Conditions: Alcohol Use Disorder (AUD)
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 36
Healthy volunteers: yes

Brief summary:
DCR-AUD will be evaluated for safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers.

Detailed description:
DCR-AUD is being developed for the treatment of alcohol use disorder (AUD) in adults using an RNA interference (RNAi) technology platform. This is a 24-week, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and PD of single-ascending doses (SAD) of DCR-AUD administered to adult HVs. The single doses of DCR-AUD will be administered to adult HVs across 4 sequential cohorts (3 planned \[80 mg, 240 mg, 480 mg\] and one optional \[960 mg\]). Each cohort will comprise a sentinel group of 3 participants (2 active, 1 placebo) and an expanded group of 6 participants (4 active, 2 placebo). The sentinel group will be followed for the assessment of safety and tolerability and characterization of PK but who will not undergo any EIAs. Participants will receive a single dose of study intervention on Day 1 and will be followed for 24 weeks. Participants who have positive ethanol reaction symptoms at the Day 169 EIA (e.g., nausea, vomiting, or substantial flushing) will return every 28 (±7) days for follow-up EIAs until the positive ethanol reaction symptoms abate. These conditional follow-up (CFU) EIAs will not require overnight admission to the clinic, but all other aspects of the EIA will be conducted (see Table 3). Participants will be observed for not less than 6 hours after ethanol administration and will not be discharged until the Investigator deems it medically safe to do so.

Arms:
arm 1: Participant received a single dose of DCR-AUD 80 mg, subcutaneous injection on Day 1. arm 2: Participant received a single dose of DCR-AUD 240 mg, subcutaneous injection on Day 1. arm 3: Participant received a single dose of DCR-AUD 480 mg, subcutaneous injection on Day 1. arm 4: Participant received a single dose of DCR-AUD 960 mg, subcutaneous injection on Day 1. arm 5: Participant received a single dose of DCR-AUD matching placebo, subcutaneous injection on Day 1.

Interventions: intervention 1: DCR-AUD intervention 2: Placebo for DCR-AUD
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 uptake 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 document:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Dicerna Pharmaceuticals, Inc. 
NCT number 
NCT05021640 
Sponsor trial ID: 
DCR-AUD-101 
Official title of study: 
A Phase 1, Double-blind, Placebo-controlled, Single-
ascending-dose, Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics Study of DCR-AUD in Healthy 
Volunteers 
Document date*: 
14-Mar-2022
*Document date refers to the date on which the document was most recently updated.


TITLE PAGE 
Protocol Title: 
A Phase 1, Double-blind, Placebo-controlled, Single-ascending-dose, 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study 
of DCR-AUD in Healthy Volunteers  
Protocol Number: 
DCR-AUD-101 
Compound: 
DCR-AUD 
Study Phase:  
1 
Short Title:  
Phase 1 SAD Study of DCR-AUD in Healthy Volunteers 
IND Number: 
152401 
Sponsor Name:  
Dicerna Pharmaceuticals, Inc. 
75 Hayden Avenue 
Lexington, MA 02421 US 
(617) 621-8097
Version History: 
Original Protocol (version 1.0) 
24-Jun-2021
Amendment 1 (version 2.0) 
09-Jul-2021
Amendment 2 (version 3.0) 
19-Jul-2021
Amendment 3 (version 4.0) 
26-Jul-2021
Amendment 4 (version 5.0) 
28-Jul-2021
Amendment 5 (version 6.0) 
14-Mar-2022
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Dicerna Protocol DCR-AUD-101 
Version 6.0, 14-Mar-2022 
 
 
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Sponsor Signature Page 
 
 
Title: 
A Phase 1, Double-blind, Placebo-controlled, Single-ascending-dose, Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in 
Healthy Volunteers  
Protocol Number: DCR-AUD-101 
 
 
Version:  
6.0 
Date: 
14-Mar-2022 
 
 
 
Dicerna Pharmaceuticals, Inc. 
 
Date 
 
 
Dicerna Pharmaceuticals, Inc. 
 
Date 
 
 
 
Dicerna Pharmaceuticals, Inc. 
 
Date 
 
 
 
DocuSign Envelope ID: 
16-Mar-2022
16-Mar-2022
16-Mar-2022


Dicerna Protocol DCR-AUD-101 
Version 6.0, 14-Mar-2022 
 
 
Page 3 
Medical Monitor and Pharmacovigilance Contact Information 
SAE Submission:  
(
 Pharmacovigilance): 
24-hour Safety Telephone:
24-hour Safety Fax: 
email: 
  
Clinical Research Organization Medical Monitor: 
 
 
 
 
 
 
 
Sponsor Medical Monitor: 
Dicerna Pharmaceuticals, Inc. 
 
 
 
 
 
Principal Investigator: 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 5: 
Overall Rationale for the Amendment: 
The 28-Jul-2021 version of the protocol was amended to remove the conduct of the interim 
analysis scheduled at the conclusion of Cohort 2, as emerging PD data did not dictate it was 
warranted. Other points of clarification for the timing and scheduling of study visits were also 
added. A summary of all changes is detailed in the following table.  
Protocol Amendment 5 Summary of Changes 
Description of Change 
Brief Rationale 
Affected Sections 
Deleted requirement for interim 
analysis (IA) and clarified that one 
or more IA may be conducted if 
warranted, dictated by the nature of 
available clinical and/or 
biomarker/PD data.  
Interim analysis may be done 
contingent on a possible 
safety or PD signal in the 
emerging blinded data.  
9.5 
Interim Analyses 
Modified text to allow visits to be 
rescheduled due to COVID-19 or 
other exceptional circumstances at 
the discretion of the Investigator, as 
appropriate. 
For clarity 
1.1.3 
Overall Design 
4.1 
Overall Design 
Modified text to state that if an EIA 
is missed, the missed EIA may be 
conducted at the next scheduled 
visit or at an unscheduled visit at 
the discretion of the Investigator. 
To allow for Investigator 
discretion in scheduling 
missed EIAs 
1.1.3 
Overall Design 
4.1 
Overall Design  
8.7.1 
Ethanol Interaction Assessments 
Clarified that a venous catheter 
would be used, and placement 
could be done at any time prior to 
sample collection as long as it was 
at least 20 minutes before ECG, 
SEAS, vital signs, and facial 
temperature were recorded. 
For clarity 
1.3 
Table 3, footnote “d” 
DOCUMENT HISTORY 
Document 
Date 
Amendment 5 (version 6.0) 
14-Mar-2022 
Amendment 4 (version 5.0) 
28-Jul-2021 
Amendment 3 (version 4.0) 
26-Jul-2021 
Amendment 2 (version 3.0) 
19-Jul-2021 
Amendment 1 (version 2.0) 
09-Jul-2021 
Original Protocol 
24-Jun-2021 
 
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Description of Change 
Brief Rationale 
Affected Sections 
Changed diastolic blood pressure 
out-of-range limit from 55 to 
50 mmHg. 
To expand the normal 
diastolic blood pressure range 
in healthy volunteers as low 
as 50 mmHg 
5.1 
Inclusion Criterion #7 
Updated the IP storage instructions 
from “2°C to 8°C” to “at or 
below 30°C; do not freeze” and 
specified DCR-AUD should be 
warmed for approximately 
1 hour before administration if 
stored at 2°C to 8°C. 
For clarity, based on updated 
guidance from Technical 
Operations  
6.2.2 
Storage 
6.2.3 
Preparation and Administration 
Clarified SRC review would 
include all available safety data 
collected before expanding or 
escalating to the next dose. 
To clarify 
1.1.3 
Overall Design 
2.3.1 
Risks Related to siRNA 
 
Molecules 
4.1 
Overall Design 
9.6 
Safety Review Committee, 
 
Table 7 
Updated the pregnancy testing 
sensitivity range from “at least 
10 mIU/mL” to “25 mIU/mL” 
To accommodate local testing 
standards  
10.4.3 
Pregnancy Testing 
Administrative updates 
To reflect new version 
Throughout the protocol 
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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 ................................................................................................15 
1.3. 
Schedules of Activities ...............................................................................................16 
2. 
INTRODUCTION ......................................................................................................20 
2.1. 
Study Rationale ...........................................................................................................20 
2.2. 
Background .................................................................................................................20 
2.2.1. 
Overview of Alcohol Use Disorder ............................................................................20 
2.2.2. 
Nonclinical Overview of DCR-AUD .........................................................................21 
2.3. 
Benefit/Risk Assessment ............................................................................................22 
2.3.1. 
Risks Related to siRNA Molecules ............................................................................22 
2.3.2. 
Risks Related to DCR-AUD Off-target Effects ..........................................................22 
2.3.3. 
Risks Related to DCR-AUD Mechanism of Action ...................................................22 
2.3.4. 
Risk Assessment .........................................................................................................24 
2.3.5. 
Benefit Assessment .....................................................................................................24 
2.3.6. 
Overall Benefit:Risk Conclusion ................................................................................25 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................26 
4. 
STUDY DESIGN .......................................................................................................27 
4.1. 
Overall Design ............................................................................................................27 
4.2. 
Scientific Rationale for Study Design ........................................................................28 
4.3. 
Justification for Dose ..................................................................................................28 
4.4. 
End of Study Definition ..............................................................................................29 
5. 
STUDY POPULATION .............................................................................................30 
5.1. 
Inclusion Criteria ........................................................................................................30 
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5.2. 
Exclusion Criteria .......................................................................................................31 
5.3. 
Lifestyle Considerations .............................................................................................33 
5.4. 
Screen Failures ............................................................................................................34 
6. 
STUDY INTERVENTION ........................................................................................35 
6.1. 
Study Intervention(s) Administered ...........................................................................35 
6.1.1. 
Dose Levels and Dose Escalation ...............................................................................35 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................36 
6.2.1. 
Handling and Accountability ......................................................................................36 
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 .........................38 
6.7. 
Concomitant Therapy .................................................................................................38 
6.7.1. 
Rescue Medicine .........................................................................................................38 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................39 
7.1. 
Participant Discontinuation/Withdrawal from the Study ...........................................39 
7.2. 
Lost to Follow up ........................................................................................................39 
7.3. 
Cohort Stopping Rules ................................................................................................40 
7.3.1. 
Dose Limiting Toxicities ............................................................................................40 
7.3.2. 
Electrocardiogram Findings ........................................................................................40 
7.4. 
Study Stopping Rules .................................................................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................41 
8.1. 
Efficacy Assessments .................................................................................................42 
8.2. 
Safety Assessments .....................................................................................................42 
8.2.1. 
Physical Examinations ................................................................................................42 
8.2.2. 
Vital Signs ..................................................................................................................42 
8.2.3. 
Electrocardiograms .....................................................................................................42 
8.2.4. 
Alcohol Consumption via Timeline Follow Back ......................................................43 
8.2.5. 
Columbia-Suicide Severity Rating Scale ....................................................................43 
8.2.6. 
Mini-International Neuropsychiatric Interview ..........................................................43 
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8.2.7. 
Clinical Safety Laboratory Assessments ....................................................................43 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................44 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event Information ....................44 
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 ...................................................................................................................45 
8.4. 
Treatment of Overdose ...............................................................................................46 
8.5. 
Pharmacokinetics ........................................................................................................46 
8.6. 
Genetics ......................................................................................................................46 
8.7. 
Pharmacodynamics .....................................................................................................47 
8.7.1. 
Ethanol Interaction Assessments ................................................................................47 
8.7.1.1. 
PD Biomarkers for EIA ..............................................................................................48 
8.7.1.2. 
Stopping Rules for an EIA ..........................................................................................49 
8.7.1.3. 
Follow-up of Participants Who Continue to Have Positive Ethanol Reaction 
Symptoms at Day 169 .................................................................................................49 
8.8. 
Immunogenicity Assessments ....................................................................................49 
8.9. 
Health Economics .......................................................................................................49 
9. 
STATISTICAL CONSIDERATIONS .......................................................................50 
9.1. 
Statistical Hypotheses .................................................................................................50 
9.2. 
Sample Size Determination ........................................................................................50 
9.3. 
Populations for Analyses ............................................................................................50 
9.4. 
Statistical Analyses .....................................................................................................50 
9.4.1. 
General Considerations ...............................................................................................50 
9.4.2. 
Primary Endpoint(s) ....................................................................................................51 
9.4.3. 
Secondary Endpoint(s) ................................................................................................51 
9.4.4. 
Exploratory Endpoint(s) .............................................................................................51 
9.4.5. 
Other Safety Analyses ................................................................................................51 
9.5. 
Interim Analyses .........................................................................................................52 
9.6. 
Safety Review Committee ..........................................................................................52 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................54 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................54 
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10.1.1. 
Regulatory and Ethical Considerations ......................................................................54 
10.1.2. 
Financial Disclosure ...................................................................................................54 
10.1.3. 
Informed Consent Process ..........................................................................................54 
10.1.4. 
Data Protection ...........................................................................................................55 
10.1.5. 
Committees Structure .................................................................................................55 
10.1.5.1. 
Safety Review Committee ..........................................................................................55 
10.1.5.2. 
Data Safety Monitoring Committee ............................................................................55 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................56 
10.1.7. 
Data Quality Assurance ..............................................................................................56 
10.1.8. 
Source Documents ......................................................................................................56 
10.1.9. 
Study and Site Start and Closure ................................................................................57 
10.1.10. 
Publication Policy .......................................................................................................57 
10.2. 
Clinical Laboratory Tests ...........................................................................................59 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................61 
10.3.1. 
Definition of Adverse Event .......................................................................................61 
10.3.2. 
Definition of Serious Adverse Event ..........................................................................61 
10.3.3. 
Definition of Adverse Events of Special Interest .......................................................62 
10.3.4. 
Recording and Follow-Up of AEs and/or SAEs .........................................................63 
10.3.4.1. 
AE and SAE Recording ..............................................................................................63 
10.3.4.2. 
Assessment of Intensity ..............................................................................................64 
10.3.4.3. 
Assessment of Causality .............................................................................................64 
10.3.4.4. 
Follow-up of AEs and SAEs .......................................................................................65 
10.3.5. 
Reporting of SAEs ......................................................................................................65 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................66 
10.4.1. 
Definitions ..................................................................................................................66 
10.4.2. 
Contraception Guidance .............................................................................................67 
10.4.3. 
Pregnancy Testing: .....................................................................................................68 
10.4.4. 
Collection of Pregnancy Information .........................................................................69 
10.4.4.1. 
Male Participants with Partners Who Become Pregnant ............................................69 
10.4.4.2. 
Participants Who Become Pregnant ...........................................................................69 
10.5. 
Genetics ......................................................................................................................70 
10.6. 
Liver Safety: Suggested Actions and Follow-up Assessments ...................................71 
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10.7. 
Abbreviations ..............................................................................................................73 
10.8. 
Investigator Signature Page ........................................................................................77 
10.9. 
Protocol Amendment History .....................................................................................78 
Amendment 5: 14-Mar-2022 .........................................................................................................78 
Amendment 4: 28-Jul-2021 ...........................................................................................................78 
Amendment 3: 26-Jul-2021 ...........................................................................................................78 
Amendment 2: 19-Jul-2021 ...........................................................................................................80 
Amendment 1: 09-Jul-2021 ...........................................................................................................80 
11. 
REFERENCES ...........................................................................................................82 
 
Table of Tables 
 
Table 1: 
Schedule of Activities .................................................................................................16 
Table 2: 
Allowed Windows for Collection of Plasma Pharmacokinetic Samples and 
for Complement Panel ................................................................................................18 
Table 3: 
Schedule of Activities: Ethanol Interaction Assessments ..........................................19 
Table 4: 
Nonclinical Safety Margins for 5-Week Repeat-dose Toxicity Studies .....................29 
Table 5: 
Study Intervention Administered ................................................................................35 
Table 6: 
Subjective Effects of Alcohol Scale (SEAS) ..............................................................48 
Table 7: 
Minimal Timing of the Safety Review Committee Data Reviews .............................53 
Table 8: 
Protocol-Required Safety Laboratory Assessments ...................................................60 
Table 9: 
Grading of Injection Site Reactions, CTCAE v 5.0 ....................................................63 
Table 10: Highly Effective Contraceptive Methods ...................................................................68 
Table 11: Liver Safety: Suggested Actions and Follow-up Assessments ...................................71 
 
 
Table of Figures 
 
Figure 1: 
Study Schematic for DCR-AUD-101 .........................................................................15 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, Double-blind, Placebo-controlled, Single-ascending-dose, Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in Healthy 
Volunteers  
Short Title:  Phase 1 SAD 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 (hybridized duplex) RNA oligonucleotide conjugated to N-acetyl-
D-galactosamine (GalNAc) ligands that enable subcutaneous delivery of stable, safe, highly 
specific, and long-acting reduction 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, tachycardia, 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. 
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. The DCR-AUD-101 study is the first human study of DCR-AUD. 
The overall goals of this study are:  
1. 
To demonstrate that DCR-AUD single doses are safe and well-tolerated  
2. 
To characterize the PK of single doses of DCR-AUD  
3. 
To characterize the PD of single doses of DCR-AUD and obtain safety data after alcohol 
exposure in adult healthy volunteers (HVs) as assessed by serial standardized Ethanol 
Interaction Assessments (EIAs) 
a. EIAs will be used to confirm target engagement. The degree of ALDH2 reduction is 
measurable only after ethanol administration, via levels of plasma acetaldehyde and 
acetate, and measurement of heart rate and facial skin temperature. 
b. The safety of ethanol ingestion in the presence of DCR-AUD will be assessed during 
EIAs, each of which will be followed by overnight admission and monitoring in a 
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Phase 1 clinical unit. The Investigator will not discharge any participant experiencing 
ongoing effects of ethanol administration until it is deemed medically safe to do so. 
c. Serial EIAs will be used to determine the duration of action of DCR-AUD, so that an 
appropriate dose and dosing interval and safety monitoring plan for participants can 
be developed for later clinical trials. 
1.1.2. 
Objectives and Endpoints: 
1.1.3. 
Overall Design 
This is a 24-week, randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, PK, and PD of single-ascending doses (SAD) of DCR-AUD administered to adult 
HVs. 
Individual participants will be screened for a period of up to 28 days. Participants may undergo 
rescreening one time at the discretion of the Investigator or Sponsor. The single doses of 
DCR-AUD will be administered to adult HVs across 3 fixed ascending-dose cohorts (80 mg, 
240 mg, 480 mg) and 1 optional cohort (960 mg). Each cohort will comprise a sentinel group of 
3 participants (2 active, 1 placebo) who will be followed for the assessment of safety and 
tolerability and characterization of PK but who will not undergo any EIAs. The sentinel group 
will remain under observation in clinic until Day 4 (after dosing on Day 1) and will return to 
clinic on Days 8 and 15 for clinical and laboratory test evaluations. The SRC will review 
available sentinel group safety data through the Day 15 assessments prior to authorizing cohort 
expansion within an individual cohort for the remaining 6 participants (4 active, 2 placebo). The 
6 participants in the expanded cohort will be followed for the assessment of safety and 
tolerability, characterization of PK, and assessment of PD (via EIA). In addition to alcohol 
exposure on Day –1 (prior to administration of study intervention), these participants will 
undergo serial EIAs on Day 4 before being discharged from clinic on Day 5, and at 6 other times 
during the 24-week study period. All EIAs will be conducted as in-clinic assessments. 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability of single doses of 
DCR-AUD administered to adult HVs  
• Incidence and severity of AEs, SAEs, and DLTs  
• Changes from baseline in vital signs, 12-lead 
ECG, clinical laboratory tests, and physical 
examination findings 
Secondary 
 
• 
To characterize the PK of single doses of DCR-AUD 
in adult HVs 
• Plasma PK parameters of DCR-AUD  
• Urine PK parameters of DCR-AUD  
• 
To characterize the PD of single doses of DCR-AUD 
in adult HVs as assessed by serial standardized EIAs 
• 
Change in PD biomarkers during standardized 
EIAs 
o 
Plasma acetaldehyde, acetate, and EtOH 
o 
Heart rate and facial skin temperature 
o 
SEAS 
Abbreviations: AE: adverse event; DLT: dose-limiting toxicity; EIA: ethanol interaction assessment; EtOH: ethanol; 
HV: healthy volunteer; PD: pharmacodynamics; PK: pharmacokinetics; SAE: serious adverse event; SEAS: Subjective 
Effects of Alcohol Scale 
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Participants who have positive ethanol reaction symptoms at the Day 169 EIA (e.g., nausea, 
vomiting, or substantial flushing) will return every 28 (±7) days for follow-up EIAs until the 
positive ethanol reaction symptoms abate. These conditional follow-up (CFU) EIAs will not 
require overnight admission to the clinic, but all other aspects of the EIA will be conducted (see 
Table 3). Participants will be observed for no less than 6 hours after ethanol administration and 
will not be discharged until the Investigator deems it medically safe to do so. 
If participants are not able to return to the site for assessments or procedures because of 
COVID-19 or other exceptional circumstances, visits may be rescheduled or conducted by 
qualified medical professionals as at-home telemedicine and/or home nursing visits at the 
discretion of the Investigator.  
All participants will be given a diary to track AEs and temperance for the study duration. 
Participants will be trained on the use of the diary prior to discharge from the clinic and will 
report on the diary at each in-clinic visit. 
The SRC will review available safety data from all participants in each cohort through at least 
the Day 15 assessments prior to authorizing dose escalation to the next cohort.  
The Study Schematic is presented in Figure 1. The schedules of activities are presented in 
Table 1 and Table 3.  
Intervention Groups and Duration: 
Doses of DCR-AUD to be administered will ascend from 80 mg in Cohort 1, to 240 mg in 
Cohort 2, to 480 mg in Cohort 3, and to 960 mg in the optional Cohort 4. 
Individual participants will be screened for a period of up to 28 days. Randomization and 
administration with a single 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 24 weeks (Day 169). 
Study Population: 
• Overtly healthy men and women aged 21 to 65 years 
• Social drinkers of modest amounts (≤ 2 drinks/day and ≤ 3 days/week) who are able 
to refrain from drinking alcohol during the outpatient portion of the trial 
• Willing to participate in repeated low-dose EIAs followed by an overnight clinic stay 
• BMI 18.0 to 32.0 kg/m2 (inclusive) 
• No history of suicidal attempt as an adult, or suicide ideation in the past year that 
resulted in pharmacologic treatment or hospitalization. In addition, any history of 
severe or recent clinically significant depression, anxiety, bipolar disorder, 
schizophrenia, or other neuropsychiatric disorder that, in the judgment of the 
investigator, represents a safety risk to the individual were they to participate in the 
trial 
• No history of substance use disorder (including AUD) or illicit drug use (excluding 
cannabis) within the preceding 12 months. Nicotine use is permitted 
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• No history of delirium tremens or alcohol-related seizures 
Treatment Blinding:  
This study will have multiple cohorts. Participants, Investigators, site staff (excluding pharmacy 
staff), the CRO staff, and the Sponsor Medical Monitor will be blinded to the randomization of 
those cohorts. However, certain members of the Sponsor staff will be unblinded to 
randomization for the duration of the study. Complete details will be presented in the Study 
Blinding Plan.  
Number of Participants: 
Up to 36 participants are planned to be enrolled in this study: 27 HVs in the 3 planned dose 
cohorts, plus an additional 9 HVs if the optional fourth cohort is enrolled. 
Safety Review Committee and Data Safety Monitoring Committee: 
An SRC will be convened to review available safety data at a predefined decision point (Visit 2, 
Day 15) to ensure the safety of the participants in all cohorts. The scope of the review meetings 
will be defined in the SRC charter. In the event that the SRC decides to suspend or interrupt the 
study, an independent DSMC may be convened to review the decision by the SRC and 
recommend whether the study should be stopped, resumed with no changes, or resumed with 
changes.  
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1.2. 
Overall Study Schema 
Figure 1: 
Study Schematic for DCR-AUD-101 
 
 
Abbreviations: CFU: conditional follow-up; D: Day; EIA: ethanol interaction assessment; IMP: investigational medicinal product; pbo: placebo; SRC: Safety 
Review Committee; V: Visit 
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1.3. 
Schedules of Activities 
Table 1: 
Schedule of Activities 
 
Screening 
Visit 1 (In-Clinic) 
V1ba 
Visit 2 
Visit 3 
Visit 4  Visits 5-6 Visit 7 
Visit 8 
EOS/ET 
Study Day 
Procedure/Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
8 
15 
±2 day 
29 
±2 day 
57 
±2 day 
85, 113  
±2 day 
141 
±2 day 
169 
±7 day 
Pre-
dose 
Post-
dose 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical site admission/discharge b 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic/baseline characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychological history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSc 
X 
X 
 
 
 
 
 
 
X 
X 
 
Xd 
 
X 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol history/consumption (TLFB) 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Diary (AEs, temperance) 
distribute/collect 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Drug/alcohol testing (urine, breath) e 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Testing for HCV, HIV, and HBV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize to study intervention 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study intervention administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication history/concomitant meds 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG f 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination g  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Screening 
Visit 1 (In-Clinic) 
V1ba 
Visit 2 
Visit 3 
Visit 4  Visits 5-6 Visit 7 
Visit 8 
EOS/ET 
Study Day 
Procedure/Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
8 
15 
±2 day 
29 
±2 day 
57 
±2 day 
85, 113  
±2 day 
141 
±2 day 
169 
±7 day 
Pre-
dose 
Post-
dose 
Pregnancy test (WOCBP only) h 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
FSH (if applicable)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical safety laboratory tests i 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Complement panel j 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Blood sample for ADA 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
SARS-CoV-2 rapid test (at site)k 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Blood sample for genotyping l 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma collection for PK analysis m 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Urine collection for PK analysis n 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Ethanol interaction assessment o 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
 
Xp 
Record AEs and SAEs q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA: antidrug antibody; AE: adverse event; CFU: conditional follow-up; C-SSRS: Columbia-Suicide Severity Rating Scale; ECG: electrocardiogram; EIA: 
ethanol interaction assessment; FSH: follicle stimulating hormone; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; ICF: informed 
consent form; MINI: Mini-International Neuropsychiatric Interview; PK: pharmacokinetic; SAE: serious adverse event; SARS-CoV-2: severe acute respiratory syndrome 
coronavirus 2; TLFB: Timeline Follow Back; WOCBP: women of childbearing potential 
a Visit 1b is only required for the 3 sentinel group participants in each cohort. 
b Participants in the expanded cohort must have fasted for at least 6 hours before admission on Day −1 and will receive a standardized meal prior to the EIA. 
Participants undergoing EIA will be discharged from the clinic on Day 5. Sentinel group participants will be discharged from the clinic on Day 4, following the 
72-hour PK blood draw and completion of pooled urine collection. 
c At Screening, the ‘C-SSRS Baseline’ form will be administered, at all other visits indicated, the ‘C-SSRS Since Last Visit’ form will be administered. 
d C-SSRS to be administered only on Day 85. 
e Urine for drugs of abuse and breathalyzer for alcohol. Cannabis will not be recorded as a drug of abuse for this study. Participants will be excluded from EIA 
evaluation that day if they test positive for breath alcohol on day of study visit prior to EIA. 
f Standard ECGs will be performed 30 minutes predose, and at 60 minutes and 150 minutes postdose. A ±15-minute window around each time point is allowed if 
multiple assessments are due. If multiple assessments are due, the order of priority should be ECG, vitals, PK, and then other assessments. 
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g Complete physical examinations will be conducted at every visit. Height will be measured and recorded at Day 1 and weight will be measured and recorded at 
every visit. 
h If a urine pregnancy test is positive, confirm with serum test for pregnancy (see Section 10.4). Local laboratory may be used. Pregnancy testing to be performed 
every 28 days throughout the study. 
i Hematology, clinical chemistry, coagulation, and urinalysis samples will be collected at every visit indicated. Only on Days −1, 4, 29, 85, and 169 will 
additional hematology analytes (mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and absolute and % of 
lymphocytes, monocytes, eosinophils, neutrophils, and basophils) be collected. See Table 8 for a complete list of parameters to be assessed. 
j During in-clinic stay at Day 1 and Day 2, blood samples will be collected for complement predose, and at 2, 8, and 24 hours postdose. 
k Participants in expanded cohorts will need to undergo SARS-CoV‑2 rapid test in compliance with clinic requirements before admittance to the unit for EIA 
testing. Refer to Study Manual for further details on the timing of this testing. 
l A separate informed consent form is needed for collection of blood sample for optional genotyping. 
m At Visit 1, plasma samples for PK analysis will be collected before study intervention administration and at 15 and 30 minutes and 1, 2, 4, 6, 8, 24, 48, and 
72 hours after the injection. At Visit 2, only one sample will be collected for PK. If multiple assessments are due, the order of priority should be ECG, vitals, 
PK, and then other assessments, with the PK sampling being performed preferably at the nominal time point. Table 2 details the windows allowed surrounding 
collection of PK samples. 
n Pooled urine collection to be done for PK analyses of DCR-AUD concentration. Participants should have an empty bladder prior to administration of study 
intervention, and 24-hr urine collection to begin with first void after study intervention administration. Urine to be collected at intervals of 0-4, > 4-8, > 8-12, 
> 12-24, > 24-48, and > 48-72 hours. Urine will be collected using a polypropylene container. 
o Each cohort will have a sentinel group (n=3) that does not undergo any EIA assessment. For all other participants, all visits on which an EIA is conducted will 
require an overnight stay in the clinic. Participants will be admitted after an overnight fast and be provided a standardized meal. EIA estimated time is 
~2.5 hours and is conducted at all visits except Visit 7 (Day 141). Note that the Day −1 assessment occurs prior to administration of study intervention and is 
intended to serve as a baseline for biomarker assessments and to confirm eligibility. See Table 3 for details of EIA. 
p Participants who have positive ethanol reaction symptoms at the Day 169 EIA (e.g., nausea, vomiting, or substantial flushing) will return every 28 (±7) days for 
follow-up EIAs until the positive ethanol reaction symptoms abate. These CFU EIAs will not require overnight admission to the clinic, but all other aspects of 
the EIA will be conducted. Participants will be observed for no less than 6 hours after ethanol administration and will not be discharged until the Investigator 
deems it medically safe to do so. 
q 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. 
 
Table 2: 
Allowed Windows for Collection of Plasma Pharmacokinetic Samples and for Complement Panel 
Nominal Postdose Sample Time 
Window 
15 minutes 
± 5 minutes 
30 minutes  
± 10 minutes 
1, 2, 4, 6, and 8 hours 
± 15 minutes 
≥ 24 hours 
± 30 minutes 
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Table 3: 
Schedule of Activities: Ethanol Interaction Assessments  
 
Time in minutes 
Procedures 
Pre-EIA 
Rest 
Test Period 
− 20 
0a 
15 
±5 
30 
±10 
45 
±10 
60 
±15 
90 
±15 
120 
±15 
150 
±15 
Admit/return to clinic (fasted 
state)b 
X 
 
 
 
 
 
 
 
 
 
Standardized mealc 
X 
 
 
 
 
 
 
 
 
 
Venous catheter placementd 
 
X 
 
 
 
 
 
 
 
 
Alcohol consumptione 
 
 
← X → 
 
 
 
 
 
Blood biomarkersf g 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
EIA 12-lead ECG g  
 
 
X 
 
 
 
X 
 
 
X 
SEAS g,h  
 
 
X 
 
X 
 
X 
X 
X 
X 
Facial skin temperature g i 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
EIA vital sign g j 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Heart rate via telemetry 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
EIA AEsk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE: adverse event; CFU: conditional follow up; ECG: electrocardiogram; EIA: ethanol interaction assessment; 
EtOH: ethanol; SEAS: subjective effects of alcohol scale;  
a Time “0” is immediately before the first sip of alcohol. All Time 0 assessments must be performed prior to initiation of alcohol 
intake. 
b All visits on which an EIA is conducted will require an overnight stay in the clinic except for any CFU visits for participants 
who have positive ethanol reaction symptoms at Day 169; these do not require an overnight stay.  
c Participants are required to fast for at least 6 hours prior to consuming the standardized meal. 
d Participants will have a venous access catheter placed for sample collection. Participant will be given a ≥20-minute rest period 
following placement of the catheter prior to recording predose ECG, SEAS, vital signs, and facial temperature. 
e After completion of the standardized meal, alcohol will be consumed in 4 aliquots over a 30-minute period. The ethanol will be 
mixed in a liquid that has no other alcohol, no caffeine, and is low in sugar. Because BAC is higher in women than men when 
given the same g/kg EtOH dose (~ 15% higher mean BAC), the EtOH dose will be 0.4 g/kg for male participants and 0.34 g/kg 
for female participants. The total dose of EtOH will not exceed 28 g in men or 24 g in women. 
f Blood samples will be collected via a venous access device for biomarker analysis, which include acetaldehyde, acetate, and 
ethanol. Blood sample collection and processing will be detailed in the Laboratory Manual.  
 g The order of assessments should be blood draw, 12-lead ECG, SEAS, vital signs, and facial temperature. 
,h Participants will rate the extent to which they are feeling each of the 14 SEAS effects in the present moment. 
 i Facial skin temperature will be measured using a surface scanning thermometer and will be collected prior to blood draws. 
 j Vital signs will be recorded prior to blood draws and include blood pressure and pulse/heart rate. 
k Adverse events associated with administration of ethanol will be recorded continuously throughout the test period, beginning 
with the first sip of alcohol. 
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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 
(hybridized duplex) RNA oligonucleotide conjugated to GalNAc ligands that enable specific 
hepatic access and uptake after subcutaneous 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, tachycardia, 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. 
Study DCR-AUD-101 is the first study of DCR-AUD in humans. The aims of the study are to 
evaluate the safety and tolerability of single-ascending-doses of DCR-AUD and to characterize 
its PK profile and PD effects. 
2.2. 
Background 
2.2.1. 
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. 
Diagnosis is defined as meeting ≥ 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; National Survey on Drug Use, 2014; 
Litten et al., 2014; Han et al., 2015; Knudsen et al., 2011).  
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; 
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Jørgensen et al., 2011; Bryson et al., 2011). Thus, there remains an unmet need for an effective 
AUD treatment. 
2.2.2. 
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 and therefore, DCR-A1203 is active in 
both nonclinical species evaluated. In addition, a stand-alone comprehensive safety 
pharmacology study in cynomolgus monkeys was conducted.  
Overall, the data support the hypothesis that DCR-A1203 has potential to yield meaningful and 
robust clinical responses across the AUD patient populations based upon the following:  
• 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. 
• 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. 
• Repeat SC administration of DCR-A1203 up to 300 mg/kg resulted in significant 
reduction of hepatic Aldh2 mRNA in mice (> 97%) and hepatic ALDH2 in monkeys 
(> 85.9%). 
• 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 the 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 5 weeks in mice and monkeys. DCR-A1203 has been evaluated for potential genotoxicity in a 
bacterial reverse mutation assay and an in vitro micronucleus study.  
• 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. 
• The administration of DCR-A1203 to mice and monkeys in the 5-week repeat-dose 
studies resulted in no DCR-A1203-related, adverse findings. The NOAEL in the 
mouse and monkey repeat-dose toxicity studies was considered by the study director 
to be 300 mg/kg, the highest dose level administered. Based on input from the FDA 
regarding clinical pathology and histopathology in a single 300 mg/kg animal in the 
monkey study, a more conservative approach is being taken, and the mid-dose of 
100 mg/kg is being treated as the NOAEL for the purpose of determining a safety 
margin for the monkey study. 
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• DCR-A1203 was not genotoxic in the bacterial reverse mutation and in vitro 
micronucleus assays. 
Overall, the nonclinical safety program of DCR-A1203 did not identify any major safety issues. 
A detailed description of the chemistry and pharmacology of DCR-AUD is provided in the 
Investigator’s Brochure.  
2.3. 
Benefit/Risk Assessment 
The summary of potential risks provided below is based on an in-depth review of literature 
relating to the proposed approach and insights from the nonclinical pharmacology and toxicology 
studies. 
2.3.1. 
Risks Related to siRNA Molecules 
The potential risks associated with DCR-AUD are limited to the risks associated with the siRNA 
oligonucleotide portion of the drug product. 
To date, DCR-A1203 has been associated with no adverse effects in nonclinical studies. Clinical 
experience in more than 200 patients and HVs with the Dicerna GalXC™ platform 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).  
As part of the study’s planned mitigation strategy, each cohort will comprise a sentinel group of 
3 participants (2 active, 1 placebo) who will be followed for the assessment of safety and 
tolerability and characterization of PK. Sentinel participants will not undergo EIA tests. The 
sentinel group will remain under observation in clinic until Day 4 (after dosing on Day 1) and 
will return to clinic on Day 8 and Day 15 for clinical and laboratory test evaluations. The SRC 
will review available sentinel group safety data, including the safety laboratory results, through 
the Day 15 assessments and PK through 72-hours postdose prior to authorizing cohort expansion 
for the remaining 6 participants, who will undergo EIA tests.  
All study participants will be monitored for signs or symptoms of systemic toxicity, decline in 
liver or kidney function, abnormalities on hematologic parameters (including platelets and 
coagulation parameters), and abnormalities in vital signs, ECGs, complement activation, or other 
relevant safety parameters. 
2.3.2. 
Risks Related to DCR-AUD Off-target Effects 
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 species evaluated. 
2.3.3. 
Risks Related to DCR-AUD Mechanism of Action 
DCR-AUD is designed to induce intolerance to high-intake alcohol consumption 
(e.g., ≥ 4 drinks/occasion in men; ≥ 3 drinks/occasion in women) by selective reduction of 
ALDH2 mRNA and ALDH2 activity in the liver, and thereby decrease the conversion of 
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acetaldehyde to acetic acid after ethanol ingestion. Acetaldehyde accumulation, in sufficient 
amounts, is associated with unpleasant effects potentially including headache, facial flushing, 
tachycardia, 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), 
EIA assessments are necessary to evaluate and confirm DCR-AUD PD activity. The 
EIA interventions in this protocol are designed to minimize the amount of alcohol to be 
administered (approximately 0.4 g/kg, equivalent to 1-2 drinks over a 30-minute period in a 
70 kg person), and the signs and symptoms of alcohol intolerance.  
 
 
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2.3.4. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
FIH study  
Standard FIH methodology for 
testing and analysis 
Study will be conducted under 
close observation in a clinical 
Phase 1 study unit. 
Study Intervention: DCR-AUD 
Dose selection (unknown human 
safety and tolerability) 
 
The dose range proposed for this 
study is justified based on the 
safety profile of such doses in 
nonclinical toxicity studies 
Sequential dose escalation; use of 
sentinel dose group in each cohort; 
SRC to review safety and PK and 
approve dose selection and dose 
escalation. 
Potential risk of DLT or other 
safety signals 
This is a FIH study and the clinical 
safety profile has not yet been 
established 
SRC may convene a DSMC to 
adjudicate DLT or safety signals 
Potential immune stimulation via 
the complement cascade 
Previously seen in highly 
phosphorothioated oligonucleotides 
Monitoring of complement factors 
within 24 hours of dosing  
Study Procedures 
EIA: alcohol administration is 
expected to cause unpleasant effects 
in participants receiving active 
DCR-AUD 
 
Required to assess and confirm 
DCR-AUD PD activity, including 
magnitude and duration of 
concomitant alcohol interaction 
Alcohol to be administered 
gradually in EIA and performed in 
a Phase 1 unit clinical setting, with 
post-administration in-clinic 
overnight observation.  
Enroll participants who are tolerant 
to amount of ethanol to be 
administered in the EIAs 
(approximately 0.4 g/kg, equivalent 
to 1-2 drinks over a 30-minute 
period in a 70 kg person)  
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 
amounts, including incidental 
exposures. 
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. 
Added CFU(s) for any participant 
who has positive ethanol reaction 
symptoms (e.g., nausea, vomiting, 
or substantial flushing) at the 
Day 169 EIA, until the symptoms 
abate. 
2.3.5. 
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. 
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RNAi-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. 
Thus, the target phenotype of DCR-AUD treatment is expected to be more analogous to that in 
individuals who are heterozygous for ALDH2 mutations and demonstrate an intermediate alcohol 
intolerance phenotype (i.e., fewer, milder symptoms at low levels of alcohol intake). 
2.3.6. 
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 the anticipated benefits that may be 
afforded to patients with AUD. 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and tolerability of single 
doses of DCR-AUD administered to adult HVs  
• 
Incidence and severity of AEs, SAEs, and DLTs  
• 
Changes from baseline in vital signs, 12-lead 
ECG, clinical laboratory tests, and physical 
examination findings 
Secondary 
 
• To characterize the PK of single doses of 
DCR-AUD in adult HVs 
• 
Plasma PK parameters of DCR-AUD  
• 
Urine PK parameters of DCR-AUD  
• To characterize the PD of single doses of 
DCR-AUD in adult HVs as assessed by 
serial standardized EIAs 
• 
Change in PD biomarkers during standardized 
EIAs 
o Plasma acetaldehyde, acetate, and EtOH 
o Heart rate and facial skin temperature 
o SEAS 
Abbreviations: AE: adverse event; DLT: dose-limiting toxicity; EIA: ethanol interaction assessment; EtOH: ethanol; HV: 
healthy volunteer; PD: pharmacodynamics; PK: pharmacokinetic; SAE: serious adverse event; SEAS: Subjective Effects of 
Alcohol Scale  
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study is a 24-week, randomized, double-blind, placebo-controlled, single-ascending-dose 
study to evaluate the safety, tolerability, PK, and PD of DCR-AUD in adult HVs. The overall 
goals of this study are:  
• To demonstrate that DCR-AUD single doses are safe and well-tolerated  
• To characterize the PK of single doses of DCR-AUD  
• To characterize the PD of single doses of DCR-AUD and obtain safety data after 
alcohol exposure in adult healthy volunteers (HVs) as assessed by serial standardized 
Ethanol Interaction Assessments (EIAs) 
Individual participants will be screened for a period of up to 28 days. Participants may undergo 
rescreening one time at the discretion of the Investigator or Sponsor. Single doses of DCR-AUD 
will be administered to adult HVs across 3 fixed ascending-dose cohorts (80 mg, 240 mg, 
480 mg) and 1 optional cohort (960 mg), each to include up to 9 participants/dose cohort 
(6 active and 3 placebo). Each participant will receive a single dose of DCR-AUD (or matching 
placebo) on Day 1. Participants will be observed to allow collection of data up to 24 weeks after 
administration of study intervention (Day 169).  
Each cohort will comprise a sentinel group of 3 participants (2 active, 1 placebo) who will be 
followed for the assessment of safety and tolerability and characterization of PK but who will not 
undergo any EIAs. The sentinel group will remain under observation in clinic until Day 4 (after 
dosing on Day 1) and will return to clinic on Days 8 and 15 for clinical and laboratory test 
evaluations. The SRC will review available sentinel group safety data through the Day 15 
assessments prior to authorizing cohort expansion within an individual cohort for the remaining 
6 participants (4 active, 2 placebo). 
The 6 study participants in the expanded cohort will undergo EIAs to evaluate the PD effects of 
ALDH2 reduction by DCR-AUD, which include plasma acetaldehyde, acetate, and ethanol; heart 
rate; facial skin temperature, and subjective feelings of alcohol intoxication or intolerance using 
the Subjective Effects of Alcohol Scale (SEAS; Table 3). All visits on which an EIA is 
conducted will require participants to check into the clinic after a 6-hour fast. Participants will be 
fed a standardized meal in the clinic prior to the EIA and will be admitted for an overnight stay 
in the Phase 1 telemetry unit. Participants will return to the site for safety, tolerability, PK, and 
PD monitoring (via serial EIAs) throughout the 24-week double-blind study period, as specified 
in Table 1. Participants who have positive ethanol reaction symptoms at the Day 169 EIA 
(e.g., nausea, vomiting, or substantial flushing) will return every 28 (±7) days for follow-up EIAs 
until the positive ethanol reaction symptoms abate. These CFU EIAs will not require overnight 
admission to the clinic, but all other aspects of the EIA will be conducted (see Table 3). 
Participants will be observed for no less than 6 hours after ethanol administration and will not be 
discharged until the Investigator deems it medically safe to do so. 
Cohort expansion will require SRC review of available Day 15 safety data for all participants in 
the sentinel group before the remainder of the cohort can be enrolled. Dose escalation will 
require SRC review of available safety data, including the safety laboratory values, for all 
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participants through at least Day 15 before the sentinel group of the next cohort can be enrolled 
(Section 9.6). 
Individual participants will be screened for a period of up to 28 days. Screening assessments will 
include a psychological history and a history of alcohol consumption using the TLFB method to 
identify participants who are HVs and meet the minimum inclusion/exclusion alcohol 
consumption requirements. TLFB is a validated method to retrospectively assess drinking 
behavior history. Randomization and administration of study intervention will occur on Day 1. 
If participants are not able to return to the site for assessments or procedures because of 
COVID-19 or other exceptional circumstances, visits may be rescheduled or conducted by 
qualified medical professionals as at-home telemedicine and/or home nursing visits at the 
discretion of the Investigator.  
All participants will be given a diary to track AEs and temperance for the study duration. 
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. 
4.2. 
Scientific Rationale for Study Design 
SAD testing in a single sequential Phase 1 study design has been successfully used to determine 
dose tolerability and PK/PD measurements. The Sponsor’s proposed Phase 1 study takes this 
approach. Further, the use of sentinel participants is intended to ensure safe, well-tolerated doses 
of DCR-AUD are used.  
Study participants will undergo EIAs to evaluate the PD effects of ALDH2 reduction by 
DCR-AUD and obtain safety data regarding alcohol exposure in adult HVs during concomitant 
alcohol consumption. Participants will be administered alcohol on Day –1 (prior to 
administration of study intervention) to establish a baseline for biomarker assessments and 
evaluate eligibility. Following administration of study intervention, participants will be 
administered serial EIAs, as specified in Table 1.  
• EIAs will be used to confirm target engagement. The degree of ALDH2 reduction is 
measurable only after ethanol administration, via levels of plasma acetaldehyde and 
acetate, and measurement of heart rate and facial skin temperature. 
• The safety of ethanol ingestion in the presence of DCR-AUD will be assessed during 
EIAs, each of which will be followed by overnight admission and monitoring in a 
Phase 1 telemetry unit. The Investigator will not discharge any participant 
experiencing ongoing effects of ethanol administration until it is deemed medically 
safe to do so. 
• Serial EIAs will be used to determine the duration of action of DCR-AUD, so that an 
appropriate dose and dosing interval and safety monitoring plan for participants can 
be developed for later clinical trials. 
4.3. 
Justification for Dose 
The initial dose levels to be administered were determined following evaluation of nonclinical 
PK/PD and safety data (FDA, 2005) and will ascend from 80 mg in Cohort 1, to 240 mg in 
Cohort 2, to 480 mg in Cohort 3, and 960 mg in the optional Cohort 4. 
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Safety margins for DCR-A1203 were determined using the HEDs of the dose levels for the 
5-week toxicity studies. The NOAEL in the mouse and monkey repeat-dose toxicity studies was 
considered by the study director to be 300 mg/kg, the highest dose level administered. Based on 
input from the FDA regarding clinical pathology and histopathology in a single 300 mg/kg 
animal in the monkey study, a more conservative approach is being taken, and the mid-dose of 
100 mg/kg is being treated as the NOAEL for the purpose of determining a safety margin for the 
monkey study. The monkey is the more relevant species due to a greater homology with the 
human transcriptome, allowing for assessment of on- and off-target effects (Cooper et al., 2003). 
For the planned starting flat dose of 80 mg, the exposure multiple relative to the monkey HED 
for 100 mg/kg would be 28-fold. For the planned high dose of 960 mg, the exposure multiple 
relative to the monkey HED for 100 mg/kg would be 2-fold (Table 4). 
Table 4: 
Nonclinical Safety Margins for 5-Week Repeat-dose Toxicity Studies 
Species 
Dose 
(mg/kg) 
HED a 
(mg/kg) 
Exposure Multiple 
Relative to 80-mg  
Clinical Dose b 
Exposure Multiple 
Relative to 960-mg 
Clinical Dose b 
Mouse 
30 
2.4 
2 
0.2 
Monkey 
9.7 
8 
0.7 
Mouse 
100 c 
8.1 
7 
0.6 
Monkey 
32.3 
28 
2 
Mouse 
300 c 
24.4 
21 
2 
Monkey 
96.8 
85 
7 
Abbreviations: HED = human equivalent dose 
a The HED is based on the Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers (FDA, 2005). 
b A 70-kg human is used for determination of mg/kg for clinical dose and margin determination 
c The NOAEL in the mouse and monkey repeat-dose toxicity studies was considered by the study director to be 
300 mg/kg, the highest dose level administered. Based on input from the FDA regarding clinical pathology and 
histopathology in a single 300 mg/kg animal in the monkey study, a more conservative approach is being taken, 
and the mid-dose of 100 mg/kg is being treated as the NOAEL for the purpose of determining a safety margin for 
the monkey study 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the last scheduled procedure shown in the SoA (Section 1.3). 
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 
Up to 36 HV participants are planned to be enrolled in this study: 27 in the planned first 3 dose 
cohorts plus an additional 9 HVs if an optional fourth cohort is enrolled. 
Protocol waivers or exemptions are not allowed. Participants may undergo rescreening one time 
at the discretion of the Investigator or Sponsor. Only pregnancy test, hematology and chemistry, 
and coagulation tests may be repeated. 
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 of age, inclusive, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Overtly healthy, as determined by medical evaluation including medical history, physical 
examination, laboratory tests, and cardiac monitoring.  
3. Social drinkers of modest amounts (≤ 2 drinks/day and ≤ 3 days/week) who are able to 
refrain from drinking alcohol during the outpatient portion of the trial. 
4. Negative screen for drugs of abuse (to include at minimum: amphetamines, barbiturates, 
cocaine, opioids, and benzodiazepines) at Screening and Day 1. Cannabis will not be 
recorded as a drug of abuse for this study.  
5. Willing to participate in repeated low-dose EIAs followed by an overnight clinic stay (see 
Table 1). 
6. Has a negative test for SARS-CoV-2 infection on Day −1 and prior to admission to the 
clinical unit. (Refer to Study Manual for details on the timing of SARS-CoV-2 testing.) 
7. Systolic BP in the range of 90 to 140 mmHg and diastolic BP in the range of 50 to 
95 mmHg. 
Sex and Childbearing Potential 
8. 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: 
− Is not a woman of childbearing potential (WOCBP) or  
− 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. 
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Weight 
9. BMI within the range 18.0 to 32.0 kg/m2 (inclusive). 
Informed Consent 
10. 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 if any of the following criteria apply: 
Medical Conditions 
1. History of any medical condition that may interfere with the absorption, distribution, or 
elimination of study intervention, or with the clinical and laboratory assessments in this 
study, including (but not limited to): chronic or recurrent renal disease, functional bowel 
disorders (e.g., frequent diarrhea or constipation), clinically significant cardiovascular or 
pulmonary disease or has cardiovascular or pulmonary disease requiring pharmacologic 
medication, GI tract disease, pancreatitis, seizure disorder, mucocutaneous, or 
musculoskeletal disorder. 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.  
2. History of suicidal attempt as an adult or suicide ideation in the past year that resulted in 
pharmacologic treatment or hospitalization. Specifically: 
• Answer of “yes” on items 4 or 5 of the Suicidal Ideation section of the C-SSRS at 
screening if ideation occurred in the previous 6 months. 
• Answer of “yes” on any item of the Suicidal Behavior section of the C-SSRS, except 
for the Non-Suicidal Self-injurious Behavior if this behavior occurred in the previous 
2 years. 
3. Any history of severe or recent clinically significant depression, anxiety, bipolar disorder, 
schizophrenia, or other neuropsychiatric disorder that, in the judgment of the Investigator, 
represents a safety risk to the individual were they to participate in the trial, as informed 
by the participant’s medical history and/or responses to the MINI Screen Questionnaire. 
4. History of delirium tremens or alcohol-related seizures.  
5. History of significant adverse reaction(s) to alcohol. 
6. 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. Clinically significant abnormalities in vital signs: pulse rate (< 40 or > 90 bpm), 
respiratory rate, or temperature 
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c. 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 
d. Diabetes mellitus treated with insulin or hypoglycemic agents (including metformin) 
or HbA1C > 7% 
e. Asthma requiring hospital admission within the preceding 12 months 
f. Currently poorly controlled endocrine conditions, except for hypothyroidism that is 
stable (no treatment change in prior 6 months)  
g. Significant infection or known systemic inflammatory process ongoing at Screening 
h. History of chronic or recurrent UTI, or UTI within 1 month prior to Screening 
7. History of malignancy within the preceding 3 years requiring treatment, with the 
exception of excised low grade basal cell skin neoplasms.  
8. History of substance use disorder (SUD), including alcohol (AUD) or illicit drug use 
(excluding cannabis) within the preceding 12 months. Nicotine use is permitted.  
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. Clinically significant illness within the 7 days prior to the administration of study 
intervention 
Prior/Concomitant Therapy 
11. History of multiple drug allergies or a history of allergic reaction to an 
oligonucleotide-based therapy 
12. 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). 
13. Receipt of any vaccine (including COVID-19) within 14 days prior to administration of 
study intervention. 
14. Regular use of OTC medications, including NSAID (Periodic or occasional NSAID use 
to control temporary pain is not exclusionary.) 
Prior/Concurrent Clinical Study Experience 
15. 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 
16. 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 
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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. 
17. Had laboratory-confirmed SARS-CoV-2 infection in the 14 days prior to randomization. 
18. Liver function test results (AST, ALT, GGT, total bilirubin) above the normal range. 
19. Safety laboratory test result considered clinically unacceptable for study participation by 
the Investigator. 
Other Exclusions 
20. 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. 
21. Scheduled for an elective surgical procedure during the conduct of this study. 
22. 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 
Caffeine, Alcohol, and Cannabis 
• During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 12 hours 
before the start of dosing until after collection of the final PK and/or PD sample. 
• Study participants are to refrain from drinking alcohol and using cannabis from the 
screening visit until the final study visit and must have a negative breath alcohol test on 
the day of the study visit prior to the EIA. 
Activity 
• Participants must not have undertaken, or plan to undertake, a significant change in 
exercise levels from 48 hours prior to entrance into the clinical research center until the 
end of study. 
• Participants should abstain from strenuous exercise for 48 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 
48-hour time period.  
Meals and Dietary Restrictions 
• Participants will be required to be fasted for at least 6 hours and then fed a standardized 
meal in the clinic prior to administration of EtOH on the days of EIAs. 
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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. Only pregnancy test, hematology and chemistry, and coagulation studies may be 
repeated. Rescreened participants should be assigned the same participant number as for the 
initial screening. 
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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 
DCR-AUD or placebo will be administered subcutaneously as fixed doses.  
6.1.1. 
Dose Levels and Dose Escalation 
Doses of DCR-AUD to be administered will ascend from 80 mg in Cohort 1, to 240 mg in 
Cohort 2, to 480 mg in Cohort 3, and 960 mg in the optional Cohort 4.  
Dose escalation refers to escalation to the next consecutive dose level in line with prespecified 
dose escalation rules. For the purpose of this protocol, escalation rules are based on the emergent 
safety and PK profiles. 
Clinical doses are expressed in terms of the weight of the DCR-AUD free acid, rather than on 
that of the sodium salt (Table 5).  
Table 5: 
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 
80 mg, 240 mg, 480 mg, or 960 mg 
single dose 
volume to match active 
single dose 
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; SC: subcutaneous 
 
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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. 
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; if the dose requires an injection volume 
> 1.5 mL, the total dose will be administered as 2 or more SC injections of equal volume at 
separate injection sites in the abdomen. 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.  
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.  
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, sponsor Medical Monitor, and study 
participants will be blinded for the duration of the study. The Sponsor will remain unblinded for 
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the duration of the study. This enables the Sponsor to immediately and comprehensively evaluate 
the safety of the study participants.  
Within each SAD cohort, the sentinel participants will be randomly assigned to DCR-AUD or 
placebo in a 2:1 ratio. The overall DCR-AUD to placebo ratio within each cohort is also 2:1. 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. 
Investigators, site staff (excluding pharmacy staff), CRO staff, sponsor Medical Monitor, and 
participants will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. To maintain this blind, the unblinded site pharmacy staff will be responsible 
for the preparation and dispensation 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 
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.  
For details regarding unblinding associated with interim analyses, see Section 9.5. 
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 
Cohorts will be filled sequentially, starting with the first dose cohort. Modified dosing regimens 
may be explored if required based on emergent safety and tolerability data or the occurrence of 
confirmed DLTs (as defined in Section 7.3.1), and available PD or PK data, where applicable.  
At each decision point listed in Section 9.6, the SRC will make a determination as whether to 
continue the dosing and enrollment as planned; to interrupt dosing and enrollment in the current 
cohort or escalation to the next dose cohort; or to stop the study. However, if the SRC decides 
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not to escalate the dose and a stopping rule has not been met, the SRC may make a 
recommendation to (1) test a lower dose than planned, (2) retest a previous dose, or (3) stop 
dosing. The SRC may also elect to have an independent expert Data Safety Monitoring 
Committee (DSMC) convene if a study stopping rule is triggered to make a recommendation as 
to resumption, permanent discontinuation, or modification of the trial that has been suspended or 
interrupted on the basis of an SRC decision (see Section 10.1.5.2).  
6.6. 
Continued Access to Study Intervention After the End of the Study 
Not applicable. 
6.7. 
Concomitant Therapy 
All study participants must abstain from taking prescription drugs (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 until EOT. Participants being treated for hypothyroid disease 
must be on stable treatment (no treatment changes in the preceding 6 months).  
Regular use of OTC medications (including NSAIDs) is not allowed. Occasional use of NSAIDs 
for pain management is acceptable. 
Regular use of vitamins is acceptable. 
Participants must not receive any vaccine in the 14 days prior to or following administration of 
study intervention. 
NOTE: Any medication (including OTC or prescription medicines, vitamins, and/or herbal 
supplements) or vaccine 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 
6.7.1. 
Rescue Medicine 
Rescue medication is permitted at the discretion of the Investigator.  
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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 and 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. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 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. 
• 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. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
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7.3. 
Cohort Stopping Rules 
If a participant experiences a DLT (Section 7.3.1), an SAE (Section 10.3.2), unless it is clearly 
the result of a non-study-related event, or a clinically relevant ECG finding as noted in 
Section 7.3.2, enrollment and dosing of additional participants will be paused while the SRC 
reviews the event. Based on this review, a decision will be made as to whether study enrollment 
and dosing may resume. 
Escalation to the next cohort will be suspended if 2 or more participants in a cohort experience 
DLTs, until the SRC convenes to review the events and the totality of the safety data generated. 
Cohorts dosed at levels lower than the dose level at which the above criteria occurred may 
continue dosing with the approval of the SRC. 
Dose escalation will not be advanced if exposure levels in humans exceed the mean AUC and 
Cmax values observed at the mid-dose level (100 mg/kg) in the 5-week monkey toxicokinetic 
study (Study Number 20-A1203-P-030; AUC0-48h 383000 hr∙ng/mL and Cmax 23300 ng/mL). 
All ongoing participants will continue to be followed for safety assessments as indicated in the 
schedule of activities. 
The Sponsor will promptly notify all sites if cohort stopping rules are triggered. 
7.3.1. 
Dose Limiting Toxicities 
A DLT is defined as:  
• an AE of ≥ Grade 3 intensity (CTCAE Version 5.0) in one participant, unless it is clearly 
the result of a non-study-related event OR 
• any 2 AEs of ≥ Grade 2 intensity in the same body system in one participant. 
7.3.2. 
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. 
• Absolute QTcF > 500 msec and/or  
• QTcF change of > 60 msec from baseline 
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: 
• 2 participants develop a Grade 3 CTCAE event unless it is clearly the result of a 
non-study-related event. 
• 1 participant develops a ≥ Grade 4 CTCAE event unless it is clearly the result of a 
non-study-related event. 
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In the event a study stopping rule is triggered and the SRC calls a halt on dosing or dose 
escalation, the SRC may request that an external, independent and 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 10.1.5.2). 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 the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. Participants may undergo rescreening one time at the discretion of 
the Investigator or Sponsor. Only pregnancy test, hematology and chemistry, and coagulation 
tests may be repeated. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness. 
Adherence to the study design requirements, including those specified in Table 1 and Table 3 
(Section 1.3), is essential and required for study conduct. Participants will be given a diary to 
track AEs and temperance for the study duration. Participants will be trained on the use of the 
diary prior to discharge from the clinic for Visit 1 and will report on the diary at each visit. 
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. 
If multiple assessments are due, the order of priority should be ECG, vitals, PK, and then other 
assessments. 
The maximum amount of blood drawn from each participant at any visit (including efficacy, PK, 
biomarker, and safety laboratory testing) will not exceed: 
• Per Visit:  
− 30 mL for Sentinel group  
− 56 mL for Expanded group 
• Per 8-week period:  
− 156 mL for Sentinel group 
− 297 mL for Expanded group 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
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8.1. 
Efficacy Assessments  
This is a Phase 1 study with the primary objective of evaluating safety. Pharmacokinetic and 
PD assessments are detailed in Sections 8.5 and 8.7, respectively.  
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. 
Site personnel will be provided training in the use of all study-specific instruments (see the Study 
Reference Manual). 
8.2.1. 
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 also be measured and 
recorded at Day 1 and weight will be measured and recorded at every visit. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses or AEs. 
• All physical examinations should include inspection of the injection site. 
8.2.2. 
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.  
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. 
8.2.3. 
Electrocardiograms 
Standard 12-lead ECGs will be performed in the supine position after the participant has rested 
comfortably for 10 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 7.3.2 for QTc withdrawal criteria and any additional readings that 
may be necessary. 
The Investigator or designee is responsible for reviewing the ECG(s) 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. 
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Note: If multiple assessments are due, the order of priority should be ECG, vitals, PK, and then 
other assessments, with the PK sampling being performed preferably at the nominal time point. 
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 eCRF. 
8.2.4. 
Alcohol Consumption via Timeline Follow Back  
Study participants are to refrain from drinking alcohol throughout the outpatient portion of the 
study (sentinel participants will refrain from alcohol throughout the in-clinic portion as well). At 
every visit, the TLFB will be used to assess each participant’s abstention from alcohol since the 
previous 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., biochemical indicators or blood alcohol tests). 
Consequently, there is no practical alternative technology other than self-reports for 
retrospectively assessing drinking. TLFB stands as the most exhaustively evaluated method that 
can be used for this purpose. 
8.2.5. 
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 training 
to administer it. The C SSRS will be administered by qualified, trained raters. 
The Baseline version will be administered at Screening and at subsequent visits the “C-SSRS 
Since Last Visit” version will be administered. 
8.2.6. 
Mini-International Neuropsychiatric Interview 
The MINI 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 
will be administered by a Health Care Provider. 
8.2.7. 
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. 
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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. 
• 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. 
• 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).  
• 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. 
8.3. 
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 
Sections 10.3.1, 10.3.2, and 10.3.4, respectively.  
AEs will be reported by the participant. 
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. 
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 (including CFU, if applicable) at the time points specified in the SoAs (Section 1.3). 
Ongoing SAEs will be followed until resolution. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
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. 
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8.3.2. 
Method of Detecting AEs and SAEs 
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. 
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. 
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. 
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 10.4.4. 
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. 
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8.4. 
Treatment of Overdose 
For this study, any dose of DCR-AUD greater than the specified dose will be considered an 
overdose. 
Dicerna does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
• Contact the CRO Medical Monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
DCR-AUD PD effects can no longer be detected. 
• Document the quantity of the excess dose. 
8.5. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of AUD and/or its 
metabolites as specified in the SoAs (see Section 1.3). Urine samples will be collected for 
measurement of urine concentrations of AUD and/or its metabolites as specified in the SoA 
(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. 
Each plasma sample will be divided into 2 aliquots (one for PK and one backup). Samples 
collected for analyses of plasma concentrations of AUD and/or 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 clearance (CL) and apparent volume 
of distribution (Vd/F) estimates, along with secondary parameters of area under the 
concentration curve (AUC), maximum observed concentration (Cmax), minimum observed 
concentration (Cmin), time to maximum concentration (Tmax), and terminal elimination half-life 
(t1/2). 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 unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.6. 
Genetics 
A sample of whole blood for DNA isolation will be collected from participants who have 
consented to participate in the optional genetic analysis component of the study. Participation is 
optional; participants who do not wish to participate in the genetic research may still participate 
in the study. 
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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 genetic research. Details on processes for collection 
and shipment and destruction of these samples can be found in the Laboratory Manual. 
8.7. 
Pharmacodynamics 
DCR-AUD is designed to selectively reduce ALDH2 activity 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) and objective physiological biomarkers (heart rate and facial skin temperature). 
Participants’ subjective experience of the effects of alcohol will be assessed using the SEAS. 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in the Laboratory Manual and the Laboratory Specification document 
8.7.1. 
Ethanol Interaction Assessments 
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, 
heart rate, facial skin temperature, and subjective feelings of alcohol intoxication or intolerance 
using the SEAS (Morean et al., 2013). Adverse events, vital signs, and ECG will also be 
monitored and recorded for safety. Assessments will be measured for up to 2.5 hours following 
ethanol administration. Published literature consistently demonstrate that administration of 
low/moderate alcohol intake (0.1-0.8 g/kg) in human ALDH2 mutation homo- or heterozygotes 
results in clearly differentiated and statistically significant increases in blood acetaldehyde, heart 
rate, and facial skin temperature 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). 
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 the next 
scheduled visit or at an unscheduled visit at the discretion of the Investigator. Participants will be 
required to be fasted for at least 6 hours prior to administration of a standardized meal and then 
ethyl alcohol (EtOH) 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. During the EIA, participants will receive nothing by 
mouth (remain NPO) except water ad libitum. 
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 0.4 g/kg ethanol for male 
participants and 0.34 g/kg ethanol for female participants, not to exceed 28 grams EtOH for men 
or 24 g EtOH for women per EIA. Ethanol will be consumed in 4 aliquots over a 30-minute 
period. Assessments will be made over an estimated 2.5-hour period, as detailed in Table 3. 
Participants will remain in the Phase 1 telemetry unit for an overnight admission. The 
Investigator will not discharge any participant experiencing ongoing effects of ethanol 
administration until it is deemed medically safe to do so. 
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8.7.1.1. 
PD Biomarkers for EIA 
8.7.1.1.1. EIA Blood Biomarkers 
Blood biomarkers to be assessed include measurement of acetaldehyde, acetate, and ethanol. 
Blood samples (maximum 32 mL/day) will be collected via a venous access device immediately 
prior to EtOH consumption (time 0) and at 15, 30, 45, 60, 90, 120, and 150 minutes postdose 
(Table 3). Additional details regarding blood sample collection and processing will be detailed in 
the Laboratory Manual. 
8.7.1.1.2. EIA Physiological Biomarkers 
EIA assessments will include measurement of heart rate and facial skin temperature. Facial skin 
temperature will be measured using a surface scanning thermometer. Heart rate will be 
monitored by telemetry during the EIAs. Site personnel will be provided training in the use of all 
study-specific instruments (see the Study Reference Manual). 
Heart rate, using telemetry, and facial skin temperature will be collected immediately predose 
(time 0) and at 15, 30, 45, 60, 90, 120, and 150 minutes postdose. 
8.7.1.1.3. EIA Subjective Effects of Alcohol Scale 
For each EIA, participants will complete the SEAS predose (during the Rest Period) and at 
30, 60, 90, 120, and 150 minutes postdose. The SEAS is a 14-item tool that allows participants to 
rate the subjective effects of alcohol described in Table 6. Participants will rate the extent to 
which they are feeling each of the effects in the present time. 
Table 6: 
Subjective Effects of Alcohol Scale (SEAS) 
Feeling 
Not at All 
Moderately 
Extremely 
Relaxed 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Wobbly 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Lively 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Secure 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Rude 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Woozy 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Fun 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Calm 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Aggressive 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Dizzy 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Demanding 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Mellow 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Funny 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Talkative 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Source: Morean et al. 2013. 
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8.7.1.2. 
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:  
• Any vomiting or severe nausea (as judged by Investigator) 
• Systolic blood pressure increase of > 25 mmHg (and/or to a level > 150 mmHg) or 
decrease of > 10 mmHg (to systolic < 90 mmHg) 
• Diastolic blood pressure decrease to < 50 mmHg or any decline accompanied by 
symptomatic hypotension (pre-syncope, syncope, lightheadedness) 
• HR increase of > 20 beats per minute (or to a level > 100 beats per minute)  
• Temperature increase of > 1°Celsius  
• Any clinically meaningful change in affect or clinical status, per Investigator or 
supervising designee’s clinical judgment. 
8.7.1.3. 
Follow-up of Participants Who Continue to Have Positive Ethanol Reaction 
Symptoms at Day 169 
Participants who have positive ethanol reaction symptoms at the Day 169 EIA (e.g., nausea, 
vomiting, or substantial flushing) will return every 28 (±7) days for follow-up EIAs until the 
positive ethanol reaction symptoms abate. These CFU EIAs will not require overnight admission 
to the clinic, but all other aspects of the EIA will be conducted (see Table 3). Participants will be 
observed for no less than 6 hours after ethanol administration and will not be discharged until the 
Investigator deems it medically safe to do so.  
8.8. 
Immunogenicity Assessments 
Antibodies to DCR-AUD will be evaluated in serum samples collected from all participants 
according to the SoA. Additionally, serum samples should also be collected at the final visit from 
participants who discontinued study intervention or were withdrawn from the study. These 
samples will be tested by the Sponsor or Sponsor's designee. 
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. 
The detection and characterization of antibodies to DCR-AUD will be performed using a 
validated assay method by or under the supervision of the Sponsor. All samples collected for 
detection of antibodies to DCR-AUD will also be evaluated for DCR-AUD serum concentration 
to enable interpretation of the antibody data. Antibodies may be further characterized and/or 
evaluated for their ability to neutralize the activity of the study intervention(s). Samples for the 
detection and characterization of antibodies to DCR-AUD will be stored until a validated assay 
method is available.  
8.9. 
Health Economics 
Health Economics parameters are not planned in this study. 
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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 following sample sizes were 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.  
• 27 HV participants (3 cohorts with 9 participants each, 2 to 1 randomization), plus an 
additional 9 HV participants (2 to 1 randomization), for a total of 36, if an optional 
fourth cohort is enrolled. 
The sample size is based on clinical rather than statistical considerations. 
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 randomly assigned to study 
intervention. 
Pharmacokinetic 
All participants randomly assigned to study intervention and who receive a 
full dose of DCR-AUD and have sufficient data for at least 1 postdose PK 
assessment. 
Pharmacodynamic 
All participants randomly assigned to study intervention and who receive a 
full dose of study intervention and have sufficient data for at least 1 postdose 
PD assessment. 
Safety  
All participants randomly assigned to study intervention and who receive a 
full dose of study intervention. Participants will be analyzed according to 
dose received. 
 
9.4. 
Statistical Analyses 
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. 
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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 subject listings. Source data for the 
summary tables and statistical analyses will be presented as subject data listings. 
9.4.2. 
Primary Endpoint(s) 
The primary endpoint for all parts of the study is assessment of the incidence and severity of 
AEs, SAEs, and DLTs. 
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 will be used to summarize 
AEs, SAEs, AEs of special interest, and AEs by relationship. Laboratory values will be reported 
by CTCAE grade and summarized, if applicable. 
By-subject listings will be provided for deaths, SAEs, and DLTs. 
9.4.3. 
Secondary Endpoint(s) 
Pharmacokinetic analyses will be performed on Pharmacokinetic Population. Actual sampling 
times will be used for all parameter estimations.  
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.  
Descriptive statistics and change from baseline will be provided for PD assessments, including 
acetaldehyde accumulation (absolute values and AUC) during the EIAs, where applicable. 
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) 
Exploratory analyses will be conducted as deemed appropriate and will be detailed in the SAP. 
9.4.5. 
Other Safety Analyses 
Descriptive statistics and change from baseline will be provided for clinical laboratory 
parameters, vital sign parameters, exploratory biomarkers, and 12-lead ECG parameters by dose 
group and visit. 
Laboratory parameter shifts from baseline to abnormal post-baseline values will be presented. 
Mean laboratory values over time will be plotted by dose group.  
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9.5. 
Interim Analyses  
One or more interim analyses (IA) may be conducted by the Sponsor contingent on a possible 
safety or PD signal in the emerging blinded data. The timing of any IA will be dictated by the 
nature of available clinical and PD data. The Sponsor may elect not to perform an IA if the 
emerging data do not warrant its conduct. 
As part of any IA, all study site personnel will remain blinded, but certain members of the 
Sponsor staff will be unblinded to randomization for the duration of the study. Complete 
information regarding unblinding of the Sponsor will be detailed in the Study Blinding Plan. 
The SAP will describe the conduct of an IA in greater detail if warranted. 
9.6. 
Safety Review Committee 
An SRC will conduct periodic reviews and will review all cumulative safety, tolerability, and 
available PD data on participants across all cohorts, approximately every 2 months during 
treatment and postdose 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. 
Table 7 shows the minimal required timing of reviews by the SRC, as well as the decisions that 
the SRC may undertake with respect to cohort expansion, dose escalation, and the possible 
occurrence of DLTs and study stopping rules (see Section 7.4).  
At its discretion, and based on clinical judgment, the SRC may suspend dosing of 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 triggers stopping rules. 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 DSMC are provided in the SRC charter.  
As noted in Section 6.1.1, progression from one cohort to the next higher dose is contingent upon 
SRC review. 
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Table 7: 
Minimal Timing of the Safety Review Committee Data Reviews 
Review of sentinel dose 
group for continuation 
of dosing within a 
cohort 
The SRC must review the available safety data (as specified in the SRC charter) 
collected on the first 3 participants (“sentinel group”) dosed in each cohort 
(randomized 2:1; DCR-AUD: placebo), through at least the Day 15 assessments 
before the dosing of the next 6 participants in the cohort can occur. 
Dose escalation to the 
next cohort  
The SRC must review the available safety data collected on all 9 participants dosed 
in a given cohort (through at least the Day 15 assessments including Day 15 EIA 
data for applicable participants) before dose escalation to the next cohort can occur. 
In addition, the SRC must review 72-hr PK data on all participants in a given cohort 
before dose escalation, to ensure that exposure levels do not exceed those observed 
at the mid-dose in the 5-week monkey toxicokinetic study 
(AUC0-48h 383000 hr•ng/mL and Cmax 23300 ng/mL). 
The data to be reviewed will be specified in the SRC charter. 
Occurrence of a DLT  
Upon the occurrence of a DLT (see Section 7.3.1), all dosing and enrollment into 
the current cohort or escalation to the next cohort will be interrupted until safety 
data can be reviewed by the SRC. The SRC will review the events associated with 
the DLT as well as the cumulative safety data collected on all participants 
previously dosed. The SRC will determine whether dosing, enrollment, and/or dose 
escalation 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: 
• Discontinuation of an individual participant 
• Discontinuation of dosing at a certain dose level 
• 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, enrollment, and/or dose escalation 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; DLT; dose-limiting toxicity; DSMC: Data Safety Monitoring 
Committee; EIA: ethanol interaction assessment; SRC: Safety Review Committee  
For additional details on the composition of the SRC and DSMC, refer to Section 10.1.5. 
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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: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 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: 
• 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 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 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. Adolescents (12 to < 18 years of age, or older than 12 years but 
younger than the age of majority according to local regulations) must be able to provide written 
assent for participation. For children younger than 12 years of age, assent will be based on local 
regulations. 
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 subinvestigator, the Sponsor Medical Monitor, and the 
CRO Medical Monitor.  
See Section 9.6 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. 
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. In compliance with the National 
Institutes of Health grant, information in the clinical trial record will be updated at least once a 
year, and tabular study summary results will be posted to www.ClinicalTrials.gov within 1 year 
of study completion. 
10.1.7. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF (eCRF), 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
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 CRF 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. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents, or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
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10.1.9. 
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: 
• Investigator noncompliance with the protocol, GCP, or regulatory requirements  
• Unsatisfactory enrollment with respect to quantity or quality 
• Incomplete data collection; inaccurate or knowingly false data submission 
• The PI is no longer capable of performing the tasks of the PI, and no replacement can 
be found. 
• The SRC determines that termination of the study is in the best interest of the 
research participants. 
• The Sponsor, Investigator or IRB/IEC determines that continuation of the study will 
not serve any scientific purpose. 
• Circumstances beyond the control of the Sponsor or Investigator make it 
unreasonable to require the study's continuation. 
• 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. 
10.1.10. 
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 Dicerna 
Pharmaceuticals, Inc. or their designees. Authorship will be determined by mutual agreement 
and in line with International Committee of Medical Journal Editors authorship requirements.  
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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 Dicerna 
Pharmaceuticals, Inc. author of the publications or presentations, a manuscript will be forwarded 
to Dicerna Pharmaceuticals, Inc. 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. 
 
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10.2. 
Clinical Laboratory Tests 
Table 8 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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Table 8: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Red blood cell count 
 hemoglobin 
 hematocrit 
 reticulocytes 
 platelet count 
Only at Days -1, 4, 29, 85, and 169  
 mean corpuscular volume (MCV) 
 mean corpuscular hemoglobin (MCH) 
 mean corpuscular hemoglobin 
concentration (MCHC) 
White blood cell count 
 
 
 
 
Only at Days -1, 4, 29, 85, and 169 
 lymphocytes, abs and % 
 monocytes, abs and % 
 eosinophils, abs and % 
 neutrophils, abs and % 
 basophils, abs and % 
Clinical Chemistry  
alanine transaminase (ALT) 
aspartate transaminase (AST) 
gamma-glutamyl transferase (GGT) 
alkaline phosphatase (ALP) 
bilirubin (total and direct) 
lactate dehydrogenase (LDH) 
total protein 
albumin 
creatine kinase (CK) 
sodium 
chloride 
potassium 
creatinine 
blood urea nitrogen (BUN) 
fasting blood glucose 
 
Routine Urinalysis 
specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick 
microscopic examination (if blood or protein is abnormal) 
Coagulation 
Parameters 
International normalized ratio (INR), PT, PTT 
Complement panel 
Bb, C3a, C5a  
Other Screening Tests 
• 
Alcohol breath test 
• 
Rapid SARS-CoV-2 (local laboratory testing) 
• 
Follicle-stimulating hormone (as needed in women of non-childbearing 
potential only) 
• 
Highly sensitive (urine; serum for confirmation if needed) human 
chorionic gonadotropin (hCG) pregnancy test (as needed for WOCBP). 
Any positive urine pregnancy test will be confirmed with a serum 
pregnancy test.  
• 
Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, and benzodiazepines) 
• 
Viral serology (human immunodeficiency virus antibody, hepatitis B 
surface antigen, and hepatitis C virus antibody) 
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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 
• 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.  
• Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 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 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 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: 
• Results in death 
• 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. 
• 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. 
• 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. 
• Is a congenital anomaly/birth defect 
• 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  
An AESI is a noteworthy event for the particular product or class of products that a Sponsor may 
wish to monitor carefully (CIOMS IV, 2005). 
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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 9 are met. Signs or 
symptoms at the injection site that occur ≥ 4 hours post-injection but are not specified in Table 9 
should be recorded as AEs. 
Table 9: 
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: 
• Not Related: Event for which sufficient evidence exists to conclude that the etiology 
is unrelated to study intervention. 
• 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.  
• 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.  
• 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. 
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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 adolescents or 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: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
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 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.  
• 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. 
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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: 
• 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, 
• 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 10 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 10.  
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Table 10: 
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  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independent a 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation  
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
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.  
• 
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.  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
 
10.4.3. 
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. 
Additional pregnancy testing should be performed as indicated in SoA (Section 1.3). 
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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.  
10.4.4. 
Collection of Pregnancy Information 
10.4.4.1. 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 
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.  
10.4.4.2. 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.  
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10.5. 
Genetics  
Use/Analysis of DNA 
• DNA samples will be used for research related to genetic allelotypes (including 
ALDH2) that could potentially influence alcohol metabolism and the impact of 
DCR-AUD. Genetic research may consist of the analysis of one or more candidate 
genes or the analysis of genetic markers throughout the genome potentially related to 
alcohol metabolism. 
• 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. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to DCR-AUD or study interventions of this class to 
understand study disease or related conditions. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 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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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 (Table 11). 
Table 11: 
Liver Safety: Suggested Actions and Follow-up Assessments 
Liver Chemistry Stopping Criteria 
ALT/AST-
absolute 
ALT or AST ≥ 3×ULN 
If ALT or AST ≥ 3×ULN AND total bilirubin  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 
Required Actions, Monitoring, and Follow-up Assessments  
Actions: 
• 
Report the event to the CRO Medical Monitor within 24 hours 
• 
Complete an SAE data collection tool if the event also met the criteria for an SAE b 
• 
Perform liver function follow-up assessments as described in the Follow Up Assessments below.  
• 
Monitor the participant until liver function test abnormalities resolve, stabilize, or return to baseline 
Monitoring: 
If ALT or AST ≥ 3×ULN AND total bilirubin  2×ULN or INR > 1.5 
• 
Repeat liver function tests (include ALT, AST, alkaline phosphatase, total bilirubin, and INR) 
and perform liver function follow-up assessments within 24 hours. 
• 
Monitor participant twice weekly until liver function test abnormalities resolve, stabilize, or 
return to baseline. 
• 
A specialist or hepatology consultation is recommended. 
If ALT or AST ≥ 3×ULN AND total bilirubin < 2×ULN and INR ≤ 1.5: 
• 
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 
• 
Monitor participants weekly until liver function abnormalities resolve, stabilize, or return to 
baseline 
Follow-Up Assessments 
• 
Viral hepatitis serology (includes: Hepatitis A immunoglobulin M [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)  
• 
Obtain serum CK, LDH, GGT, GLDH, and serum albumin 
• 
Fractionate bilirubin, if total bilirubin  2×ULN 
• 
Obtain complete blood count with differential to assess eosinophilia 
• 
Record the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on 
the eCRF 
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• 
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. 
• 
Record alcohol use on the eCRF 
If ALT or AST ≥ 3×ULN AND total bilirubin  2×ULN or INR > 1.5 obtain the following in 
addition to the assessments listed above: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin G (IgG) or gamma globulins 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) and/or liver 
biopsy to evaluate liver disease  
• 
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. 
 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention if ALT ≥ 3×ULN and total bilirubin ≥ 2×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 All events of ALT ≥ 3×ULN and total bilirubin ≥ 2×ULN (> 35% direct bilirubin) or ALT ≥ 3×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).  
 
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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 
DLT 
dose-limiting toxicity 
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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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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 
MINI 
Mini International Neuropsychiatric Interview 
miRNA 
micro-RNA 
mRNA 
messenger ribonucleic acid 
mg 
milligram(s) 
min 
minute(s) 
mL 
milliliter(s) 
mRNA 
messenger ribonucleic acid 
M&S 
modeling and simulation 
NOAEL 
no observed adverse effect level 
NPO 
nothing by mouth 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over the counter 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic 
PI 
Principal Investigator 
QTcF 
QT interval (Fridericia correction) 
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Abbreviation 
Description 
RNA 
ribonucleic acid 
RNAi 
RNA interference 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SEAS 
Subjective Effects of Alcohol Scale 
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 
 
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10.8. 
Investigator Signature Page 
 
A Phase 1, Double-blind, Placebo-controlled, Single-ascending-dose, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in Healthy Volunteers 
 
Protocol Number:  
DCR-AUD-101 
Version: 
6.0 
Date:  
14-Mar-2022 
 
 
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: 
 
 
 
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10.9. 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
 
Amendment 5: 14-Mar-2022 
Overall Rationale for Amendment 5: 
The 28-Jul-2021 version of the protocol was amended to remove the conduct of the interim 
analysis scheduled at the conclusion of Cohort 2, as emerging PD data did not dictate it was 
warranted. Other points of clarification for the timing and scheduling of study visits were also 
added.  
 
Amendment 4: 28-Jul-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The 26-Jul-2021 version of the protocol was amended to address the concerns and questions 
raised by the FDA in their review of Amendment 3 of the protocol.  
Protocol Amendment 4 Summary of Changes 
Description of Change 
Brief Rationale 
Affected Sections 
Added group mean AUC0-48 and 
Cmax values from the 100 mg/kg 
dose in the 5-week monkey toxicity 
study to the dose escalation 
stopping criteria. 
For clarity 
2.3.4 
Risk Assessment 
7.3 
Cohort Stopping Rules 
9.6 
Safety Review Committee 
Administrative updates 
To reflect new version 
Throughout the protocol 
 
Amendment 3: 26-Jul-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The 19-Jul-2021 version of the protocol was amended to address the concerns and questions 
raised by the FDA in their review of Amendment 2 of the protocol.  
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Protocol Amendment 3, Summary of Changes 
Description of Change 
Brief Rationale 
Affected Sections 
Added PK stopping criteria and 
updated the text around the 
nonclinical safety program to 
align with changes related to the 
justification of dose 
To ensure that exposure levels in 
humans do not exceed mean AUC 
and Cmax values observed at the 
mid-dose in the 5-week monkey 
toxicology study (Study Number 
20-A1203-P-030) and to align with 
FDA input by taking a more 
conservative approach to safety 
margins 
2.2.2 
Nonclinical Overview of 
DCR-AUD 
2.3.1 
Risks Related to siRNA 
Molecules 
4.3 
Justification for Dose 
6.1.1 
Dose Levels and Dose 
Escalation 
6.5 
Dose Modification 
7.3 
Cohort Stopping Rules 
9.6 
Safety Review Committee 
11 
References 
Added assessment of 
complement levels (Bb, C3a, 
C5a) and revised maximum 
planned blood volume to be 
drawn 
To monitor for potential 
immunostimulatory effects 
1.3 
Schedule of Activities 
2.3.1 
Risks Related to siRNA 
Molecules 
2.3.4 
Risk Assessment 
8 
Study Assessments and 
Procedures 
10.2 
Clinical Laboratory Tests 
(Table 8) 
Added CFU for participants with 
ethanol reaction symptoms at 
Day 169 to return q28 days for 
follow up 
To ensure participants have no 
residual IP-related symptoms from 
EIA 
1.1.3 
Overall Design 
1.2 
Study Schema 
1.3 
Schedule of Activities 
2.3.4 
Risk Assessment  
4.1 
Study Design 
8.3.1 
Time Period and Frequency 
for Collecting Adverse Event 
Information 
8.7.1.3 Follow-up of Participants 
Who Continue to Have 
Positive Ethanol Reaction 
Symptoms at Day 169 
Removed the maximum number 
of EIAs participants may 
undergo 
To account for possibility of 
additional EIAs during CFU 
1.1.3 
Overall Design 
2.3.4 
Risk Assessment 
4.2 
Scientific Rationale for Study 
Design 
5.1 
Inclusion Criteria 
Other editorial changes 
Correction of errors and to reflect 
new version and amendment 
number, and for consistency, 
accuracy, and precision 
8.2.2 
Vital Signs 
9.5 
Interim Analyses 
Global updates to headers, version 
history, signature pages, abbreviations 
list 
 
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Amendment 2: 19-Jul-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The 09-Jul-2021 version of the protocol was amended to address the concerns and questions 
raised by the FDA in their review of Amendment 1 of the protocol.  
Protocol Amendment 2, Summary of Changes 
Description of Change 
Brief Rationale 
Affected Sections 
Updated name of CRO medical 
monitor 
Changed to Dr. 
  
Medical Monitor Contact Information 
Corrected error in study schema 
that V3 is on Day 29 
To ensure schema aligns with 
schedule of assessments  
1.2 
Figure 1 
Specified blood pressure criteria for 
eligibility range of 90-140 mmHg 
systolic and 55-95 mmHg diastolic 
To ensure participants’ BPs are 
neither too high nor too low 
5.1 
Inclusion criteria 
5.2 
Exclusion criteria 
8.7.1.2 Stopping Rules for an EIA 
Specified heart rate increase of 
> 20 bpm or to a level of > 100 bpm 
would prompt stoppage of EIA 
To ensure participant safety 
8.7.1.2 Stopping Rules for an EIA 
Clarified that participants with 
adverse reactions to alcohol or 
underlying conditions that should 
preclude alcohol consumption 
should not be enrolled or allowed to 
continue 
To ensure participant safety 
5.2 
Exclusion criteria 
7.1 
Participant 
Discontinuation/Withdrawal 
from the Study 
8.7.1 
Ethanol Interaction 
Assessment 
Added statement about required 
overnight stay in the Phase 1 unit 
after EIA and that participants will 
not be discharged until deemed 
medically safe 
To ensure participant safety 
8.7.1 
Ethanol Interaction 
Assessment 
Added clarifications about Day -1 
alcohol exposure, which is not part 
of an EIA assessment 
To emphasize the predose 
exposure to alcohol to ensure 
eligibility and establish baseline 
for biomarker assessments 
1.1.3 
Overall Design 
1.3 
Footnote “n” of Table 1 
4.2 
Scientific Rationale for Study 
Design 
 
 
Amendment 1: 09-Jul-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
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The 24-Jun-2021 version of the protocol was amended to address the concerns and questions 
raised by the FDA in their review of the PIND.  
Protocol Amendment 1, Summary of Changes 
Description of Change 
Brief Rationale 
Affected Sections 
Provided additional 
information about placebo 
Specified physiologic saline (0.9% 
aqueous sodium chloride) would be 
used for placebo  
6.1.1 
Dose Levels and Dose 
Escalation (Table 5) 
6.2.3 
Preparation and Administration 
Added use of the Mini 
International 
Neuropsychiatric Interview 
(MINI) 7.0.2 
To further identify and monitor 
participant psychological status 
1.3 
Schedule of Activities 
5.2 
Exclusion Criteria 
8.2.6 
Mini-International 
Neuropsychiatric Interview 
Specified which liver 
function test results will be 
used to determine eligibility 
To ensure participant safety 
5.2 
Exclusion Criteria 
Clarified instructions about 
treatment administration  
Specified that for dose levels requiring 
>1 injection, treatment would be 
administered by multiple injections in 
the abdomen 
6.2.3  Preparation and Administration 
Made all physical 
examinations full 
examinations  
Eliminated option for brief physical 
examinations for clarity 
1.3 
Schedule of Activities 
8.2.1 
Physical Examinations 
Clarified documentation of 
start date of AEs and SAEs 
and defined start date of 
TEAE  
All AEs and SAEs will be collected 
after signature of the ICF. AEs will be 
defined as treatment-emergent if they 
occur after administration of study 
intervention.  
7.3 
Cohort Stopping Rules 
9.4.2 
Primary Endpoint(s) 
Clarified SAE, DLT, and 
study stopping criteria  
This is a FIH study, so all AEs, SAEs, 
and DLTs will considered at least 
possibly related unless clearly a result 
of a non-study related event. 
7.3 
Cohort Stopping Rules 
7.3.1 
Dose Limiting Toxicities 
7.4 
Study Stopping Rules 
 
Removed mention of 
progression of underlying 
disease 
This is a FIH study, so removed 
references to disease progression as 
this is not applicable. 
8.2.7  Clinical Safety Laboratory 
 Assessments 
10.3.1 Definition of Adverse Event 
10.3.2 Definition of Serious Adverse 
 Event 
10.3.4.3 Assessment of Causality 
10.5 
Genetics 
Increased requirement for 
contraceptive use from 12 to 
24 weeks 
Increased requirement of 
contraceptive use to cover the full 
duration of the study. 
5.1 
Inclusion Criteria  
8.3.5 
Pregnancy 
10.4.2 Contraception Guidance 
Added summary of changes 
for Amendment 1 (dated 
09-Jul-2021) 
For clarity 
 
 
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11. 
REFERENCES 
Ahmadzada T, Reid G, McKenzie DR. Fundamentals of siRNA and miRNA therapeutics and a 
review of targeted nanoparticle delivery systems in breast cancer. Biophys Rev. 2018 
Feb;10(1):69-86. 
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.  
Campral® (acamprosate calcium) [package insert]. Revised Jan 2012. St. Louis, MO: Forest 
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https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021431s015lbl.pdf. 
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.  
Cooper GM, Brudno M, NISC Comparative Sequencing Program, Green ED, Batzoglou S, 
Sidow A. Quantitative estimates of sequence divergence for comparative analyses of mammalian 
genomes. Genome Res. 2003; 13:813-20. 
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http://dicerna.com/our-technology/dicernas-delivery-platforms/. Accessed 20 October 2020. 
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. 
Eng MY, Luczak SE, Wall TL. ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature 
review. Alcohol Res Health. 2007;30(1):22-7.  
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. 
Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland 
JE, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase 
subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy 
volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014 Jan 
4;383(9911):60-8. 
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.  
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: 
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https://www.samhsa.gov/data/report/receipt-services-behavioral-health-problems-results-2014-
national-survey-drug-use-and-health. 
Huang Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol 
Ther Nucleic Acids. 2017 Mar 17;6:116-32. 
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.  
Kaczmarek JC, Kowalski PS, Anderson DG. Advances in the delivery of RNA therapeutics: 
from concept to clinical reality. Genome Med. 2017 Jun 27;9(1):60.  
Knudsen HK, Abraham AJ, Roman PM. Adoption and implementation of medications in 
addiction treatment programs. J Addict Med. 2011 Mar;5(1):21-7.  
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. 
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.  
Morean ME, Corbin WR, Treat TA. The subjective effects of alcohol scale: development and 
psychometric evaluation of a novel assessment tool for measuring subjective response to alcohol. 
Psychol Assess. 2013 Sept;25(3):doi:10.1037/a0032542.  
National Cancer Institute [Internet]. Bethesda (MD): National Cancer Institute (US); Common 
Terminology Criteria for Adverse Events Version 5.0.; [cited 2019 Mar 22]. Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
CTCAE_v5_Quick_Reference_5x7.pdf. 
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. Pharmacogenetics and 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. 
Rozema DB, Lewis DL, Wakefield DH, Wong SC, Klein JJ, Roesch PL, et al. Dynamic 
PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci U S 
A. 2007 Aug 7;104(32):12982-7. 
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 
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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. 
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for 
Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics 
in Adult Healthy Volunteers. July 2005. Available from 
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Vivitrol® [package insert]. Revised July 2020. Alkermes, Inc. Available at: 
https://www.vivitrol.com/content/pdfs/prescribing-information.pdf.  
Wittrup A, Lieberman J. Knocking down disease: a progress report on siRNA therapeutics. Nat 
Rev Genet. 2015;16(9):543–52. 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Dicerna Pharmaceuticals, Inc. 
NCT number 
NCT05021640 
Sponsor trial ID: 
DCR-AUD-101 
Official title of study: 
A Phase 1, Double-blind, Placebo-controlled, Single-
ascending-dose, Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics Study of DCR-AUD in Healthy 
Volunteers 
Document date*: 
22 Feb 2023 
*Document date refers to the date on which the document was most recently updated.


 
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Page 1 of 46 
 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101 
A Phase 1, Double-blind, Placebo-controlled, Single-ascending-dose, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in Healthy Volunteers
Statistical Analysis Plan 
Version: 2.0 




 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
 
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 SIGNATURE PAGE 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with SOP-
GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the following: 
Signatory 
Author 
 
Project Role: 
  
Signatory 
Author 
  
Project Role: 
 
Signatory 
Reviewer 
  
Project Role: 
 


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
 
Project Document Version No. 2.0 
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Page 4 of 46 
TABLE OF CONTENTS 
1
INTRODUCTION .................................................................................................................... 10
2
STUDY OBJECTIVES ............................................................................................................ 10
2.1
Primary Objective(s) ........................................................................................................ 10
2.2
Secondary Objective(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
Safety Variables .......................................................................................................... 13
3.2.2
Pharmacokinetic Variables ......................................................................................... 14
3.2.3
Pharmacodynamic Variables ...................................................................................... 16
3.2.4
Immunogenicity Variables .......................................................................................... 17
3.2.5
Efficacy Variables ....................................................................................................... 17
3.2.6
Exploratory Variables ................................................................................................. 17
4
STATISTICAL METHODS..................................................................................................... 17
4.1
Data Quality Assurance ................................................................................................... 17
4.2
General Presentation Considerations ............................................................................... 17
4.2.1
Treatment .................................................................................................................... 18
4.2.2
Baseline ....................................................................................................................... 18
4.2.3
End of Study ............................................................................................................... 18
4.2.4
Study Day ................................................................................................................... 18
4.2.5
Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment ....................... 18
4.3
Software ........................................................................................................................... 18
4.3.1
Summary and Representation of Data ........................................................................ 18
4.4
Analysis Population ......................................................................................................... 19
4.5
Study Participants ............................................................................................................ 19
4.5.1
Disposition of Participants .......................................................................................... 19
4.5.2
Protocol Deviations ..................................................................................................... 19
4.5.2.1 Protocol Deviations with PK Implications ................................................................. 19
4.5.2.2 Protocol Deviations with Non-PK Implications ......................................................... 20
4.6
Demographics and Baseline Characteristics .................................................................... 20
4.7
Medical History and Concomitant Illnesses .................................................................... 20
4.8
Prior and Concomitant Medications ................................................................................ 20
4.9
Treatment Exposure ......................................................................................................... 21
4.10 Pharmacokinetics Analysis, Concentration, and Parameter TFLs, and Statistical Analysis of 
Pharmacokinetic Parameters for Final Analysis .............................................................. 21
4.10.1
Pharmacokinetic Concentrations ................................................................................ 21
4.10.2
Pharmacokinetic Parameters ....................................................................................... 23
4.10.3
Pharmacokinetic Analysis ........................................................................................... 26
4.11 Pharmacodynamics Analysis, Concentration, and Parameter TFLs, and Statistical Analysis of 
Pharmacodynamic Parameters ......................................................................................... 27
4.11.1
Pharmacodynamic Parameters .................................................................................... 28
4.11.1.1 Ethanol Interaction Assessments ................................................................................ 28
4.11.1.2 PD Biomarkers for EIA .............................................................................................. 30
4.11.1.2.1
EIA Blood Biomarkers ................................................................................... 30
4.11.1.2.2
EIA Physiological Responses ......................................................................... 31


 
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4.11.1.2.3
EIA Subjective Effects of Alcohol Scale ....................................................... 32
4.11.2
Immunogenicity .......................................................................................................... 32
4.12 Safety Evaluation ............................................................................................................. 32
4.12.1
Adverse Events ........................................................................................................... 33
4.12.2
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 34
4.12.3
Clinical Laboratory Evaluation ................................................................................... 34
4.12.4
Vital Signs ................................................................................................................... 35
4.12.5
Physical Examination ................................................................................................. 36
4.12.6
Alcohol Consumption via Timeline Follow Back ...................................................... 36
4.12.7
Columbia-Suicide Severity Rating Scale .................................................................... 36
4.12.8
Dose Limiting Toxicities ............................................................................................ 37
4.12.9
ECG ............................................................................................................................ 37
4.13 Safety Review Committee ............................................................................................... 37
4.14 Interim Analysis .............................................................................................................. 38
4.15 Determination of Sample Size ......................................................................................... 38
4.16 Changes in the Conduct of the Study or Planned Analysis ............................................. 38
5
REFERENCES ......................................................................................................................... 38
6
APPENDICES .......................................................................................................................... 39
6.1
Schedule of Activities ...................................................................................................... 39
6.2
Imputation Rules for Partial Dates .................................................................................. 43
LIST OF TABLES  
Table 3-1 Plasma Pharmacokinetic Parameters of DCR-AUD After Single Subcutaneous Dose 
Administration ........................................................................................................... 14
Table 3-2 Urine Pharmacokinetic Parameters of DCR-AUD After Single Subcutaneous Dose 
Administration ........................................................................................................... 16
Table 3-3 Plasma Pharmacodynamic Parameters of DCR-AUD After Single Subcutaneous Dose 
Administration ........................................................................................................... 17
Table 4-1 
Pharmacokinetic Parameter and Estimation .............................................................. 23
Table 4-2 Subjective Effects of Alcohol Scale (SEAS) ..................................................................... 32
Table 6-1 Schedule of Activities ........................................................................................................ 39
Table 6-2 Allowed Windows for Collection of Plasma Pharmacokinetic Samples and for 
Complement Panel ..................................................................................................... 42
Table 6-3 Schedule of Activities: Ethanol Interaction Assessments ................................................. 42
Table 6-5
Algorithm for Prior/Concomitant Medications Categorization: ................................ 45
Table 6-6 Safety Laboratory Assessments ......................................................................................... 46
LIST OF FIGURES 
Figure 3-1 Study Schematic of DCR-AUD-101 ................................................................................ 12


 
Dicerna Pharmaceuticals, Inc. 
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Page 6 of 46 
REVISION HISTORY 
Version No. 
Effective Date 
Summary of Change(s) 
Final 1.0 
14 Dec 2021 
New Document 
Final 2.0 
Date of Last Signature 
Update as per Protocol Amendment 5. 
Pharmacokinetic and Pharmacodynamic analysis 
section update. 


 
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Page 7 of 46 
LIST OF ABBREVIATIONS 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALDH2 
Aldehyde dehydrogenase 2 
ALDH2 
Gene for aldehyde dehydrogenase 2 
ALP
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
AUCAbove
Area under the curve that is above the baseline  
AUCBelow
Area under the curve that is below the baseline 
BMI 
Body Mass Index 
BP 
Blood pressure 
Bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CCRS 
Columbia-Suicide Severity Rating Scale 
CL/F 
Apparent clearance following extravascular (non-intravenous) 
administration 
Clast
Last quantifiable concentration at tlast
CLR
Renal clearance of drug from plasma 
Cmax
Maximum observed concentration 
Cmin
Minimum observed concentration at steady state  
CPMS 
Clinical Pharmacology, Modeling, and Simulation 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough
Concentration at the end of a dosing interval  
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
EIA 
Ethanol interaction assessment 


 
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Abbreviation / Acronym 
Definition / Expansion 
GGT 
Gamma-glutamyl transferase  
HR 
Heart rate 
HV 
Healthy Volunteers 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio 
ISR 
Injection site reaction 
L  
Linearity index 
LDH 
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
Mini-International Neuropsychiatric Interview 
NA 
Not available 
NCS 
Not clinically significant 
NK 
Not known 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PKP 
Pharmacokinetic Population 
PP 
Pharmacodynamic Population 
QT 
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave 
QTc 
Corrected QT interval 
QTcB 
QT corrected using Bazett’s formula 
QTcF 
QT corrected using Fridericia’s formula 
RNA 
Ribonucleic acid 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation or single dose 


 
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Statistical Analysis Plan 
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Abbreviation / Acronym 
Definition / Expansion 
SEAS 
Subjective Effects of Alcohol Scale  
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SP 
Safety Population 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event 
TLFB 
Timeline Follow Back 
WHO-DD 
World Health Organization - Drug Dictionary 


 
Dicerna Pharmaceuticals, Inc.  
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                                                Statistical Analysis Plan 
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1
INTRODUCTION 
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 (hybridized duplex) RNA oligonucleotide conjugated to N-acetyl-D-
galactosamine (GalNAc) ligands that enable subcutaneous (SC) delivery of stable, safe, highly 
specific, and long-acting reduction of mRNA in the liver via hepatic GalNAc carbohydrate receptors. 
DCR-AUD is designed to selectively reduce ALDH2 mRNA and ALDH2 levels in the liver, and 
thereby decrease the conversion of acetaldehyde to acetic acid after ethanol ingestion. The DCR-
AUD-101 study is the first human study of DCR-AUD. 
The overall goals of this study are: 
1. To demonstrate that DCR-AUD single doses are safe and well-tolerated. 
2. To characterize the PK of single doses of DCR-AUD 
3. To characterize the PD of single doses of DCR-AUD and obtain safety data after alcohol 
exposure in adult healthy volunteers (HVs) as assessed by serial standardized Ethanol 
Interaction Assessments (EIAs) 
a.
EIAs will be used to confirm target engagement. The degree of ALDH2 reduction is 
measurable only after ethanol administration, via levels of plasma acetaldehyde and 
acetate, quantitative assessment of 6 symptom responses during EIAs, and 
measurement of heart rate and facial skin temperature. 
b. The safety of ethanol ingestion in the presence of DCR-AUD will be assessed during 
EIAs, each of which will be followed by overnight admission and monitoring in a 
Phase 1 clinical unit. The Investigator will not discharge any participant experiencing 
ongoing effects of ethanol administration until it is deemed medically safe to do so. 
c.
Serial EIAs will be used to determine the duration of action of DCR-AUD, so that an 
appropriate dose and dosing interval and safety monitoring plan for participants can 
be developed for later clinical trials. 
The SAP describes the variables and populations, anticipated data transformations and manipulations 
and other details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described in this SAP are based upon the following study documents: 

Study Protocol, Final, Amendment 5 (version 6.0) (Mar 14, 2022) 

Case Report Forms (Sep 08, 2022) 
The SAP will be finalized prior to database lock or first unblinding of the study; whichever is earlier 
and describes the statistical analysis as it is foreseen when the study is being planned. If circumstances 
should arise during the study rendering this analysis inappropriate, or if improved methods of analysis 
should arise, updates to the analyses may be made and the SAP will be amended. Post database lock, 
modifications will be documented as Statistical Analysis Modification Requests and documented in 
Clinical Study Report (CSR). 
2
STUDY OBJECTIVES 
2.1
Primary Objective(s) 

To evaluate the safety and tolerability of single doses of DCR-AUD administered to adult 
HVs. 


 
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2.2
Secondary Objective(s) 

To characterize the PK of single doses of DCR-AUD in adult HVs 

To characterize the PD of single doses of DCR-AUD in adult HVs as assessed by serial 
standardized EIAs 
2.3
Exploratory Objective(s) 
Not Applicable 
3
INVESTIGATIONAL PLAN 
3.1
Overall Study Design and Plan 
This phase I trial is a 24-week, randomized, double-blind, placebo-controlled study to evaluate the 
safety, tolerability, PK, and PD of single-ascending doses (SAD) of DCR-AUD administered to adult 
HVs. The study schematic diagram is shown in Figure 3-1. 


 
Dicerna Pharmaceuticals, Inc.  
DCR-AUD-101 
                                                         Statistical Analysis Plan 
TP-GDO-WW-133-02                                                                                          
 
Project Document Version No. 2.0 
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Figure 3-1 Study Schematic of DCR-AUD-101 


 
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Individual participants will be screened for a period of up to 28 days. Participants may undergo 
rescreening one time at the discretion of the Investigator or Sponsor. The single doses of DCR-AUD 
will be administered to adult HVs across 3 fixed ascending-dose cohorts (80 mg, 240 mg, 480 mg) 
and 1 optional cohort (960 mg). Each cohort will comprise a sentinel group of 3 participants (2 active, 
1 placebo) who will be followed for the assessment of safety and tolerability and characterization of 
PK but who will not undergo any EIAs. The sentinel group will remain under observation in clinic 
until Day 4 (after dosing on Day 1) and will return to clinic on Days 8 and 15 for clinical and 
laboratory test evaluations. The SRC will review available sentinel group safety data through the Day 
15 assessments prior to authorizing cohort expansion within an individual cohort for the remaining 6 
participants (4 active, 2 placebo). The 6 participants in the expanded cohort will be followed for the 
assessment of safety and tolerability, characterization of PK, and assessment of PD (via EIA). In 
addition to alcohol exposure on Day –1 (prior to administration of study intervention), these 
participants will undergo serial EIAs on Day 4 before being discharged from clinic on Day 5, and at 
6 other times during the 24-week study period. All EIAs will be conducted as in-clinic assessments. 
An SRC will be convened to review available safety data at a predefined decision point (Visit 2, Day 
15) to ensure the safety of the participants in all cohorts. The scope of the review meetings will be 
defined in the SRC charter. In the event that the SRC decides to suspend or interrupt the study, an 
independent DSMC may be convened to review the decision by the SRC and recommend whether 
the study should be stopped, resumed with no changes, or resumed with changes. 
3.2
Endpoints and Associated Variables 
Primary Endpoint 

Incidence and severity of AEs, SAEs, and DLTs 

Changes from baseline in vital signs, 12-lead ECG, clinical laboratory tests, and physical 
examination findings 
Secondary Endpoint 

Plasma PK parameters of DCR-AUD 

Urine PK parameters of DCR-AUD 

Change in PD biomarkers during standardized EIAs 
o
Quantitative assessment of 6 symptom responses during EIAs 
o
Plasma acetaldehyde, acetate, and EtOH 
o
Heart rate and facial skin temperature 
o
SEAS 
3.2.1
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 
•
Clinical laboratory tests (hematology, clinical chemistry, coagulation and routine urinalysis 
parameters) 
•
Adverse event (AE) assessments 
•
Dose Limiting Toxicity (DLT) 


 
Dicerna Pharmaceuticals, Inc.  
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                                                Statistical Analysis Plan 
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•
Concomitant medication assessments 
•
Complement Panel 
•
SARS-CoV-2 
3.2.2
Pharmacokinetic Variables 
Pharmacokinetic concentration data will be obtained at time points described in the protocol version 
6.0 as follows: 
Plasma PK concentrations of DCR-AUD will be determined at the following nominal times: 0 (before 
study intervention administration) and at 15 and 30 minutes and 1, 2, 4, 6, 8, 24, 48, 72 hours and on 
day 15±2 after the SC injection. 
Urine samples will be collected to measure urine concentrations of DCR-AUD at following nominal 
times: 4 hour (sample from pooled urine collection in period 0 - 4 hours after dosing), 8 hour (sample 
from pooled urine collection in period 4 - 8 hours after dosing), 12 hour (sample from pooled urine 
collection in period 8 -12 hours after dosing), 24 hour (sample from pooled urine collection in period 
12 - 24 hours after dosing), 48 hour (sample from pooled urine collection in period 24 - 48 hours after 
dosing), and 72 hour (sample from pooled urine collection in period 48 - 72 hours after dosing). 
Derivation of PK parameters will be the responsibility of Clinical Pharmacology, Modeling and 
Simulation (CPMS) group, 
 under supervision of Dicerna Pharmaceuticals, Inc. The details 
about PK parameter derivation and creation of Tables Listings and Figures related to PK will be 
described in this SAP. 
If calculable, the following PK parameters listed in Table 3-1 will be determined for DCR-AUD in 
plasma following single subcutaneous dose administration.  
Table 3-1 Plasma Pharmacokinetic Parameters of DCR-AUD After Single Subcutaneous Dose 
Administration
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
tlast
Tlast 
TLST 
t½
HL_Lambda_z 
LAMZHL 
Apparent terminal elimination half-life 
λz 
Lambda_z 
LAMZ 
Terminal elimination rate constant 


 
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Parameter 
WNL  
Name 
CDISC 
Name 
Definition 
AUC0-last
AUClast 
AUCLST 
AUC from time zero to the last 
quantifiable concentration 
AUC0-t
AUCT 
AUCINT(0-
X) 
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
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. 
All urine samples will be collected in the following intervals, 0-4, >4-8, >8-12, >12-24, >24-48, and 
>48-72 hours. Urine concentrations (Cur0-4, Cur4-8, Cur8-12, Cur12-24, Cur24-48, Cur48-72) and 
volume of urine collected (Vur0-4, Vur4-8, Vur8-12, Vur12-24, Vur24-48, Vur48-72) in each collection 
interval will be listed in the Urine PK Concentration Listing. The PK parameters listed in Table 3-2 
will be calculated for DCR-AUD in urine following treatment administration. 


 
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Table 3-2 Urine Pharmacokinetic Parameters of DCR-AUD After Single Subcutaneous Dose 
Administration
Protocol 
Parameter
WNL Name 
CDISC Name 
Definition 
Aet1-t2
Amount Recovered 
RCAMINT 
Amount of unchanged drug excreted in 
urine at each interval collection (t1 to t2), 
e.g. 0-4, >4-8, >8-12, >12-24, >24-48, and 
>48-72 (e.g. Ae0-4, Ae4-8, Ae8-12, Ae12-24, 
Ae24-48, Ae48-72 ). 
Ae0-t 
Amount_Recovered
RCAMINT 
Cumulative amount of unchanged drug 
excreted at a given time up to t hours, 
where t is 4, 8, 12 or 24, 48, 72 hours (e.g. 
Ae0-4, Ae0-8, Ae0-12, Ae0-24, Ae0-48, Ae0-72) 
Fe%0-t
Percent_Recovered 
RCPCINT 
Urinary cumulative excretion as % of 
unchanged drug up to t hours, where t is 4, 
8, 12, 24, 48, or 72 hours, (e.g. Fe0-4, Fe0-8, 
Fe0-12, Fe0-24, Fe0-48, Fe0-72) 
CLR 
CLR@ 
RENALCL 
Renal clearance of the drug from plasma 
@Obtained through additional calculations in WNL outside of NCA model, as described in Table 4-1. 
3.2.3
Pharmacodynamic Variables 
To assess the effect of DCR-AUD on pharmacodynamic (PD) variables using blood biomarkers 
(alcohol, acetaldehyde, and acetate), blood samples will be collected at the times specified in the 
Schedule of Assessments. The PD biomarker variables to be estimated will be Tmax, Cmax, and 
AUC0-2.5h by dose cohorts and EIA days which can be calculated using the same methods as the 
correspondent PK parameters described in Table 3-1. Objective physiological biomarkers (heart 
rate and facial skin temperature) will also be assessed at the times specified in the Schedule of 
Assessments. Participants’ subjective experience of the effects of alcohol will be assessed using the 
Subjective Effects of Alcohol Scale (SEAS). 
Each cohort will have a sentinel group (n=3) that does not undergo any EIA assessment. 
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. In addition, a 
descriptive quantitative evaluation of 6 symptoms actively assessed at each of 4 time points during 
EIA challenges will be included.  
Drug effect model will be used to derive the PD parameters listed in table below using Phoenix 
version 8.3 or higher. Derivation of these PD parameters will be the responsibility of CPMS group. 
The details of PD parameters are provided in Table 3-3. 


 
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Table 3-3 Plasma Pharmacodynamic Parameters of DCR-AUD After Single Subcutaneous 
Dose Administration
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 the 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) 
AUC0-2.5h
AUCT 
Area under the curve from time 0 to 2.5 hours (for 
acetaldehyde, acetate, and alcohol)  
3.2.4
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. 
3.2.5
Efficacy Variables 
Not Applicable. 
3.2.6
Exploratory Variables 
Not Applicable.    
4
STATISTICAL METHODS 
4.1
Data Quality Assurance 
All tables, figures, and data listings (except PK data) to be included in the report will be independently 
checked for consistency, integrity, and in accordance with Standard Operating Procedures (SOPs) of 
. 
4.2
General Presentation Considerations 
The participants, who received “Placebo” in Cohort 1 to 4, will be pooled into a single placebo group 
(Pooled Placebo) for all summaries and presentation related to PD variables and safety for this study. 
The PK outputs will be generated for DCR-AUD by each dose cohort, as applicable. 


 
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4.2.1
Treatment 
Cohort 1: 80 mg, 
Cohort 2: 240 mg, 
Cohort 3: 480 mg, 
Cohort 4: 960 mg, 
Pooled Placebo  
4.2.2
Baseline 
Baseline is defined as the last non-missing measurement prior to the date and time of the dose of 
study intervention (Day -1). 
4.2.3
End of Study
‘End of Study’ for a participant is defined as the last available post-treatment assessment. 
4.2.4
Study Day 
Study days will be numbered relative to the first day of study drug administration. 

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] in each period)

If the date of event is on or after the study drug administration, then: 
Study day = (Date of measurement – Date of study drug administration [i.e. Day 1] in each period) + 
1 
4.2.5
Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment  
This section is not applicable for PK data. 
Repeat, retest, and unscheduled assessment will not be considered for the calculation of summary 
statistics and figures, unless assessment qualifies as baseline. 
The average of controlled and planned (scheduled) assessments 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.  
4.3
Software 
All report outputs will be produced using SAS® version [9.4] or a later version in a secure and 
validated environment.  
The PK and PD blood biomarker 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/PDF format.   
4.3.1
Summary and Representation of Data  
All data will be listed according to the number of decimal places presented in the source data. 
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, inter 
quartile range (IQR), minimum, maximum, and number of observations, unless otherwise stated. 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean, IQR, and median will be reported to one more decimal place 


 
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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 statistic. 
Departure from these general rules will be specified in the output shell document. 
Categorical data will be summarized in terms of the number of participants providing data at the 
relevant time point (n), frequency counts and percentages.  
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts.  
4.4
Analysis Population 
For the purpose of analysis, the following population are defined. 
Enrolled Population: All participants who sign the ICF. 
Randomized Population: All participants who sign the ICF and who are randomly assigned to study 
intervention. 
Safety Population (SP): All participants randomly assigned to study intervention and who receive 
the full dose of study intervention. Participants will be analyzed according to dose received. 
Pharmacokinetic Population (PKP): All participants randomly assigned to study intervention and 
who receive a full dose of DCR-AUD and have sufficient data for at least 1 postdose PK assessment. 
Pharmacodynamic Population (PP): All participants randomly assigned to study intervention and 
who receive a full dose of study intervention and have sufficient data for at least 1 postdose PD 
assessment. 
4.5
Study Participants 
4.5.1
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 enrolled population. 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 enrolled population. The 
listing will include dose 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 randomized population. 
4.5.2
Protocol Deviations 
All protocol deviations are predefined in the separate document, Protocol Deviation Specification. 
4.5.2.1
Protocol Deviations with PK Implications 
Protocol deviations that may potentially impact PK parameter deviations include, but are not limited 
to: 

SC administration deviations – interruption of administration, etc. 


 
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
Missed PK samples that impact estimation of PK parameter(s) 

Concomitant medications not authorized by protocol 

PK samples obtained out of allowance window that may impact the estimation of PK 
parameter(s) 
4.5.2.2
Protocol Deviations with Non-PK Implications 
The defined protocol deviations will be collected during the study period by the 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.  
Protocol deviations (mentioned in Sections 4.5.2.1 and 4.5.2.2) and analysis population will be 
reviewed in the data review report meeting to decide on the inclusion or exclusion of participant(s) 
from the analysis sets. 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. 
Post database lock and based on PK and PD data availability all Analysis Datasets and TLFs related 
to PK and PD analysis set will be created and discussed with the sponsor in the data review meeting 
post DBL. Data review meeting minutes will be documented as an update to DRR minutes and 
approved by sponsor and 
 team. 
A by-participant listing of major and minor protocol deviations will be provided including participant 
identifier, exclusion from specific analysis population, and protocol deviation classification and 
description. 
All protocol deviations will be listed by participant for the randomized population. Protocol 
Deviations related to COVID-19 will be listed separately. 
A summary table of major protocol deviations by cohort, treatment, pooled placebo, and overall will 
also be provided for randomized population. 
4.6
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 cohort, treatment, 
pooled placebo, and overall, for the SP.  
4.7
Medical History and Concomitant Illnesses 
Medical history data will be summarized by cohort, treatment, pooled placebo, and overall for the SP 
and listed by participant including visit, description of the disease/procedure, Medical Dictionary for 
Regulatory Activities (MedDRA Version 25.1 or latest) system organ class (SOC), MedDRA 
preferred term, start date, and stop date (or ongoing if applicable). 
4.8
Prior and Concomitant Medications 
Medication start and stop dates will be compared to the date of study drug administration to allow 
medications to be classified as either Prior only, both Prior and Concomitant, or Concomitant only.  


 
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Medications starting after the completion/withdrawal date will be listed but will not be classified or 
summarized. 
Prior medications are those that started and stopped prior to the study drug administration.  
Concomitant medications are those taken before or after study drug administration (including 
medications that started prior to dosing and continued after) and up to end of trial. 
If a medication starts before the date of study drug administration and stops on or after the study drug 
administration, then the medication will be classified as both Prior and Concomitant.   
If missing data prevents the medication being classified as prior or concomitant, the medication will 
be considered as concomitant for the data listings. 
Prior and concomitant medication will be coded according to the World Health Organization Drug 
Dictionary (WHO-DD) (Version Sep, 2022 B3, or latest) and will be classified by Anatomical 
Therapeutic Chemical (ATC) categories. 
Prior and concomitant medications will be summarized based on SP and will be listed by participant 
and will include the following information: reported name, preferred term, the route of administration, 
dose, frequency, start date/time, end date/time and indication. 
4.9
Treatment Exposure  
A listing of DCR-AUD administration will be created and will include the dose cohort, treatment 
received, date and time of administration, dose (unit), dose form, route of administration. 
A summary table for DCR-AUD administration will also be provided based on SP. 
4.10 Pharmacokinetics Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacokinetic Parameters for Final Analysis 
4.10.1 Pharmacokinetic Concentrations 
Concentration Listings:  
Pharmacokinetic concentration data for DCR-AUD, will be listed by dose cohort (80 mg, 240 mg, 
480 mg, and 960 mg), timepoint, 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 and urine 
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 considered 
excluded from PK analysis.  
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 subjects who 
received treatment), n (number of subjects with non-missing values), and n(BLQ) (the number of 
subjects with BLQ samples). 
Concentration for DCR-AUD and will be summarized by dose cohort, and nominal timepoint with 
descriptive statistics for the PKP.  The following descriptive statistics will be presented for plasma 
and/or urine 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-


 
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1)*100; where s is the SD of the log-transformed values), median, IQR, minimum, and maximum 
values.  
For summary tables, all BLQs will be considered zero, except for presentation of the geometric mean 
and geometric CV, which will use ½ the LLOQ. 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 reported 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. capped at 3 
Mean/SD/Median/Geomean
n s.f. capped at 3 
CV%/gCV%
n s.f. capped 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 geometric mean linear/linear graphs, all BLQ values will be substituted with ½ the LLOQ for 
calculation of geometric mean and for log/linear graphs the log transformed geometric mean will be 
displayed. 
For individual linear/linear and log/linear graphs all BLQ values will be substituted as follows: 

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. 

BLQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing. 

Single BLQs which fall between two measurable concentrations will be set to missing.  

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 dose cohorts, the 
descriptive PK graphs listed below will be generated

Figure x.x.x: Individual participant profiles for DCR-AUD Plasma Concentration Time Data by 
dose cohort – (Linear Scale and Semi-Logarithmic Scale) (SP)  

Figure x.x.x: Mean (± SD) DCR-AUD Plasma Concentration Time Data – (Linear Scale and 
Semi-Logarithmic Scale) by (dose cohort) (PKP) 

Figure x.x.x: Overlaid individual participant profiles for DCR-AUD Plasma Concentration Time 
Data by dose cohort – (Linear Scale and Semi-Logarithmic Scale) (SP)


 
Dicerna Pharmaceuticals, Inc.  
DCR-AUD-101 
                                                Statistical Analysis Plan 
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
Figure x.x.x: Mean (± SD) Cumulative Amount of DCR-AUD in Urine Versus Time by dose 
cohort (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).  
4.10.2 Pharmacokinetic Parameters 
PK parameters will be provided by CPMS group at 
. PK parameters of DCR-AUD, will be 
calculated by NCA methods from the concentration-time data using Phoenix® WinNonlin® Version 
8.3 or higher following these guidelines: The Phoenix WinNonlin project file including all settings 
and analysis input file will be transferred to Dicerna when the PK analyses are completed.  

Actual time from single SC dose will be used in the calculation of all derived pharmacokinetic 
parameters, except when parameters are calculated for safety/dose escalation meetings when 
nominal times may be used to calculate PK parameters.   

There will be no imputation of missing data.  

Handling of BLQ samples for 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. 

BLQs in urine samples will be assigned to zero. 
Pharmacokinetic parameters will be estimated according to the guidelines presented in Table 4-1. 
Table 4-1  
Pharmacokinetic Parameter and Estimation 
Parameter 
Guideline for Derivation 
Cmax, Cmin, tmax, 
Clast 
Obtained directly from the observed concentration-time data 
AUC0-last (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: 
AUC0-t=∫𝐶last ∗𝑑𝑡
t
0
AUC0-inf
The area from zero time extrapolated to infinite time will be calculated as follows:  
AUC0-inf = AUC0-t+
𝐶last
𝜆𝑧
where Clast is the last observed quantifiable concentration. 


 
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Parameter 
Guideline for Derivation 
%AUCex
The percentage of AUC0-inf obtained by extrapolation will be calculated as follows:  
%AUCex =
AUC0-inf  ꟷ𝐴𝑈𝐶0-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 (ie, AUC0-inf, MRT, Vz and CL) will be flagged in listings and excluded from 
summary tables and statistical analysis of PK parameters, unless instructed otherwise by the 
Sponsor. 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 <0.85, then λz and all the λz dependent 
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 (based 
on sponsor specific requirements) 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 identified in the study report with a 
rationale for exclusion.
CL/F 
Following SC administration, systemic clearance of parent drug will be calculated 
from:  
CL = 
Dose
AUC0-inf
Apparent clearance (CL/F) following SC dosing will be calculated. 
Vz/F 
Volume of distribution at terminal phase following SC dosing will be calculated from: 
Vz/F = 
Dose
λz×AUC0-inf = (CL/F)/ z 
CLR
Renal clearance will be calculated from the ratio of the appropriate values for urinary 
recovery and area under the concentration-time curve. Depending on the actual data, 
the "x" will be determined in the PK section of the CSR.


 
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Parameter 
Guideline for Derivation 
CLR = 
)
0
(
)
0
(
x
x
AUC
Ae


Ae
Amount of unchanged drug recovered in urine is calculated as  
Ae = Urine drug concentration * urine volume 
This is calculated for each urine collection interval and then summed for the cumulative Ae. 
Fe% 
The percent of drug recovered in urine is calculated as  
Fe = 100 * Ae/Dose 
This is calculated for each urine collection interval and then summed for the cumulative Fe%. 
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: 
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 dose cohort with descriptive statistics for the PKP. 
Tabular summaries for PK parameters will report N (number of subjects who received treatment) and 
n (number of subjects with non-missing values). 
Descriptive statistics for calculated PK parameters will include N, n, arithmetic mean, SD, CV%, 
geometric mean, gCV%, median, IQR, minimum, and maximum values. For tmax, only N, n, median,  
minimum, 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
3 s.f. 
p-values
4 d.p. 
N/n
Whole number 
Exceptions for PK Tables 


 
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tmax individuals and min/max
Determined based on the raw data for timing) 
tmax median only
Determined based on the raw data for timing 
s.f = significant figures, d.p. = decimal place
4.10.3 Pharmacokinetic Analysis 
Assessment of Dose Proportionality 
Dose proportionality will be assessed for Cmax, and AUC0-last (or AUC0-t), or AUC0-inf of DCR-AUD 
in the dose range of 80 mg to 960 mg using a power model. AUC0-inf will also be evaluated if AUC0-
inf is evaluable for >80% of participants.        
Individual PK parameter values will be used to perform a least-squares linear regression analysis, 
using the formula log_pkvar=A log_dose + B, where ‘log_pkvar’ represents the natural log 
transformed Cmax, and AUC0-last or AUC0-inf ‘log_dose’ represents the natural log transformed dose. 
An estimate of the slope of the regression line and corresponding 95% confidence interval (CI) will 
be obtained. 
The following sample SAS code will be used: 
PROC REG DATA=pkparam alpha=0.05; 
MODEL log_pkvar = log_dose / CLB; 
RUN; 
Where, CLB = 100(1 - α)% confidence limits for the parameter estimates. 
For each of the parameters Cmax and AUC0-last, or AUC0-inf  a plot of the log-transformed concentration 
against the log-transformed dose will be constructed including the fitted line from the linear 
regression and the line of unity. 
Dose proportionality will be declared when the 90% CI for A lies completely within the critical region 
defined as: 
1 + ln (θ𝐿)
ln (𝑟) , 1 + ln (θ𝐻)
ln (𝑟)
r: ratio of the highest to lowest administered doses 
θL = the lowest critical limit of the ratio of dose-normalized mean values (Rdnm); and 
θH = the upper critical limit of Rdnm. 
PK dose proportionality will be concluded if the 90% C.I. of A for Cmax, and AUC0-last or AUC0-inf
are entirely contained within the following bounds that depend on the dose range ratio (SmithBP, 
2000) [2] (i.e., ln (960/80) = ln (12)): 

Lower bound = 1+ln (0.80)/ln (12) = 0.9102 and 

Upper bound = 1+ln (1.25)/ln (12) = 1.0898 
If dose proportionality is not declared for any of the PK parameters by smith criteria (θL=0.8, 
θH=1.25), 90% CI for A would be compared to a less stringent critical region based on (θL=0.5, θH=2) 
(Hummel, 2006) [3]. 


 
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                                                Statistical Analysis Plan 
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
Lower bound = 1+ln (0.50)/ln (12) = 0.7211 and 

Upper bound = 1+ln (2)/ln (12) = 1.2789  
4.11 Pharmacodynamics Analysis, Concentration, and Parameter TFLs, and Statistical 
Analysis of Pharmacodynamic Parameters 
Individual participant’s biomarker (acetaldehyde, acetate, and ethanol) plasma concentration values 
both unadjusted and adjusted for baseline, will be provided by Frontage Laboratories.  Baseline 
unadjusted and adjusted acetaldehyde, acetate, and ethanol concentration values will be listed by dose 
cohort, timepoint, EIA days, and participant for the PP. 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, see 
Table 6-1. A by participant listing of ALDH2 genetic mutation will also be provided. For the 
biomarker concentration summary tables, descriptive statistics (N, n, arithmetic mean, SD, CV%, 
geometric mean, gCV%, median, IQR, minimum, and maximum values) will be presented by dose 
cohort (placebo, 80 mg, 240 mg, 480 mg, and 960 mg), with and without the subjects with ALDH2 
mutant(s), nominal timepoint, and EIA days. For time variables only median, Tmin and Tmax will be 
presented. 
To visualize the comparison between dose cohorts the descriptive biomarker graphs will be generated. 

Figure x.x.x: Individual Participant Profiles for acetaldehyde, acetate, and ethanol, Plasma 
Concentration Time Data (Unadjusted and Adjusted for Baseline) by dose cohort and EIA day 
(SP) 

Figure x.x.x: Overlaid Individual Participant Profiles for acetaldehyde, acetate, and ethanol 
Plasma Concentration Time Data (Unadjusted and Adjusted for Baseline) by dose cohort and 
EIA day (SP) 

Figure x.x.x: Mean (± SD) baseline adjusted acetaldehyde, acetate, and ethanol Plasma 
Concentration Time Data by dose cohort and EIA day (PP) 

Figure x.x.x: Mean (± SD) baseline adjusted acetaldehyde, acetate, and ethanol Plasma 
Concentration Time Data by dose cohort and EIA day (PP) and with and without the subjects 
with ALDH2 Mutant 

Figure x.x.x:  The Mean (± SD) baseline unadjusted acetaldehyde, acetate, and ethanol Plasma 
Concentration Time profiles by dose cohorts and EIA days (PP) 

Figure x.x.x:  The Mean (± SD) baseline unadjusted acetaldehyde, acetate, and ethanol Plasma 
Concentration Time profiles by dose cohorts and EIA days (PP) with and without the subjects 
with ALDH2 Mutant 

Figure x.x.x: The mean (± SD) Cmax (in the units of µM and ng/mL) and AUC0-2.5h (in the unit of 
ng*h/mL) of acetaldehyde, acetate, and ethanol following 4 Alcohol Drinks in 30 Minutes and 
Single Dose Administration of DCR AUD in Healthy Adults will be plotted with EIA days by 
dose cohorts (PP) 

Figure x.x.x: The mean (± SD) Cmax (in the units of µM and ng/mL) and AUC0-2.5h (in the unit of 
ng*h/mL) of acetaldehyde, acetate, and ethanol following 4 Alcohol Drinks in 30 Minutes and 


 
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DCR-AUD-101 
                                                Statistical Analysis Plan 
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Single Dose Administration of DCR AUD in Healthy Adults with and without ALDH2 Mutant(s) 
will be plotted with EIA days by dose cohorts  (PP) 
For each figure, subjects belonging to each category will be shown on the same plot with separate 
figures for each level of dose.  Participant level figures will use actual time, while mean plots will 
use planned time, except for predose time point(s), where time 0 will be used rather than actual time.  
All placebo data will be put into one group in the figures regardless of dose cohort. 
4.11.1 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 plasma biomarkers (alcohol, acetaldehyde, and 
acetate), assessment of 6 symptoms and their severity induced during EIAs, and objective 
physiological responses (heart rate and facial skin temperature). Participants’ subjective experience 
of the effects of alcohol will be assessed using the SEAS. 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 described in Section 2.2.3 for
alcohol, acetaldehyde, and acetate unadjusted and adjusted for baseline will be estimated for each 
cohort dose, with and without the subjects with ALDH2 mutant(s), and pooled placebo. 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. Descriptive statistics (number, 
arithmetic mean, SD, CV%, geometric mean, gCV%, median, IQR, minimum, and maximum) of 
adjusted and unadjusted parameters will be presented by dose cohort, with and without the subjects 
with ALDH2 mutant(s) and pooled placebo.  For time variables only median, Tmin and Tmax will be 
presented. 
To visualize the comparison between dose cohort following alcohol consumption the Cmax and AUC0-
2.5h parameters will be plotted as described in Section 4.11.
All placebo data will be put into one group in the figures regardless of dose cohort. Two-way ANOVA 
will be performed to compare the Cmax and AUC of the biomarkers between the treatment cohorts 
and placebo group on the EIA days. 
4.11.1.1 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 


 
Dicerna Pharmaceuticals, Inc.  
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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 will be given a composite 
score for that timepoint as sum of all six symptom scores.   
Baseline is defined as last non-missing value prior to alcohol administration. 
Descriptive statistics of EIA composite score (n, mean, median, IQR, minimum and maximum) for 
absolute values and changes from baseline will be presented by dose cohort, Pooled DCR-AUD, 
pooled placebo, visit and EIA time point. 
Descriptive statistics of 6 symptom EIA assessment (n, mean, median, IQR, minimum and maximum) 
for Total Scores, Peak post-alcohol administration Composite Score, Cmax acetaldehyde, 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 subject on day -1,  Delta 3: The highest score attained by 
that subject in Delta 1 over all 6 tests after DCR-AUD was administered will be presented by dose 
cohort, pooled DCR-AUD, pooled placebo, and EIA Days/timepoint. 
Peak EIA composite score for each subject at each EIA is defined as the highest post-dose composite 
score selected from the 3 post alcohol administration time points for that EIA. 
To visualize subject-level composite score and the comparison between each cohort 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 cohort, (SP) 

Figure xx.1: Combined Individual DCR-AUD and placebo Peak EIA composite score-Visit 
(Days) Profiles (Linear Scale) by Treatment cohort, (SP) 
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 using the SEAS. Adverse events, vital signs, and ECG will also be monitored and 
recorded for safety. 
In addition to above plots, following plots will also be generated: 
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 for that cohort (i.e. On day of EIA challenge before 
IMP was administered) 
(It is expected that most subjects 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 


 
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DCR-AUD-101 
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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 subject 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.)    
4.11.1.2 PD Biomarkers for EIA 
4.11.1.2.1 EIA Blood Biomarkers 
Plasma biomarkers to be assessed include measurement of acetaldehyde, acetate, and ethanol. Blood 
samples (maximum 32 mL/day) will be collected via a venous access device immediately prior to 
EtOH consumption (time 0) and at 15, 30, 45, 60, 90, 120, and 150 minutes post dose. 
A by-patient 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, dose cohort, with and 
without the subjects with ALDH2 mutant(s) and pooled 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. 
EIA related plots are described in Section 4.11.  
To compare the Cmax and AUC0-2.5h of the biomarkers between the active treatment doses and placebo 
on the EIA days, two-way ANOVA will be performed for participants with and without ALDH2 
mutant(s): 

80mg vs Placebo 

240mg vs Placebo 

480mg vs Placebo 

960mg vs Placebo 
Primary PK parameters will be separately analyzed (Two-way ANOVA) using a mixed effects model. 
The dependent variable will be the ln-transformed primary PK parameters (Cmax and AUC0-2.5h) and 
the independent variables will include fixed effects for treatment and participant as a random effect. 
Geometric least-squares means for each treatment dose, point estimates and associated 90% CIs for 
the ratios for each primary PK parameter will be produced in tabular format. This will be anti-log 
transformed to obtain the point estimates and the 90% CI for the geometric mean ratio on the original 
scale. 
Sample SAS Code: 


 
Dicerna Pharmaceuticals, Inc.  
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ODS SELECT NOPRINT(NOWARN); 
                ODS OUTPUT CovParms= Cv1 lsmeans=lsm estimates=est Diffs=diff1; 
                PROC MIXED DATA=DATA1 NOITPRINT; 
                BY COMPOUND ANALYTE PPSPEC PARAMN PARAMCD PARAM; 
                CLASS SUBJID TRTA; 
                MODEL LN_PK = TRTA/DDFM=KR; 
                RANDOM SUBJID ; 
                LSMEANS TRTA/PDIFF ALPHA=0.10 CL; 
                ESTIMATE “DCR-AUD vs PLACEBO” TRTA 1 -1 /CL ALPHA=0.10; 
                RUN; 
where: 
COMPOUND: compound used in the study 
ANALYTE : analyte of the drug (can be parent or metabolite) 
PPSPEC : Specification (e.g. Plasma/Urine/CSF) 
PARAMN : numerical order of PK parameter 
PARAMCD :short name of PK parameter 
PARAM: PK parameter  
LN_PK; natural log transformed value of PK parameter 
SUBJID: Participant 
TRTA: actual treatment 
4.11.1.2.2 EIA Physiological Responses 
Heart rate and facial Skin temperature: 
EIA assessments will include measurement of heart rate and facial skin temperature. Facial skin 
temperature will be measured using a surface scanning thermometer. Heart rate will be monitored by 
telemetry during the EIAs. Site personnel will be provided training in the use of all study-specific 
instruments (see the Study Reference Manual). 
Heart rate, using telemetry, and facial skin temperature will be collected immediately pre dose (time 
0) and at 15, 30, 45, 60, 90, 120, and 150 minutes post dose. 
A by-participant listing of EIA physiological responses will be presented. 
Descriptive statistics of Peak Heart rate and Facial skin temperature (n, mean, SD, median, IQR, 
minimum and maximum) for peak absolute values and peak changes from baseline will be presented 
by active dose cohort, pooled DCR-AUD, pooled placebo, and visit/timepoint. 


 
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Peak EIA Heart rate/Facial skin temperature is defined as maximum recorded Heart rate/Facial ski 
temperature from pre-alcohol administration baseline for each visit/timepoint. 
4.11.1.2.3 EIA Subjective Effects of Alcohol Scale 
For each EIA, participants will complete the SEAS pre dose (during the Rest Period) and at 30, 60, 
90, 120, and 150 minutes post dose. The SEAS is a 14-item tool that allows participants to rate the 
subjective effects of alcohol. Participants will rate the extent to which they are feeling each of the 
effects in the present time. 
Table 4-2 Subjective Effects of Alcohol Scale (SEAS)  
Factor 
Feeling 
Not at All 
Moderately 
Extremely 
High Arousal Negative 
Demanding 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Rude 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Aggressive 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
High Arousal Positive 
Woozy 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Dizzy 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Wobbly 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
High Arousal Positive 
Fun 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Lively 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Funny 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Talkative 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
High Arousal Positive 
Mellow 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Secure 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Relaxed 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Calm 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
A by-participant listing of SEAS feeling categories will be presented. 
A summary table will be presented by factored “feeling” category, visit, time point, active dose 
cohort, pooled DCR-AUD, and pooled placebo in PD population. 
4.11.2 Immunogenicity  
The ADA samples collected in this study will be stored and analyzed in the future. 
4.12 Safety Evaluation 
All safety summaries and analyses will be 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, DLT, and ECG parameters will 
be evaluated as following (mentioned in section 4.12.1 to section 4.12.9). 


 
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4.12.1 Adverse Events 
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. 
Concomitant illnesses, which existed before entry into the clinical study, will not be considered AEs 
unless they worsen during the treatment period. Pre-existing conditions will be recorded as part of 
the participant’s medical history. 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in 
severity after the study drug has been administered. 
Adverse Events of Special Interest 
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. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.1 or higher and CTCAE Version 5.0. 
Unless specified otherwise, all adverse event summaries will include the TEAEs only. 
The following summaries will be presented: 

A table of number (percentage) of participants with adverse events and number of adverse 
events with an overview of treatment emergent adverse events (TEAE), related TEAEs, SAE, 
potential DLT AE leading to discontinuation and AE leading to death will be presented by  
cohort, treatment, pooled placebo and overall. 

A table of number (percentage) of participants with treatment emergent adverse events and 
number of treatment emergent adverse events (TEAE), and SAE summarized by SOC and 
PT, cohort, treatment, pooled placebo and overall. This table will be sorted by decreasing 
frequency of the overall column. 

A table of number (percentage) of participants with treatment emergent adverse events and 
number of treatment emergent adverse events (TEAE) summarized by SOC, PT, relationship, 
cohort, treatment, pooled placebo and overall. If more than one event with the same preferred 
term occurred for the same participant, then the participant was counted only once for that 
preferred term under the strongest causality. This table will be sorted by decreasing frequency 
of the overall column. 


 
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
A table of number (percentage) of participants with treatment emergent adverse events and 
number of TEAE summarized by SOC, PT, maximum severity, cohort, treatment, pooled 
placebo and overall will be presented. If more than one event occurred with the same preferred 
term for the same participant, then the participant was counted only once for maximum 
severity level of that preferred term for the summarization of severity. This table will be sorted 
by decreasing frequency of the overall column. 

A table of number (percentage) of participants with adverse events leading to discontinuation 
summarized by cohort, treatment, pooled placebo and overall. This table will be sorted by 
decreasing frequency of the overall column. 

A table of number (percentage) of participants with adverse events leading to death 
summarized by cohort, treatment, pooled placebo and overall. This table will be sorted by 
decreasing frequency of the overall column. 

A table of number (percentage) of participants with adverse events of special interest and 
number of adverse events of special interest (AESI) summarized by SOC and PT, cohort, 
treatment, pooled placebo and overall. This table will be sorted by decreasing frequency of 
the overall column. 

A table of number (percentage) of participants with adverse events and number of treatment 
emergent adverse events (TEAE) summarized by SOC, PT, relationship with EIA, cohort, 
treatment, pooled placebo and overall. If more than one event with the same preferred term 
occurred for the same participant, then the participant was counted only once for that preferred 
term under the strongest causality. This table will be sorted by decreasing frequency of the 
overall column. 
A listing will be created for all Adverse Events (AEs), which will include treatment received, 
Verbatim term, preferred term (PT), system organ class (SOC), AE onset date (and time), AE end 
date (and time), counter measure taken on AE, relationship to study drug, AE outcome, severity, 
frequency, concomitant medication (if administered), TEAE indicator flag, SAE indicator flag, DLT 
indicator flag. 
4.12.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 

A by-participant listing of all deaths that occurred during the study 

A by-participant listing of all SAEs 

A by-participant listing of all AES leading to discontinuation from the study 

A by-participant listing of all other significant AEs. 
4.12.3 Clinical Laboratory Evaluation 
Hematology:  

Red blood cell count (hemoglobin, hematocrit, reticulocytes, platelet count). 

Only at Days -1, 4, 29, 85, and 169 
o
mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC) 

White blood cell count 


 
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
Only at Days -1, 4, 29, 85, and 169 
o
lymphocytes, abs and %, monocytes, abs and %, eosinophils, abs and %, neutrophils, 
abs and %, basophils, abs and % 
Clinical Chemistry: alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl 
transferase (GGT), alkaline phosphatase (ALP), bilirubin (total and direct), lactate dehydrogenase 
(LDH), total, protein, albumin, creatine kinase (CK), sodium, chloride, potassium, creatinine, blood 
urea nitrogen (BUN), fasting blood glucose. 
Routine Urinalysis: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick, microscopic examination (if blood or protein is abnormal). 
Coagulation: International normalized ratio (INR), PT, PTT 
Complement Panel: Bb, C3a, C5a. 
Other Screening Test: 

Alcohol breath test 

Rapid SARS-CoV-2 (local laboratory testing) 

Follicle-stimulating hormone (as needed in women of non-childbearing potential only) 

Highly sensitive (urine; serum for confirmation if needed) human chorionic gonadotropin 
(hCG) pregnancy test (as needed for WOCBP). Any positive urine pregnancy test will be 
confirmed with a serum pregnancy test. 

Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
and benzodiazepines) 

Viral serology (human immunodeficiency virus antibody, hepatitis B surface antigen, and 
hepatitis C virus antibody) 
Laboratory values (Observed and change from baseline) (hematology, clinical chemistry urinalysis, 
coagulation and complement panel) will be listed by participant and summarized by time point,  
cohort, treatment , and pooled placebo. The baseline for the laboratory values will be defined as the 
last non-missing measurement prior to the date and time of the dose of study intervention. Laboratory 
values (routine urinalysis, complement panel, coagulation and other screening test) will be listed by 
participant. 
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal 
values will be flagged with ‘L’ for values below the lower limit of the clinical reference range and 
‘H’ for values above the upper limit of the clinical reference range and included in the listings. The 
Investigator will assess whether the values outside the clinical reference range are clinically 
significant, and these will be reported as abnormal not clinically significant (NCS) or abnormal 
clinically significant (CS).  
Shift tables will be presented for select laboratory parameters (chemistry and hematology). 
4.12.4 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 


 
Dicerna Pharmaceuticals, Inc.  
DCR-AUD-101 
                                                Statistical Analysis Plan 
TP-GDO-WW-133-02 
 
Project Document Version No. 2.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
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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. The baseline for the 
vital signs measurements will be defined as the last non-missing measurement prior to the date and 
time of the dose of study intervention. 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 cohort, treatment, and pooled placebo and time-point. 
4.12.5 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. 

Investigators should pay special attention to clinical signs related to previous serious 
illnesses or AEs. 

All physical examinations should include inspection of the injection site. 

Abnormal physical examination findings will be listed. 
4.12.6 Alcohol Consumption via Timeline Follow Back 
Study participants are to refrain from drinking alcohol throughout the outpatient portion of the study 
(sentinel participants will refrain from alcohol throughout the in-clinic portion as well). At every visit, 
the TLFB (Timeline Follow Back) will be used to assess each participant’s abstention from alcohol 
since the previous visit. The TLFB was developed as a procedure to aid recall of past drinking. 
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., biochemical indicators or blood alcohol tests). Consequently, there is no practical 
alternative technology other than self-reports for retrospectively assessing drinking. TLFB stands as 
the most exhaustively evaluated method that can be used for this purpose. 
Alcohol Consumption via Timeline Follow Back will be summarized and listed by cohort and visit. 
4.12.7 Columbia-Suicide Severity Rating Scale 
The C-SSRS is a suicidal ideation rating scale created by researchers at Columbia University. It 
measures an individual's degree of suicidal ideation and behaviour. 
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. 
The Baseline version will be administered at Screening and at subsequent visits the “C-SSRS Since 
Last Visit” version will be administered. 
C-SSRS will be listed by participant. 


 
Dicerna Pharmaceuticals, Inc.  
DCR-AUD-101 
                                                Statistical Analysis Plan 
TP-GDO-WW-133-02 
 
Project Document Version No. 2.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 37 of 46 
4.12.8 Dose Limiting Toxicities 
A DLT is defined as: 

an AE of ≥ Grade 3 intensity (CTCAE Version 5.0) in one participant, unless it is clearly the 
result of a non-study-related event OR 

any 2 AEs of ≥ Grade 2 intensity in the same body system in one participant. 
DLT will be summarized as follows: 

A table of number (percentage) of participants with treatment emergent adverse events and 
number of treatment emergent adverse events (TEAE) summarized by cohort, treatment, 
pooled placebo and overall.  
4.12.9  ECG 
Standard safety 12-lead ECGs will be performed as shown in the Table 6-3 Schedule of Activities. 
The following ECG parameters will be recorded: 

RR-interval (msec).

QRS-interval (msec) 

PR-interval (msec) 

QT-interval (msec) 

QTc-interval (msec) 

QT-interval corrected using the Fridericia correction formula (QTcF) (msec) 

Heart rate (HR) (beats per minute [bpm]) 
For QTcF, QT will be corrected as:  
QTcF = 
𝑄𝑇
𝑅𝑅
1
3
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or ‘Abnormal, CS’. 
All ECG parameters will be listed by participant for each dose cohort and time point including 
changes from baseline.  
Baseline is defined as the last non-missing measurement prior to the date and time of the dose of 
study intervention. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes 
from baseline will be presented by cohort, treatment, pooled placebo, and time point.  
A summary of the number and percentage of participants with QT/QTc intervals exceeding some 
predefined upper limits (e.g. >450ms, >480ms, >500ms for measured values as well as. >30ms, 
>60ms for changes from baseline) of ECG parameters will be displayed in a frequency table. 
4.13 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 across all cohorts, approximately every  2 
months 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 and to determine dose advancement from sentinel to expanded and 
for dose escalation to next cohort throughout the study. 
Details about the SRC will be provided in the SRC charter Version 1.0 dated Aug 12, 2021. 


 
Dicer n a P har mace uticals, I nc.  
D C R- A U D- 1 0 1 
                                                Statistical A nal ysis Pla n 
T P- G D O- W W- 1 3 3- 0 2 
 
Pr oject D oc u m e nt Versi o n N o . 2. 0 
Effecti ve Date:  2 6 N o v 1 9 
Pr oject D oc u me nt Effecti ve D ate : Date of last si g nat ure 
Relate d t o:  S O P- G D O- W W- 0 1 9 
Pa g e 3 8 of 4 6 
S R C Ta bles a n d fi g ures will s u m marize d b y c o h ort a n d o verall. S R C Listi n gs will be liste d b y c o h ort 
a n d partici pa nt. 
S R C T F Ls will be pre pare d as me nti o ne d i n S R C T F Ls S H E L Ls Versi o n 1. 0 date d Oct 1 9, 2 0 2 1 
S u m mar y statistics f or la b orat or y para meters will s u m marize d b y c o h ort a n d o verall f or se nti nel 
s u bjects se paratel y. 
4. 1 4 I nteri m A n al ysis 
N o i nteri m a nal ysis is pla n ne d f or t his st u d y. 
4. 1 5
Dete r mi n ati o n of S a m ple Size 
N o f or mal sa m ple size esti mati o ns were perf or m e d. T he f oll o wi n g sa m pl e sizes were c o nsi dere d 
s ufficie nt t o pr o vi de a n i nitial assess me nt of t he safet y pr ofile of D C R- A U D i n H Vs, a n d a de q uate 
f or t he p ur p ose of descri bi n g P K/ P D data i n H Vs. 

2 7 H V partici pa nts ( 3 c o h orts wit h 9 partici pa nts eac h, 2 t o 1 ra n d o mizati o n), pl us a n 
a d diti o nal 9 H V partici pa nts ( 2 t o 1 r a n d o mizati o n), f or a t otal of 3 6, if a n o pti o nal f o urt h 
c o h ort is e nr olle d. 
T he sa m ple size is bas e d o n cli nical rat her t h a n statistical c o nsi derati o ns. 
4. 1 6
C h a n ges i n t he C o n d uct of t he St u d y or Pl a n ne d A n al ysis 
I n a d diti o n t o t he pla n ne d sec o n dar y e n d p oi nts, Q ua ntitati ve assess me nt of 6 s y m pt o m res p o nses 
d uri n g EI As ha ve bee n a d de d t o t his st u d y as a sec o n dar y e n d p oi nt. M ore details o n t his ha v e bee n 
pr o vi de d i n res pecti ve P har mac o d y n a mic e n d p oi nts a n d a nal ysis secti o ns. 
5  
R E F E R E N C E S 
[ 1] S A S®  Versi o n 9. 4 of t he S A S S yste m f or Pers o nal C o m p uters. C o p yri g ht ©2 0 0 2- 2 0 0 3. S A S 
I nstit ute I nc. S A S a n d all ot her S A S I nstit ute I nc. pr o d uct or ser vi ce na m es are r e gistere d 
tra de mar ks or tra de m ar ks of S A S I nstit ute I nc., Car y, N C, U S A. 
[ 2] S mit h, Bria n & Va n de n he n de, Fr a nc ois & De Sa nte, Karl & Fari d, N a g y & Wel c h, Pa mela & 
Calla g ha n, J o h n & F or g ue, S.. ( 2 0 0 0). C o nfi de nce I nter val Criteria f or Assess me nt of D ose 
Pr o p orti o nalit y. P har mace utical Researc h. 1 7. 1 2 7 8- 1 2 8 3. 1 0. 1 0 2 3/ A: 1 0 2 6 4 5 1 7 2 1 6 8 6. 
[ 3] H u m mel J, Mc Ke n dri c k S, Bri n dle y C, Fre nc h R. E x pl orat or y assess me nt of d ose 
pr o p orti o nalit y: re vie w of c urr e nt a p pr o ac hes a n d pr o p osal f or a practical criteri o n. P har m Stat. 
2 0 0 9 Ja n- Mar; 8( 1): 3 8- 4 9. d oi: 1 0. 1 0 0 2/ pst. 3 2 6. P MI D: 1 8 3 8 6 7 6 6.


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02                                                                                              
                                                                   Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                                                                                                                     Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                                                                                                                 Page 39 of 46 
6
APPENDICES 
6.1
Schedule of Activities 
Table 6-1 Schedule of Activities
Screening 
Visit 1 (In-Clinic) 
V1ba
Visit 2 
Visit 3 
Visit 4 
Visits 5-6
Visit 7 
Visit 8 
EOS/ET 
Study Day
Procedure/Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
8 
15 
±2 day
29 
±2 day 
57 
±2 day 
85, 113 
±2 day 
141
±2 day 
169 
±7 day 
Pre-
dose 
Post-
dose 
Informed consent 
X 
Clinical site admission/discharge b
X 
 
X 
Inclusion/exclusion criteria 
X 
X 
X 
Demographic/baseline characteristics 
X 
General medical history 
X 
Psychological history 
X 
C-SSRSc
X 
X 
X 
X 
Xd
X 
MINI 
X 
Alcohol history/consumption (TLFB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary (AEs, temperance) distribute/collect 
X 
X 
X 
X 
X 
X 
X 
Drug/alcohol testing (urine, breath) e
X 
X 
X 
X 
X 
X 
X 
X 
Testing for HCV, HIV, and HBV 
X 
Randomize to study intervention 
X 
Study intervention administration 
X 
Medication history/concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02                                                                                              
                                                                   Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                                                                                                                     Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                                                                                                                 Page 40 of 46 
Screening 
Visit 1 (In-Clinic) 
V1ba
Visit 2 
Visit 3 
Visit 4 
Visits 5-6
Visit 7 
Visit 8 
EOS/ET 
Study Day
Procedure/Assessment 
-28 to -2 
-1 
1 
2 
3 
4 
8 
15 
±2 day
29 
±2 day 
57 
±2 day 
85, 113 
±2 day 
141
±2 day 
169 
±7 day 
Pre-
dose 
Post-
dose 
12-lead ECG f
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination g
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (WOCBP only) h
X 
X 
X 
X 
X 
X 
X 
FSH (if applicable)  
X 
Clinical safety laboratory tests i
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Complement panel j
X 
X 
X 
 
Blood sample for ADA 
X 
X 
X 
SARS-CoV-2 rapid test (at site)k
X 
X 
X 
X 
X 
Blood sample for genotyping l
X 
Plasma collection for PK analysis m
X 
X 
X 
X 
X 
X 
Urine collection for PK analysis n
X 
X 
X 
X 
Ethanol interaction assessment o
X 
 
X 
X 
X 
X 
X 
Xp
Record AEs and SAEs q
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA: antidrug antibody; AE: adverse event; CFU: conditional follow-up; C-SSRS: Columbia-Suicide Severity Rating Scale; ECG: electrocardiogram; EIA: ethanol interaction 
assessment; FSH: follicle stimulating hormone; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; ICF: informed consent form; MINI: Mini-International 
Neuropsychiatric Interview; PK: pharmacokinetic; SAE: serious adverse event; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLFB: Timeline Follow Back; WOCBP: women of 
childbearing potential 
a Visit 1b is only required for the 3 sentinel group participants in each cohort. 


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02                                                                                              
                                                                   Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                                                                                                                     Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                                                                                                                 Page 41 of 46 
b Participants in the expanded cohort must have fasted for at least 6 hours before admission on Day −1 and will receive a standardized meal prior to the EIA. Participants undergoing 
EIA will be discharged from the clinic on Day 5. Sentinel group participants will be discharged from the clinic on Day 4, following the 72-hour PK blood draw and completion of 
pooled urine collection. 
c At Screening, the ‘C-SSRS Baseline’ form will be administered, at all other visits indicated, the ‘C-SSRS Since Last Visit’ form will be administered. 
d C-SSRS to be administered only on Day 85. 
e Urine for drugs of abuse and breathalyzer for alcohol. Cannabis will not be recorded as a drug of abuse for this study. Participants will be excluded from EIA evaluation that day if 
they test positive for breath alcohol on day of study visit prior to EIA. 
f Standard ECGs will be performed 30 minutes predose, and at 60 minutes and 150 minutes postdose. A ±15-minute window around each time point is allowed if multiple 
assessments are due. If multiple assessments are due, the order of priority should be ECG, vitals, PK, and then other assessments. 
g Complete physical examinations will be conducted at every visit. Height will be measured and recorded at Day 1 and weight will be measured and recorded at every visit. 
h If a urine pregnancy test is positive, confirm with serum test for pregnancy (see Section Protocol section 10.4). Local laboratory may be used. Pregnancy testing to be performed 
every 28 days throughout the study. 
i Hematology, clinical chemistry, coagulation, and urinalysis samples will be collected at every visit indicated. Only on Days −1, 4, 29, 85, and 169 will additional hematology 
analytes (mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and absolute and % of lymphocytes, monocytes, eosinophils, 
neutrophils, and basophils) be collected. See Table 6-6 for a complete list of parameters to be assessed. 
j During in-clinic stay at Day 1 and Day 2, blood samples will be collected for complement predose, and at 2, 8, and 24 hours postdose. 
k Participants in expanded cohorts will need to undergo SARS-CoV‑2 rapid test in compliance with clinic requirements before admittance to the unit for EIA testing. Refer to Study 
Manual for further details on the timing of this testing. 
l A separate informed consent form is needed for collection of blood sample for optional genotyping. 
m At Visit 1, plasma samples for PK analysis will be collected before study intervention administration and at 15 and 30 minutes and 1, 2, 4, 6, 8, 24, 48, and 72 hours after the 
injection. At Visit 2, only one sample will be collected for PK. If multiple assessments are due, the order of priority should be ECG, vitals, PK, and then other assessments, with the 
PK sampling being performed preferably at the nominal time point. Table 6-2 details the windows allowed surrounding collection of PK samples. 
n Pooled urine collection to be done for PK analyses of DCR-AUD concentration. Participants should have an empty bladder prior to administration of study intervention, and 24-hr 
urine collection to begin with first void after study intervention administration. Urine to be collected at intervals of 0-4, > 4-8, > 8-12, > 12-24, > 24-48, and > 48-72 hours. Urine 
will be collected using a polypropylene container. 
o Each cohort will have a sentinel group (n=3) that does not undergo any EIA assessment. For all other participants, all visits on which an EIA is conducted will require an overnight 
stay in the clinic. Participants will be admitted after an overnight fast and be provided a standardized meal. EIA estimated time is ~2.5 hours and is conducted at all visits except 
Visit 7 (Day 141). Note that the Day −1 assessment occurs prior to administration of study intervention and is intended to serve as a baseline for biomarker assessments and to 
confirm eligibility. See Table 6-3 for details of EIA. 
p Participants who have positive ethanol reaction symptoms at the Day 169 EIA (e.g., nausea, vomiting, or substantial flushing) will return every 28 (±7) days for follow-up EIAs 
until the positive ethanol reaction symptoms abate. These CFU EIAs will not require overnight admission to the clinic, but all other aspects of the EIA will be conducted. 
Participants will be observed for no less than 6 hours after ethanol administration and will not be discharged until the Investigator deems it medically safe to do so. 
q 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. 


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02 
                    
Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                         Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                    Page 42 of 46 
Table 6-2 Allowed Windows for Collection of Plasma Pharmacokinetic Samples and for 
Complement Panel
Nominal Postdose Sample Time 
Window 
15 minutes 
± 5 minutes 
30 minutes  
± 10 minutes 
1, 2, 4, 6, and 8 hours 
± 15 minutes 
≥ 24 hours 
± 30 minutes 
Table 6-3 Schedule of Activities: Ethanol Interaction Assessments 
Time in minutes
Procedures 
Pre-EIA 
Rest 
Test Period 
− 20 
0a
15 
±5
30 
±10
45 
±10
60 
±15
90 
±15
120 
±15
150 
±15
Admit/return to clinic (fasted 
state)b
X 
Standardized mealc
X 
Venous catheter placementd
X 
Alcohol consumptione
← X → 
Blood biomarkersf g
X 
X 
X 
X 
X 
X 
X 
X 
EIA 12-lead ECG  
X 
X 
X 
SEASh 
X 
X 
X 
X 
X 
X 
Facial skin temperaturei
X 
X 
X 
X 
X 
X 
X 
X 
EIA vital signj
X 
X 
X 
X 
X 
X 
X 
X 
Heart rate via telemetry 
X 
X 
X 
X 
X 
X 
X 
X 
EIA AEsk
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE: adverse event; CFU: conditional follow up; ECG: electrocardiogram; EIA: ethanol interaction assessment; 
EtOH: ethanol; SEAS: subjective effects of alcohol scale;  
a.
Time “0” is immediately before the first sip of alcohol. All Time 0 assessments must be performed prior to initiation of 
alcohol intake. 
b.
All visits on which an EIA is conducted will require an overnight stay in the clinic except for any CFU visits for participants 
who have positive ethanol reaction symptoms at Day 169; these do not require an overnight stay.  
c.
Participants are required to fast for at least 6 hours prior to consuming the standardized meal. 
d.
Participants will have a venous access catheter placed for sample collection. Participant will be given a≥20-minute rest period 
following placement of the catheter prior to recording predose ECG, SEAS, vital signs, and facial temperature. 
e.
After completion of the standardized meal, alcohol will be consumed in 4 aliquots over a 30-minute period. The ethanol will 
be mixed in a liquid that has no other alcohol, no caffeine, and is low in sugar. Because BAC is higher in women than men 
when given the same g/kg EtOH dose (~ 15% higher mean BAC), the EtOH dose will be 0.4 g/kg for male participants and 
0.34 g/kg for female participants. The total dose of EtOH will not exceed 28 g in men or 24 g in women. 
f.
Blood samples will be collected via a venous access device for biomarker analysis, which include acetaldehyde, acetate, and 
ethanol. Blood sample collection and processing will be detailed in the Laboratory Manual.  
g.
The order of assessments should be blood draw, 12-lead ECG, SEAS, vital signs, and facial temperature. 
h.
Participants will rate the extent to which they are feeling each of the 14 SEAS effects in the present moment. 
i.
Facial skin temperature will be measured using a surface scanning thermometer and will be collected prior to blood draws. 
j.
Vital signs will be recorded prior to blood draws and include blood pressure and pulse/heart rate. 
k.
Adverse events associated with administration of ethanol will be recorded continuously throughout the test period, beginning 
with the first sip of alcohol.


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02 
                    
Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                         Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                    Page 43 of 46 
6.2
Imputation Rules for Partial Dates 
Imputed dates and time will NOT be presented in the listings. 
Table 6-4 and Table 6-5 present algorithm for imputing partial dates for TEAE and  prior/concomitant 
medication respectively.   
Table 6-4 
Algorithm for Treatment-Emergent Adverse Events: 
Start/Increase Severity Date 
Stop Date 
Action 
Known 
Known 
Considered as a treatment-emergent adverse event 
(TEAE) if start date on or after the date of the first dose 
of investigational product (IP)  
Partial 
Considered as a TEAE if start date on or after the date 
of the first dose of IP. The last day of the month and the 
last month (ie, December) will be used if the stop 
day/month is missing. 
Missing 
Considered as a TEAE if start date on or after the date 
of the first dose of IP 
Partial, but known components show 
that it cannot be on or after first IP taken 
date 
Known 
Not a TEAE. The first day of the month and January 
will be used if the start day/month is missing. 
Partial 
Not a TEAE. The first day of the month and January 
will be used if the start day/month is missing. The last 
day of the month and the last month (ie, December) will 
be used if the stop day/month is missing. 
Missing 
Not a TEAE. The first day of the month and January 
will be used if the start day/month is missing. 
Partial, could be on or after first IP taken 
date 
Known 
Considered as TEAE, if stop date is after first IP taken 
date. The first IP taken date will be used if start date is 
in the same month/year with first IP taken date, or the 
first day of the month and January will be used if the 
start day/month is after first IP taken date 
Considered as not TEAE, if stop date is prior to first IP 
taken date. The first day of the month and January will 
be used if the start day/month is missing. 
Partial 
Considered as TEAE. The first IP taken date will be 
used if start date is in the same month/year with first IP 
taken date, or the first day of the month and January will 
be used if the start day/month is after first IP taken date. 
The last day of the month and the last month (ie, 
December) will be used if the stop day/month is 
missing. 
Missing 
Considered as TEAE. The first IP taken date will be 
used if start date is in the same month/year with first IP 
taken date, or the first day of the month and January will 
be used if the start day/month is after first IP taken date. 
Missing 
Known 
Considered as TEAE if stop date is on or after the date 
of the first dose of IP. 
Partial 
The last day of the month and the last month (ie, 


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02 
                    
Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                         Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                    Page 44 of 46 
Start/Increase Severity Date 
Stop Date 
Action 
December) will be used if the stop day/month is 
missing. If the imputed stop date is on or after the first 
dose of IP considered as a TEAE; if the year is missing, 
considered as a TEAE 
Missing 
Considered as a TEAE 


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02 
                    
Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                         Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                    Page 45 of 46 
Table 6-5 
Algorithm for Prior/Concomitant Medications Categorization: 
Start Date 
Stop Date 
Action 
Known 
Known 
If stop date is prior to the date for the first dose of IP, considered as prior; if 
stop date is on or after the date for the first dose of IP, considered as 
concomitant. 
Partial 
The last day of the month and the last month (ie, December) will be used if the 
day/month of stop date is missing. If the impuated stop date is prior to the date 
for the first dose of IP, considered as prior; if the imputed stop date is on or 
after the date for the first dose of IP, considered as concomitant. 
Missing 
Considered as concomitant. 
Partial 
Known 
If stop date is prior to the date for the first dose of IP, considered as prior; If 
stop date is on or after the date for the first dose of IP, considered as 
concomitant. 
The first day of  the month and January will be used if the start day/month is 
missing. 
Partial 
The last day of the month and the last month (ie, December) will be used if the 
day/month of stop date is missing. If the impuated stop date is prior to the date 
for the first dose of IP, considered as prior; if the imputed stop date is on or 
after the date for the first dose of IP, considered as concomitant. 
The first day of  the month and January will be used if the start day/month is 
missing. 
Missing 
Considered as concomitant. The first day of  the month and January will be 
used if the start day/month is missing. 
Missing 
Known 
If stop date is prior to the date for the first dose of IP, considered as prior; if 
stop date is on or after the date for the first dose of IP, considered as 
concomitant. 
Partial 
The last day of the month and the last month (ie, December) will be used if the 
day/month of stop date is missing. If the impuated stop date is prior to the date 
for the first dose of IP, considered as prior; if he imputed stop date is on or 
after the date for the first dose of IP, considered as concomitant. 
Missing 
Considered as concomitant. 


 
Dicerna Pharmaceuticals, Inc. 
DCR-AUD-101                                                                                                                                  Statistical Analysis Plan 
TP-GDO-WW-133-02 
                    
Project Document Version No. 2.0 
Effective Date:  26 Nov 19                                                         Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                    Page 46 of 46 
Table 6-6 Safety Laboratory Assessments
Laboratory 
Assessments 
Parameters 
Hematology 
Red blood cell count 
 hemoglobin 
 hematocrit 
 reticulocytes 
 platelet count 
Only at Days -1, 4, 29, 85, and 169  
 mean corpuscular volume (MCV) 
 mean corpuscular hemoglobin (MCH) 
 mean corpuscular hemoglobin 
concentration (MCHC) 
White blood cell count 
Only at Days -1, 4, 29, 85, and 169 
 lymphocytes, abs and % 
 monocytes, abs and % 
 eosinophils, abs and % 
 neutrophils, abs and % 
 basophils, abs and % 
Clinical Chemistry  
alanine transaminase (ALT) 
aspartate transaminase (AST) 
gamma-glutamyl transferase (GGT) 
alkaline phosphatase (ALP) 
bilirubin (total and direct) 
lactate dehydrogenase (LDH) 
total protein 
albumin 
creatine kinase (CK) 
sodium 
chloride 
potassium 
creatinine 
blood urea nitrogen (BUN) 
fasting blood glucose 
Routine Urinalysis 
specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
microscopic examination (if blood or protein is abnormal) 
Coagulation Parameters 
International normalized ratio (INR), PT, PTT 
Complement panel 
Bb, C3a, C5a  
Other Screening Tests 

Alcohol breath test 

Rapid SARS-CoV-2 (local laboratory testing) 

Follicle-stimulating hormone (as needed in women of non-childbearing potential 
only) 

Highly sensitive (urine; serum for confirmation if needed) human chorionic 
gonadotropin (hCG) pregnancy test (as needed for WOCBP). Any positive urine 
pregnancy test will be confirmed with a serum pregnancy test.  

Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, and benzodiazepines) 

Viral serology (human immunodeficiency virus antibody, hepatitis B surface 
antigen, and hepatitis C virus antibody) 


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