the Investigator.
The following symptom scoring framework would be described as an arbitrary point system, where:
Symptom
No Symptom
Mild symptom
Moderate symptom
Severe symptom
Score
0
1
2
3
Each participant at each timepoint in an EIA after alcohol administration begins will be given a 
composite score for that timepoint as sum of all six symptom scores.  
Baseline for EIA is defined as last non-missing value prior to alcohol administration.
Descriptive statistics of EIA composite score (n, mean, median,Q1 (25 percentile), Q3 (75 percentile),
minimum and maximum) for absolute values and changes from baseline will be presented by, 
treatment, placebo, visit and time point. 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 30 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Descriptive statistics of Peak EIA composite score (n, mean, median, Q1, Q3, minimum and 
maximum) for absolute values and changes from baseline will be presented by, treatment, placebo, 
and visit (Days).
Descriptive statistics of Peak EIA score in a Day (Column U) (n, mean, median, Q1, Q3, minimum 
and maximum) for absolute values and changes from baseline will be presented by, treatment, 
placebo, and visit (Days).
Peak EIA composite score is defined as maximum composite score at each visit.
To visualize participant-level composite score and the comparison between treatment the EIA graphs 
listed below will be generated.  
•
Figure xx.1: Combined Individual DCR-AUD and placebo EIA composite score-Time 
Profiles (Linear Scale) by Treatment, (Safety Population)
•
Figure xx.1: Combined Individual DCR-AUD and placebo Peak EIA composite score-Visit 
(Days). Profiles (Linear Scale) by Treatment, (Safety Population)
•
Figure xx.1: Combined Individual DCR-AUD and placebo Peak EIA score in a Day (Column 
U)-Visit (Days). Profiles (Linear Scale) by Treatment, (Safety Population)
Serial EIAs will be performed in designated participants to assess the indirect PD effects of ALDH2 
reduction (acetaldehyde increase), including plasma acetaldehyde, acetate, and ethanol levels, 
induced symptoms, heart rate, facial skin temperature, and subjective feelings of alcohol intoxication 
or intolerance. Adverse events, vital signs, and ECG will also be monitored and recorded for safety.
To be clear, of interest would be 2 things in addition to plots above:
o
At each EIA, change in peak symptom score from baseline after alcohol administration from 
pre-administration score on that day
o
For each EIA change in the peak symptom score on that test day after alcohol administration 
from the peak score change on day –1 (i e. On day of EIA challenge before IMP was administered)
(It is expected that most participants would have Day –1 pre-EIA challenge composite score of zero 
(0), i.e. Reporting none of 6 active surveillance symptoms before IMP and before any alcohol was 
administered on day –1.  However, to the extent that some or few patients might have some 
symptoms, the most informative change metric that would reflect what the participant experiences is 
the change in peak composite score at any given EIA after dosing from that pre-IMP and pre-alcohol, 
i.e. Baseline score at day –1.)
4.12.1.2
PD Biomarkers for EIA
4.12.1.2.1
EIA Blood Biomarkers
Blood biomarkers to be assessed include measurement of acetaldehyde, acetate, and ethanol. A by-
participant listing of EIA blood biomarkers will be presented in SP. A summary table of Tmax, Cmax, 
and AUC0-2.5h of blood biomarkers will be presented by biomarker parameter, visit, time point, EIA 
days, treatment and placebo in PD population. The same PK parameter analysis method described in 
Section 4.10 will be applied to the calculations of these biomarker parameters.
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 31 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
The mean (± SD) plasma concentration – time profiles of these biomarkers will be plotted by 
treatment and EIA days. 
The mean (± SD) Cmax and AUC0-4.0h of acetaldehyde, acetate, and ethanol will be plotted with 
EIA days by treatment.
4.12.1.2.2
EIA Physiological Responses
Quantitative assessment of 6 symptom responses during EIAs:
6 symptom variables include flushing, headache, lightheadedness, palpitations, nausea and vomiting 
assessed at regular intervals during the EIAs and assessed semi-quantitatively (i.e.  mild, moderate, 
or severe)
Descriptive statistics of 6 symptom EIA assessment (n, mean, median, Q1, Q3, minimum and 
maximum) for Total Scores, Highest Post Dose Score, Delta 1: Peak post-dose score for a given 
visit’s test minus the score at the pre-alcohol administration time on that day,  Delta 2: Peak post 
alcohol administration score on the day of the test, minus the peak post-alcohol administration score 
for the same participant on day -1,  Delta 3: The highest score attained by that participant in Delta 1 
over all 6 tests after DCR-AUD was administered will be presented by treatment, placebo, and visit.
4.12.1.2.3 Relationship of acetaldehyde Cmax and EIA symptom score by EIA days
Mean (±SD) and individual EIA days, Acetaldehyde Cmax (μM) data, and EIA symptom score will 
be plotted on the x-axis, left y-axis, and right y axis, respectively. The acetaldehyde Cmax (μM) and 
EIA symptom score profiles should be plotted with different line types and symbols and 
distinguishable. .
4.13 Safety Evaluation
All safety summaries and analyses will b  based upon the SP. All safety and tolerability parameters 
(AEs, laboratory data [hematology, coagulation, clinical chemistry, routine urinalysis, complement 
panel, and other screen test parameters], vital signs, physical exam findings, Alcohol Consumption 
via Timeline Follow Back, Columbia-Suicide Severity Rating Scale, Mini-International 
Neuropsychiatric Interview, and ECG parameters will be evaluated as following.
4.13.1 Adverse Events
All outputs for AEs/treatment-emergent adverse events (TEAEs) will be based on the SP unless
specified separately in TLF shells. Describe the AE dictionary including version that is to be used to 
classify the AEs.
All AE summaries should provide the number and percentages of participants reporting at least one
AE and the total number of events reported. 
Summaries of AEs will include the following:
x
Incidence of AEs - Overview (by treatment and overall)
x
Incidence of TEAEs (by treatment and overall, SOC, and PT)
x
Incidence of TEAEs by maximum relationship (by treatment and overall, SOC, and PT)
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 32 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
x
Incidence of TEAEs by maximum severity (mild/moderate/severe, by treatment  and overall, 
SOC, and PT)
Summary tables will contain counts of participants, percentages of participants in parentheses, and 
the number of events where applicable. A participant who has multiple events in the same SOC and 
PT will be counted only once in the participant counts, but all events will be included.
All Adverse Events (AEs)
All AEs will be listed including pretreatment AEs.
Treatment-emergent Adverse Event
A TEAE will be defined as any AE that emerges during treatment (i.e., AE which started after study 
drug administration or pre-existed that worsened in severity after study drug administration) and those 
will be analyzed for the purpose of safety analysis.
TEAEs will be summarized by SOC and PT, including the number and percentage of participants
experiencing events, separately.
Severity
TEAEs will be summarized by SOC, PT, and severity, including the number and percentage of 
participants experiencing events. If a participant reports the same TEAE more than once within that 
SOC and PT, the TEAE with the highest severity will be used in the corresponding severity 
summaries.
The summaries including severity will be rep rted by Common Terminology Criteria for Adverse 
Events (CTCAE) grade presented as below.
x
Grade 1: Mild; 
x
Grade 2: Moderate;. 
x
Grade 3: Severe or medically signifi ant but not immediately life-threatening; 
x
Grade 4: Life-threatening consequences; 
x
Grade 5: Death related to AE.
participants who experience the same event multiple times will be included in the most severe 
category. Events with missing intensity will be considered as ‘Grade 3’ events for summary purposes 
but recorded as missing in the listings.
.
Relationship (Causality)
TEAEs will be summarized by SOC, PT, and causality, including the number and percentage of 
participants experiencing events. Relationship to study drug will be tabulated respectively. If a 
participant reports the same TEAE more than once within that SOC and PT, the TEAE with the worst-
case relationship to study drug will be in summaries including relationship to study treatment, the 
following relationships will be summarized: ‘Not related’, ‘Possibly Related’, 'Probably Related’ and 
‘Definitely Related’. Participants who experience the same event multiple times will be included in 
the most related category. Events with missing relationship will be considered as ‘Probably Related’ 
to the last given study drug for summary purposes but recorded as missing in the listings.
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AE.
e sam
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 33 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Adverse Events of Special Interest (AESI)
An Injection Site Reaction (ISR) is characterized by an intense adverse reaction (usually 
immunologic) developing at the site of an injection after 4 or more hours post-injection. Subcutaneous 
administration of the study intervention may cause a specific local reaction originating around the 
injection site, such as erythema, itching, discomfort, and pain, and could include more severe 
manifestations such as ulceration or necrosis. 
Potential ISRs will be evaluated and recorded as follows: 
Individual signs or symptoms at the injection site with an onset of less than 4 hours from the time of 
study intervention administration will be recorded as individual AEs (bruising, itching, transient 
erythema, swelling, etc.) and not as ISRs. 
Signs or symptoms at the injection site with a time to onset of 4 or more hours post-injection will be 
recorded as an ISR if any of the CTCAE criteria for ISR detailed below are met. Signs or symptoms 
at the injection site that occur ı 4 hours post-injection but are not specified in Table 7 should be 
recorded as AEs.
x
Grade 1: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching). 
x
Grade 2: Pain, lipodystrophy; edema; phlebitis.
x
Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated.
x
Grade 4: Life-threatening consequences; urgent intervention indicated. 
x
Grade 5: Death .
AESI will be summarized by SOC and PT, including the number and percentage of participants
experiencing events. Listing of AESI will be provided.
4.13.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events
Describe the listings that are to be provided.  These may include the following listings:
x
A by-participant listing of all deaths that occurred during the study
x
A by-participant listing of all SAEs
x
A by-participant listing of all AES leading to discontinuation of study treatment
x
A by-participant listing of all other significant AEs
Listings should follow the format described for AEs in Section 4.13.1 if appropriate.
4.13.3 Clinical Laboratory Evaluation
Clinical laboratory test results of hematology, biochemistry, urinalysis, urinary drug screening, 
coagulation and serology will be provided by participant. A list of current reference ranges of 
laboratory assessments is included in Section 6.3. Since laboratory ranges can be participant to 
changes over time the reference ranges presented in Section 6.3 might differ from the ones actually 
used and presented on SDTM. For analysis purposes only the ranges present on the SDTM will be 
used.
All TLFs will display only the standard international (SI) units after conversion by means of standard 
conversion factors. 
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othe
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 34 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Quantitative clinical laboratory variables, ie, hematology, biochemistry, and urinalysis will be 
summarized using descriptive statistics (n, mean, SD, minimum, maximum and median) by treatment
arm and time-point. Additionally, a within-participant change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized in the same way. 
Baseline definition will be defined in section 4.2.4.
Any quantitative laboratory parameters that are given as '<xx' or '>xx' in the database will be imputed 
with the absolute value of the number without the sign (e.g., <2.2 will be imputed as 2.2) for the 
calculation of the changes from baseline and for the descriptive statistics. In the listings, no 
imputations will be performed, and all data will be displayed as recorded in the database.
Each laboratory result will be classified as low (L), normal (N), or high (H) at each time point 
according to the laboratory supplied reference ranges. For hematology and biochemistry, shift tables 
will be presented showing the number and percentage of participants with shifts from baseline to each 
postdose time point. Tabulations will be presented by treatment arm.
Measurements obtained at Screening and EOS will not be included in the shift tables.
Measurements obtained prior to dosing in each period will be included in the tabulations for the 
treatment received in that specific treatment period.
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be presented by 
treatment and time-point.
All laboratory data will be displayed in listings
Laboratory abnormalities that are considered clinically significant (CS) are recorded in the database 
as AEs. Therefore, no tabulation of laboratory values meeting any CS criteria (except liver chemistry) 
will be presented as all relevant information will be presented in the AE summaries.
Results of pregnancy tests (females only), serology, drugs of abuse and alcohol tests will be listed 
only.
4.13.4 Vital Signs,
Temperature (by skin refraction), pulse rate, respiratory rate, and blood pressure will be assessed.
Blood pressure and pulse measurements will be assessed in the seated position with a completely 
automated device. Heart rate will be measured using telemetry during EIAs. Manual techniques will 
be used only if an automated device is not available. Blood pressure and pulse measurements should 
be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).
Temperature will be obtained in degrees Celsius (°C), pulse rate will be counted for a full minute and 
recorded in beats per minute, and respirations will be counted for a full minute and recorded in breaths 
per minute.
Vital signs data will be listed by participant including changes from baseline. Vital signs will be 
summarized in tabular format to include descriptive statistics (n, mean, SD, median, minimum, 
maximum) for absolute values and changes from baseline will be presented by treatment, and placebo 
and time-point.
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 35 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.13.5 ECG
Standard safety 12-lead ECGs will be performed as shown in the Schedule of Assessments.
The following ECG parameters will be recorded:
x
RR-interval (msec).
x
QRS-interval (msec)
x
PR-interval (msec)
x
QT-interval (msec)
x
QTc-interval (msec)
x
QT-interval corrected using the Fridericia correction formula (QTcF) (msec)
x
Heart rate (HR) (beats per minute [bpm])
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or ‘Abnormal, CS’.
All ECG parameters will be listed by participant including changes from baseline. 
Baseline is defined in section 4.2.4.
Descriptive statistics for absolute values and changes from baseline will be presented by treatment.
Measurements obtained at Screening and EOS will not be included in the shift tables.
Measurements obtained prior to dosing in each period will be included in the tabulations for the 
treatment received in that specific treatment period.
The listing of ECG abnormality will be presented separately.
4.13.6 Physical Examination
Physical examinations will include, at a minimum, assessments of the Cardiovascular, Respiratory, 
Gastrointestinal, Neurological, and Skin systems. Height will also be measured and recorded at Day 
1 and weight will be measured and recorded at every visit.
x
Investigators should pay special attention to clinical signs related to previous serious 
illnesses or AEs.
x
All physical examinations should include inspection of the injection site.
x
Abnormal physical examination findings will be listed.
4.13.7 Other Analysis
4.13.7.1 Columbia-Suicide Severity Rating Scale
The C-SSRS is a suicidal ideation rating scale created by researchers at Columbia University. It rates 
an individual's degree of suicidal ideation on a scale, ranging from "wish to be dead" to "active 
suicidal ideation with specific plan and intent."
The scale identifies behaviors that may be indicative of an individual's intent to commit suicide. The 
C-SSRS is used extensively across primary care, clinical practice, surveillance, research, and 
institutional settings and is part of a national and international public health initiative involving the 
assessment of suicidal ideation and behavior. The C-SSRS requires no mental health training to 
administer it. The C SSRS will be administered by qualified, trained raters.
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$SSURYHG
ng chang
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rom basel
will not be include
not be inc
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period w
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eriod.
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'RZQORDGHGE\
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 36 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
The Baseline version will be administered at Screening and at subsequent visits the “C-SSRS Since 
Last Visit” version will be administered.
C-SSRS and Domain wise scores will be summarized by treatment arm and visit. C-SSRS will be 
listed by participant.
4.13.7.2 Exploratory Analyses
The descriptive statistics of participant’s alcohol consumption measured by TLFB will be present for 
each arm and study days. Each of the drinks will be multiplied by 14g to achieve the alcohol amount. 
[3]. Change of baseline from both day -1 and screening visit will be presented for each arm. The mean 
difference and its 95% CI will be presented for the change from baseline of alcohol consumption for 
each assessment day. Similar analysis will also be performed for total alcohol consumed from 
baseline.
For PEth descriptive statistics will be present for assessment days. The mean difference and its 95% 
CI will be presented for the change from baseline of PEth levels for each assessment day.
By participant listings will be present for the exploratory analyses for SP.
4.13.8 Daylight Saving Time (DST):
Not applicable.
4.13.9 Safety Review Committee
A Safety Review Committee (SRC) will conduct periodic reviews and will review all cumulative 
safety, tolerability, and available PD data on participants, approximately every month or every 3 
weeks during treatment and post dose follow-up. Participant safety will be continuously monitored 
by the SRC by ongoing review of AEs, laboratory results, and other protocol-specified assessments, 
to allow safety signal detection throughout the study.
4.14 Cardio Dynamic Analyses
Not applicable.
4.15 Biomarkers
4.16 Adjustments for Covariates
Not applicable
4.17 Handling of Dropouts or Missing Data
Not applicable.
4.18 Subgroup Analysis
Not Applicable
4.19 Planned Interim Analyses
Not Applicable.
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lev
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ry analyses
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ill conduct period
onduct pe
data on participa
on par
ose follow
ollow-up. Par
up.
f AEs, laboratory r
, laborat
throughout 
ughout the stu
the st
lyses
tes
t
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 37 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
4.20 Determination of Sample Size
No formal sample size estimations were performed. The sample size of 16 participants (12 active and 
4 placebo) was considered sufficient to provide an initial assessment of the safety profile of DCR-
AUD in HVs, and adequate for the purpose of describing PK/PD data in HVs.
The sample size is based on clinical rather than statistical considerations.
4.21 Changes in the Conduct of the Study or Planned Analysis
Not Applicable.
5
REFERENCES
[1] SAS® Version 9.4 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.
[2] Phoenix®WinNonlin® Software Version 8.3. https://www.certara.com
[3] What Is A Standard Drink? | National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
(nih.gov)
6
APPENDICES
6.1
Schedule of Assessments
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NC, USA.
, USA.
ps://www.certara.
ww.cert
HG
e on Alcohol Abus
Alcohol
H
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RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 38 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Table 6-1
Schedule of Activities – Screening, Dosing, EOS, and CFU Visits (see Table 6-2 for non-dosing visits)
Screen
Dosing Visits
EOS/ET 
a
CF
Ub
Study Week
—
4
8
24
28
Study Day −28 to −2
−1
1
2
4
28
29
30
32
56
57
58
16
8
16
9
197
Window (days) c
–
–
–
–
–
±2
–
–
–
±2
–
–
±7
±7
Procedure/Assessment
Pre
Post
Pre
Post
Pre
P
o
st
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographic characteristics
X
General medical history
X
Medication history
X
Psychological history
X
Urine drug testing d
X
Screening laboratory testing 
e
X
ALDH2 genotyping f
X
MINI Screen
X
C-SSRS g
X
X
X
X
X
Alcohol TLFB h
X
X
X
X
X
X
6HS'&5$8'6WDWLVWLFDO$QDO\VLV3ODQ_9970)_
$SSURYHG
29
29
±2
±2
G
H
Pre
P
Post
P
HG
HG
HG
YHG
RY
RY
RYH
YH
YH
YH
RYH
RY
RY
RY
URY
UR
SUR
SU
SU
SU
$SSU
$S
$S
$SS
$SS
$S
$S
$SS
$SS
$S
$S
$S
$S
$
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 39 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Screen
Dosing Visits
EOS/ET 
a
CF
Ub
Study Week
—
4
8
24
28
Study Day −28 to −2
−1
1
2
4
28
29
30
32
56
57
58
16
8
16
9
197
Window (days) c
–
–
–
–
–
±2
–
–
–
±2
–
–
±7
±7
Procedure/Assessment
Pre
Post
Pre
P st
Pre
P
o
st
Pregnancy test i
X
X
X
X
X
X
SARS-CoV-2 test j
X
X
X
X
Drug/alcohol screen k
X
X
X
X
Clinic site admission l
X
X
X
X
Clinic site discharge m
X
X
X
X
EIA n
X
X
X
X
Randomize
X
Administer study 
intervention
X
X
X
12-lead ECG o
X
X
X
X
X
X
X
X
Vital signs
X p
X
X q
X
X q
X
X
q
X
Physical examination r
X
X
X
X
X
Blood sample for PEth s
X
X
X
6HS'&5$8'6WDWLVWLFDO$QDO\VLV3ODQ_9970)_
$SSURYHG
±2
±2
Pre
P st
P st
G
HG
X
HG
HG
HG
HG
YHG
X
YH
YH
YH
RYH
X
RY
RY
RY
URY
X
UR
SUR
X
SU
SU
SU
$SSU
$S
$S
$SS
$SS
X
$S
$S
$SS
$S
X
$S
$S
$S
$S
X
'RZQORDGHGE\
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 40 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Screen
Dosing Visits
EOS/ET 
a
CF
Ub
Study Week
—
4
8
24
28
Study Day −28 to −2
−1
1
2
4
28
29
30
32
56
57
58
16
8
16
9
197
Window (days) c
–
–
–
–
–
±2
–
–
–
±2
–
–
±7
±7
Procedure/Assessment
Pre
Post
Pre
P st
Pre
P
o
st
Hematology, chemistry, UA 
t
X
X
X
X
Coagulation panel u
X
X
X
X
Complement panel v
X
X
X
X
X
X
Blood sample for ADA w
X
X
Blood sample for PK x
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol use symptom diary 
y
X
X
X
X
X
X
X
X
Record AEs & SAEs z
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record concomitant meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: ADA=antidrug antibody; AE=adverse event; ALDH2=aldehyde dehydrogenase 2 gene; CBC=complete blood count; CFU=conditional follow-up visit; 
C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EIA=ethanol interaction assessment; EOS=end of study; ET=early termination; 
FSH=follicle-stimulating hormone; HbA1c=hemoglobin A1c; ICF=informed consent form; MINI=Mini-International Neuropsychiatric Interview; PEth=phosphatidylethanol; 
PK=pharmacokinetic; RBC=red blood cell; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SIB=suicidal ideation or behavior; 
TLFB=Timeline Follow Back; UA=urinalysis
a At the time of discontinuation for the study, an early termination (ET) visit should be conducted, if possible.
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$SSURYHG
±2
±2
Pre
P st
P st
G
HG
X
HG
HG
HG
HG
RYHG
X
RY
RY
RY
URY
X
UR
SUR
SU
SU
SUR
SSUR
X
X
X
SS
$SS
X
$S
$S
$SS
$SS
X
$S
$S
$S
$S
X
$
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RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 41 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
b Participants with significant symptoms at the Day 168 EIA will be followed for an additional 4 weeks at the discretion of the Investigator.
c Visits without a specified window are to be conducted relative to the associated scheduled visit. For example, Day 28 will always be the day prior to the Day 29 visit, regardless 
of where Day 29 falls within the ± 2-day visit window
d Screening tests positive for cannabis are not exclusionary.
e To include hematology (CBC with differential and RBC indices), clinical chemistry, coagulation panel, urinalysis, viral serology, HbA1c, and FSH (as indicated). See protocol 
for a complete list of parameters.
f Baseline genetic testing for ALDH2 mutations. Participation is optional; participants who do not wish to undergo genotyping may still participate in the study.
g The Baseline version will be administered at Screening and at subsequent visits the “C-SSRS Since Last Visi ” version will be administered. Participants who exhibit signs of 
Suicidal Ideation or Behavior (SIB) should undergo a risk assessment. All factors contributing to SIB should be evaluated and consideration should be given to discontinuation 
of study intervention. 
h TLFB will be completed for the 2-week period that precedes each study visit, including Screening.
i Pregnancy testing required only in female participants. If a urine pregnancy test is positive, confirm with serum pregnancy test. Local laboratory may be used. Female 
participants must have a negative pregnancy test prior to overnight admission.
j Testing to be performed at the site upon admission. Participants with a positive SARS-CoV-2 tes  will not be admitted to clinic and will not receive study intervention or undergo 
EIA. Other assessments not requiring clinic admission (i.e., safety assessments) will be perf rmed. Testing will be performed per site standard processes.
k Study participants are to refrain from drinking alcohol and using cannabis for 24 hours prior to each EIA. Participants with a positive urine-drug or breath-alcohol test will not be 
admitted to clinic and will not undergo EIA. Participants with a positive urine drug test on Day −1 will be excluded from the study.
l Participants must be fasting for at least 3 hours prior to admission to the clinic.
m Participants may be discharged from clinic following collection of the 24-hour postdose PK sample. Participants will return to clinic for collection of PK samples at  72 hours 
postdose on Days 4 and 32.
n EIA will be conducted on the first day of the visit once ll other ass ssments fo  that day have been completed. A total of 10 EIAs will be conducted. The timing of assessments 
and ethanol administration are detailed in protocol Table 6-3
o On dosing days, ECGs will be conducted approximately 30 minutes predose and 15-to-30 minutes postdose. If multiple assessments are due, the order of assessment should be 
ECG, vitals, PK, and then other assessments; with PK sample collection occurring at the nominal time. At Screening and EOS, one ECG will be performed. Screening ECGs
may be repeated one time for determination of eligibility.
p Blood pressure, if out of range at Screening, may be repeated one time for determination of eligibility.
q Blood pressure and pulse rate to be recorded 15 (±5) minutes postdose.
r Height will be measured and recorded at Screening. Weight will be measured and recorded at every visit.
s Sample to be collected prior to ethanol administration.
t Hematology to include complete blood count with differential and RBC indices. See protocol for a complete list of parameters.
u See protocol for a complete list of parameters.
v Blood samples for complement testing to be collected predose and 2, 8, and 24 hours postdose on Day 1 and Day 57.
w Blood sample for ADA testing to be drawn at same time as predose PK sample on Day 1.
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$SSURYHG
g
Visi ” ve
si ” 
 should be
d be eval
ev
ening.
ve, confirm with serum pregnanc
firm with serum pr
SARS-CoV
oV-2 tes  will not be adm
2 tes  w
nts) will be perf rmed.
will be perf rm
Testing w
T
is for 24 hours prior to each EIA
hours prior to
itive urine drug test on Day 
ine drug test on Da −1 w
on to the clinic.
clinic.
ction of the 
the 24
24-hour postdose PK
hour postd
once ll other ass ssments fo  tha
e ll other ass ssments fo  th
ol Tablele 6-3
ately 30 minutes predos
30 minutes predos
K sample collectio
mpl
y
ted
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 42 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
x Plasma samples for PK analysis to be collected predose and at 1, 2, 4, 6, 8, 24, and 72 hours postdose (exception: no 72-hour PK sample is required at Day 57). A single sample 
will be collected on Day 168. If multiple assessments are due, the order of testing should be ECG, vitals, PK, and then other assessments, with the PK sampling performed 
preferably at the nominal time point. A ±15-minute window will be allowed for collections at 1, 2, 4, 6, and 8 hours postdose. A ±30-minute window will be allowed for 
collection at 24 hours postdose. A ±60-minute window will be allowed for collection at 72 hours postdose.
y Participants to record any symptoms associated with use of alcohol outside of in-clinic EIAs. Diary to be issued at time of discharge from clinic and collected and reviewed upon 
return to clinic.
z AEs and SAEs will be recorded from time ICF is signed. SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up. 
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$SSURYHG
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 43 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Table 6-2:
Schedule of Activities – Non-dosing Visits (see Table 6-1 for Screening, Dosing, and EOS Visits)
Week
2
6
10
12
16
20
Study Day
14
15
42
43
70
71
84
85
112
113
140
141
Visit Window (days) a
–
±2
–
±2
–
±3
–
±5
–
±7
–
±7
Procedure/Assessment
Drug/alcohol screen b c
X
X
X
X
X
X
Pregnancy test d
X
X
X
X
X
X
SARS-CoV-2 test e c
X
X
X
X
X
X
Clinical site admission f
X
X
X
X
X
X
Physical examination g
X
X
X
X
X
X
C-SSRS h
X
Hematology, chemistry, UA i j
X
Coagulation panel j
X
Blood sample for ADA k
X
X
X
Blood sample for PK k
X
X
X
Blood sample for PEth k
X
EIA l
X
X
X
X
X
X
Alcohol TLFB m
X
X
X
X
X
X
Alcohol use symptom diary n
X
X
X
X
X
X
X
X
X
X
X
X
Record AEs and SAEs o
X
X
X
X
X
X
X
X
X
X
X
X
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$SSURYHG
X
G
X
G
HG
X
X
HG
HG
HG
YHG
X
YH
YH
RYH
X
RY
URY
UR
UR
UR
SUR
SU
$SSU
$S
$S
$SS
SS
SS
$SS
X
$S
$S
$SS
SS
SS
$SS
X
$S
$S
$S
$S
$
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 44 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Week
2
6
10
12
16
20
Study Day
14
15
42
43
70
71
84
85
112
113
140
141
Visit Window (days) a
–
±2
–
±2
–
±3
–
±5
–
±7
–
±7
Procedure/Assessment
Record concomitant meds 
X
X
X
X
X
X
X
X
X
X
X
X
Clinical site discharge p
X
X
X
X
X
X
Abbreviations: ADA=antidrug antibody; AE=adverse event; C-SSRS=Columbia-Suicide Severity Rating Scal ; EIA=ethanol interaction assessment; 
PEth=phosphatidylethanol; PK=pharmacokinetics; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SIB=suicidal ideation or 
behavior; TLFB=Timeline Follow Back; UA=urinalysis
a Visits without a specified window are to be conducted relative to the associated schedul d visit. For example, Day 14 will always be the day prior to the Day 15 
visit, regardless of where Day 15 falls within the ± 2-day visit window.
b Study participants are to refrain from drinking alcohol and using cannabis for 24 hours prior to each EIA. Participants with a positive urine-drug or breath-
alcohol test will not be admitted to clinic and will not undergo EIA. Other assessments not requiring clinic admission (i.e., safety assessments) should be 
performed.
c Other assessments not requiring clinic admission (i.e., safety 
sessments) should be performed.
d Pregnancy testing required only in female participants. If a urine pregnancy test is positive, confirm with serum pregnancy test. Local laboratory may be used. 
Female participants must have a negative pregnancy test prio  to overnight admission.
e Participants with a positive SARS-CoV-2 test will not be admit ed to clinic and will not undergo EIA. Testing will be performed per site standard processes.
f Participants must be fasting for at least 3 hours prior to admission to the clinic.
g Weight will be measured and recorded at each visit.
h The “C-SSRS Since Last Visit” version will be administered. Participants who exhibit signs of SIB should undergo a risk assessment. 
i Hematology to include complete blood count. 
j See Section 10.2 for complete list of testing parameters.
k Sample to be collected prior to ethanol administration for EIA.
l EIA will be conducted once all other assessments for that day have been completed. The timing of assessments and ethanol administration are detailed in 
protocol.
m TLFB will be completed for the 2-week period that precedes each study visit.
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X
G
HG
erity Rating Scal ;
Rating Scal ; EIA=etha
EIA=
V-2=severe acute respiratory sy
evere acute respira
HG
HG
HG
sociated schedul d visit. For e
iated schedul d 
ow.
g cannabis for 24
bis for 24 hours prior t
our
go EIA. Other assessments no
. Other assessme
., safety 
sessments) should 
y 
sessments)
ipants. If a urine
pants. If a urine pregnancy te
pregnanc
egnancy test prio  to overnigh
ncy test prio  to overnigh
st will not be admit ed to 
l not be admit ed t
prior to admission
r to admission
it.
iniste
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 45 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
n Participants to record any symptoms associated with use of alcohol outside of in-clinic EIAs. Diary to be issued at time of discharge from clinic and collected 
and reviewed upon return to clinic.
o AEs and SAEs will be recorded from time ICF is signed. SAEs will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up. 
p Participants will be discharged in the morning when the PI deems it medically appropriate to do so.
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$SSURYHG
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 46 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Table 6-3:
Schedule of Activities - 4-Hour Ethanol Interaction Assessments 
Pre-EIA
EIA Test Period
Time (minutes)
-50
-20
0 a
20
30
40
60
90
120
150
180
210
240
Window (minutes)
-
±5
±5
±5
±10
±10
±10
±10
±10
±10
±10
Procedure:
Standard meal b
X
Venous catheter placement c
X
12-lead ECG d
X
X
X
Vital signs d e
X
X
X
X
X
X
X
X
X
Plasma biomarker sample d f
X
X
X
X
X
X
X
Questionnaire of 6 EIA symptoms d g
X
X
X d
X
X
Ethanol consumption h
X
X
X
X
EIA AEs i
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE=adverse event; ECG=electrocardiogram; EIA=ethanol interaction assessment; PK=pharmacokinetics
a
“Time 0” is immediately before the first sip of ethanol is consumed  All Time 0 assessments must be performed prior to initiation of alcohol intake.
b
Participants will arrive at the site after a minimum 3-hour fast, then will be provided a standardized meal before receiving the first drink. Participants will be given 30 minutes to consume the meal.
c
Catheter placement may be performed earlier in the day if preferred, but participants must be given at least a 20-minute rest period following placement of the venous access catheter prior to 
recording predose vital signs and ECG. For EIAs conducted prior to a dosing day, the venous catheter will be left in place for PK sample collections.
d
If multiple assessments are due at the same timepoint, the order of assessments should be ECG, vitals, blood draw, then any other assessments. The 60-minute symptom assessment should be 
conducted before the start of the 4th drink.
e
To include pulse rate and blood pressure.
f
Blood samples will be collected via venous access device. To include acetaldehyde, acetate, and ethanol.
g
Participants will be questioned by site staff to assess the 6 symptoms (flushing, headache, lightheadedness, palpitations, nausea, and vomiting) associated with increased blood acetaldehyde levels.
h
Ethanol will be consumed in 4 aliquots over an 80-minute period (20 minutes for each aliquot). Time windows do not apply to ethanol consumption. The ethanol will be mixed in a liquid that has no 
other alcohol, no caffeine, and is low in sugar. The dose of ethanol will be 0.8 g/kg (to a maximum of 56 g) for men and 0.68 g/kg (to a maximum of 48 g) for women. See protocol for ethanol 
administration stopping rules.
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$SSURYHG
HG
HG
HG
HG
YHG
X
YHG
HG
HG
RYHG
X
X
RY
URY
X
X
UR
UR
URY
SUR
X
X
SUR
SUR
UR
$SSUR
X
X
$S
$SS
SS
SS
$SS
X
$S
$SS
$SS
SS
$S
$S
$SS
A=ethanol interaction 
hanol interaction 
med  All Time 
ed  A
en will be
en
d b
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 47 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
i
AEs associated with administration of ethanol will include events spontaneously reported by participants beginning with the first sip of ethanol (symptoms elicited under direct questioning [footnote 
g] are not considered AEs).
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$SSURYHG
'RZQORDGHGE\
RQ6HS


Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 48 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
6.2
Imputation Rules for Partial Dates
Imputed dates and time will NOT be presented in the listings. 
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 49 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
Table 6-4 and Table 6-5 present algorithm for imputing partial dates for TEAE and prior/concomitant 
medication respectively.   
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Dicerna Pharmaceuticals
DCR-AUD-102
Statistical Analysis Plan
Project Document Version No.: 2.0; Document Effective Date:  01 Sep 2023
TP-GDO-WW-133-04
Effective Date:  28 Jul 22
Related to:  SOP-GDO-WW-019
Page 54 of 54
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001
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