Alcohol Use Disorder
Conditions
Brief summary
The goal of this clinical trial is to test the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of of repeat doses of DCR-AUD in adult healthy volunteers who are social drinkers. The main questions it aims to answer are: * Are repeat doses of DCR-AUD safe and well-tolerated in healthy adults who are social drinkers? * How does the drug behave inside the human body and how it is removed from the human body? * What are the symptoms the drug may cause with alcohol consumption? Participants will: * Receive multiple doses of DCR-AUD. * Have assessment visits through Week 24. * Participate in up to 10 Ethanol Interaction Assessments (EIAs) to see how the body is affected by DCR-AUD. Researchers will compare the groups of participates who receive study drug with the group of participants who receive placebo to see if the study drug is safe and tolerable and whether the study drug has any real effect.
Interventions
DRUGDCR-AUD
DCR-A1203, the drug substance of DCR-AUD, is a synthetic double-stranded (hybridized duplex) RNA oligonucleotide conjugated to GalNAc ligands that enable specific hepatic access and update after subcutaneous administration. DCR-AUD is a sterile solution of DCR-A1203 at a concentration of 160 mg/mL in water for injection (WFI).
DRUGPlacebo
0.9% saline for injection.
Sponsors
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Participants and site study staff will be blinded to the randomization. Some members of the Sponsor team will be unblinded.
Intervention model description
Participants will be randomized 3 to 1 to DCR-AUD or placebo.
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. 21 to 65 years, inclusive, at the time of signing informed consent. 2. Overtly healthy volunteers, as determined by medical evaluation including medical history, physical examination, and laboratory testing. 3. No diagnosis of AUD within the preceding 12 months per Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 4. Social drinkers who consume, on average, 5 to 20 drinks per week for men or 5 to 14 drinks per week for women over the 4 weeks prior to Screening, and not more than 8 drinks in a single day. 5. No evidence of overt or sub-clinical hepatic pathology, as manifest by serologic tests demonstrating hepatic inflammation or compromised hepatic synthetic function (i.e., AST, ALT, GGT, total bilirubin \< 1.5 times the ULN at Screening and Day -1). 6. eGFR ≥ 60 mL/min/1.73 m2 at Screening. 7. No history of significant adverse reaction(s) to alcohol. Participant should be expected to tolerate the amount of alcohol administered during EIAs. 8. Willing to participate in up to 10 EIAs. 9. Has a negative test for SARS-CoV-2 infection on Day -1. 10. Systolic BP in the range of 80 to 140 mmHg and diastolic BP in the range of 50 to 95 mmHg at Screening. If out of range, BP may be repeated once at the discretion of the Investigator. 11. Male or female * Male participants with partners of childbearing potential must agree to use contraception from Screening through at least 24 weeks after the last dose of study intervention and refrain from donating sperm during this period (see Section 10.4). * Female participants may not be pregnant or breastfeeding, and at least one of the following conditions must apply: * 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. 12. BMI within the range 18.0 to 32.0 kg/m2 (inclusive). 13. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion criteria
History of any medical condition that may interfere with the metabolism of study intervention or with the clinical and laboratory assessments in this study. 2. History of serious, persistent medical conditions, including liver, gastrointestinal, pulmonary, renal, or cardiovascular abnormalities. 3. History of suicidal attempt at any time or an answer of yes on any of the following items in the C-SSRS at Screening: 1. Items 1 or 2 of the Suicidal Ideation section, if ideation occurred in the previous 12 months. 2. Items 4 or 5 of the Suicidal Ideation section, in lifetime. 3. Any item of the Suicidal Behavior section of the C-SSRS, in lifetime. 4. Any history of severe or recent clinically significant depression, anxiety, bipolar disorder, schizophrenia, or other neuropsychiatric disorder that, in the judgement of the Investigator, represents a safety risk to the participant were they to participate in the trial, as informed by the participant's medical history and/or responses to the MINI Screen Questionnaire. 5. History of substance use disorder (SUD) or illicit drug use (excluding cannabis) within the preceding 12 months. 6. History of alcohol withdrawal symptoms including delirium tremens or alcohol-related seizures. 7. Any condition that, in the opinion of the Investigator, would make the participant unsuitable for participation or could interfere with participation in or completion of the study, including: a. Poorly controlled or unstable hypertension. b. Diabetes mellitus treated with insulin or hypoglycemic agents (including metformin) or HbA1C \> 7%. Asthma requiring hospital admission within the preceding 12 months. NOTE: Persons with clinically stable asthma who have not been hospitalized in the prior year and are treated only with orally inhaled medications are not excluded. d. Currently poorly controlled endocrine conditions, except for hypothyroidism that is stable (no treatment change in prior 6 months). e. Significant infection or known systemic inflammatory process ongoing at Screening. f. History of chronic or recurrent UTI, or UTI within 1 month prior to Screening. 8\. History of malignancy within the preceding 5 years requiring treatment, with the exception of excised low grade basal cell skin neoplasms. 9. History of any concomitant medical condition for which alcohol consumption is prohibited or advised against by the participant's physician or health care provider. 10\. SARS-CoV-2 infection in the 14 days prior to randomization. 11. Clinically significant illness within the 7 days prior to the first administration of study intervention. History of multiple drug allergies or a history of allergic reaction to an oligonucleotide based therapy. 13\. Use of prescription medications (except for hormonal replacement/contraceptive medication for women and inhaled medication for treatment of clinically stable asthma) within 14 days or 5 half-lives (whichever is longer) prior to administration of study intervention. Participants being treated for hypothyroid disease must be on stable treatment (no treatment changes in the preceding 6 months). 14. Receipt of any vaccine (including COVID-19) within 14 days prior to the first administration of study intervention. 15. Regular use of OTC medications, including NSAID (periodic or occasional NSAID use to control temporary pain is not exclusionary). 16. Previously participated in Dicerna Study DCR-AUD-101. 17. Has received an investigational agent within 30 days or 5 half-lives (whichever is longer) prior to dosing or is in follow-up of another clinical study prior to initial dosing with the study intervention. 18. Clinically significant abnormalities in vital signs at Screening: pulse rate (\< 40 bpm or \> 90 bpm), respiratory rate, or temperature. 19. Clinically significant abnormalities in 12-lead ECG at Screening or predose on Day 1, including QTcF \> 470 msec in females and \> 450 msec in males. 20. Positive urine drug test at Screening or Day -1. Tests positive for cannabis are not exclusionary. 21. Seropositive for antibodies to HIV, HBV, or HCV at Screening (historical testing may be used if performed within the 3 months prior to screening). NOTE: In participants with previous treatment for hepatitis C with direct-acting HCV medication and seropositivity for HCV, or in participants with prior infection and spontaneous resolution, HCV RNA must be undetectable (at least 2 negative HCV RNA tests at least 12 weeks apart), and the HCV infection must have been resolved or cured \> 3 years prior to initial dosing with the investigational medication. 22. Safety laboratory test result at Screening considered clinically unacceptable for study participation by the Investigator. 23. History of intolerance to SC injection(s) or significant abdominal scarring that could potentially hinder study intervention administration or evaluation of local injection site tolerability. 24. Scheduled for an elective surgical procedure during the conduct of this study. 25\. Donation of \> 500 mL of blood within the 2 months prior to administration of study intervention or donation of plasma within 7 days prior to Screening. Life Style Considerations: 1. Study participants are to refrain from drinking alcohol for 24 hours prior to each EIA and must have a negative breath-alcohol test on the day of the study visit. 2. Study participants will be advised to avoid consuming more than 4 drinks during any drinking session outside of in-clinic EIAs. 3. Study participants will be instructed to stop drinking at the onset of any ethanol reaction symptoms during outside drinking sessions. 4. Tobacco/nicotine use is not restricted. 5. Study participants are to refrain from using cannabis for 24 hours prior to each EIA and must have a negative urine-drug test on the day of the study visit. 6. Study participants should abstain from strenuous exercise for 24 hours before each blood collection for clinical laboratory tests. Participants may participate in light recreational activities (e.g., walking at a pace \< 3 miles per hour, shopping, watering plants) in that 24-hour time period. 7. For each EIA study visit, participants will be required to fast for at least 3 hours and then will be fed a standardized meal in the clinic prior to administration of ETOH for the EIA.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From Day 1 up to 24 Weeks | An Adverse event (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. A TEAE is defined as an AE that begins or that worsens in severity after the study drug has been administered. An SAE is defined as any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly /birth defect, is the other important medical event. |
| Number of Participants With Severity Grades of TEAEs | From Day 1 up to 24 Weeks | 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. A TEAE is defined as an AE that begins or that worsens in severity after the study drug has been administered. As per the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated; Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living; Grade 3: severe or medically significant but not immediately lifethreatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; Grade 4: life-threatening consequences; urgent treatment indicated; Grade 5: fatal. |
| Number of Participants With Change From Baseline in Clinically Significant Abnormal Vital Signs | From Baseline (Day -1) up to 24 weeks | Number of participants with change from baseline in clinically significant abnormal vital signs (temperature, pulse rate, respiratory rate, and blood pressure) is presented. |
| Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG) | From Baseline (Day -1) up to 24 weeks | Number of participants with change from baseline in clinically significant abnormal ECG findings (Heart rate, PR interval, QRS interval, QT interval and QT interval using Fridericia's correction \[QTcF\]) is presented. |
| Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values | From Baseline (Day -1) up to 24 weeks | Number of participants with change from baseline in clinically significant abnormal laboratory values (hematology, clinical chemistry, coagulation and routine urinalysis parameters) is presented. |
| Number of Participants With Change From Baseline in Clinically Significant Physical Examination Findings | From Baseline (Day -1) up to 24 weeks | Number of participants with change from baseline in clinically significant physical examination findings (assessments of the cardiovascular, respiratory, gastrointestinal, neurological, and skin systems and inspection of the injection site) is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Heart Rate | Baseline, Day 169 | Heart rate is measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIA. Heart rate was monitored by telemetry during the EIAs. |
| Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day -1 (baseline), Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168 | The degree of aldehyde dehydrogenase 2 (ALDH2) reduction was measured by quantitative assessment of 6 symptom (flushing, headache, palpitations, light-headedness, nausea, and vomiting) responses during EIAs. Each of 6 symptoms was assessed at each of the 4 time points during each EIA. Composite score at each time point was the sum of severity ratings for each of the 6 symptoms. Peak composite score (of the 3 post-alcohol initiation composite scores at each EIA test) was used as the subject's peak score for that EIA test. The point system was as follows: 0 point = symptom not present, 1 point = mild severity of symptom, 2 points = moderate severity of symptom and 3 points = severe severity of symptom. Participants were given a composite score, which was the sum of the scores of all 6 symptoms (highest possible score is 18). |
| Change From Baseline in Facial Skin Temperature | Baseline, Day 169 | Change in facial skin temperature was measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs. |
| AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD | Day 1, Day 29 and Day 57 | AUC0-last is defined as the area under the plasma concentration curve from time zero to the last quantifiable concentration of DCR-AUD. |
| Cmax: Maximum Observed Plasma Concentration of DCR-AUD | Day 1, Day 29 and Day 57 | Cmax is defined as maximum observed plasma concentration of DCR-AUD is presented. |
| Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax) | Day 1, Day 29 and Day 57 | Tmax is defined as time to reach the maximum plasma concentration (Cmax) of DCR-AUD. |
| Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day -1 (baseline), Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168 | Maximum observed plasma concentration of acetaldehyde levels was measured to evaluate the pharmacodynamic effects of ALDH2 reduction by DCR-AUD during serial EIAs. |
| AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day -1, Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168 | Area under the concentration time curve from time 0 to fixed time 4 of acetaldehyde levels was measured to evaluate the pharmacodynamic effects of ALDH2 reduction by DCR-AUD during serial EIAs. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 1 site in the United States of America.
Pre-assignment details
In this trial total 16 healthy participants were randomized in 3:1 ratio to DCR-AUD or placebo.
Participants by arm
| Arm | Count |
|---|---|
| DCR-AUD Participant received DCR-AUD 480 mg, subcutaneous injection on Day 1, Day 29 and Day 57. | 12 |
| Placebo Participant received DCR-AUD matching placebo, subcutaneous injection on Day 1, Day 29 and Day 57. | 4 |
| Total | 16 |
Baseline characteristics
| Characteristic | Placebo | Total | DCR-AUD |
|---|---|---|---|
| Age, Continuous | 38.0 Years STANDARD_DEVIATION 3.37 | 39.0 Years STANDARD_DEVIATION 8.64 | 39.3 Years STANDARD_DEVIATION 9.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 10 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 11 Participants | 9 Participants |
| Sex: Female, Male Female | 1 Participants | 10 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 4 |
| other Total, other adverse events | 11 / 12 | 3 / 4 |
| serious Total, serious adverse events | 0 / 12 | 0 / 4 |
Outcome results
Primary
Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG)
Number of participants with change from baseline in clinically significant abnormal ECG findings (Heart rate, PR interval, QRS interval, QT interval and QT interval using Fridericia's correction \[QTcF\]) is presented.
Time frame: From Baseline (Day -1) up to 24 weeks
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DCR-AUD | Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG) | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG) | 0 Participants |
Primary
Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values
Number of participants with change from baseline in clinically significant abnormal laboratory values (hematology, clinical chemistry, coagulation and routine urinalysis parameters) is presented.
Time frame: From Baseline (Day -1) up to 24 weeks
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DCR-AUD | Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values | 0 Participants |
Primary
Number of Participants With Change From Baseline in Clinically Significant Abnormal Vital Signs
Number of participants with change from baseline in clinically significant abnormal vital signs (temperature, pulse rate, respiratory rate, and blood pressure) is presented.
Time frame: From Baseline (Day -1) up to 24 weeks
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DCR-AUD | Number of Participants With Change From Baseline in Clinically Significant Abnormal Vital Signs | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in Clinically Significant Abnormal Vital Signs | 0 Participants |
Primary
Number of Participants With Change From Baseline in Clinically Significant Physical Examination Findings
Number of participants with change from baseline in clinically significant physical examination findings (assessments of the cardiovascular, respiratory, gastrointestinal, neurological, and skin systems and inspection of the injection site) is presented.
Time frame: From Baseline (Day -1) up to 24 weeks
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DCR-AUD | Number of Participants With Change From Baseline in Clinically Significant Physical Examination Findings | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in Clinically Significant Physical Examination Findings | 0 Participants |
Primary
Number of Participants With Severity Grades of TEAEs
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. A TEAE is defined as an AE that begins or that worsens in severity after the study drug has been administered. As per the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated; Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living; Grade 3: severe or medically significant but not immediately lifethreatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; Grade 4: life-threatening consequences; urgent treatment indicated; Grade 5: fatal.
Time frame: From Day 1 up to 24 Weeks
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DCR-AUD | Number of Participants With Severity Grades of TEAEs | Grade 2 | 3 Participants |
| DCR-AUD | Number of Participants With Severity Grades of TEAEs | Grade 4 | 0 Participants |
| DCR-AUD | Number of Participants With Severity Grades of TEAEs | Grade 3 | 0 Participants |
| DCR-AUD | Number of Participants With Severity Grades of TEAEs | Grade 5 | 0 Participants |
| DCR-AUD | Number of Participants With Severity Grades of TEAEs | Grade 1 | 11 Participants |
| Placebo | Number of Participants With Severity Grades of TEAEs | Grade 5 | 0 Participants |
| Placebo | Number of Participants With Severity Grades of TEAEs | Grade 1 | 3 Participants |
| Placebo | Number of Participants With Severity Grades of TEAEs | Grade 2 | 0 Participants |
| Placebo | Number of Participants With Severity Grades of TEAEs | Grade 3 | 0 Participants |
| Placebo | Number of Participants With Severity Grades of TEAEs | Grade 4 | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An Adverse event (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. A TEAE is defined as an AE that begins or that worsens in severity after the study drug has been administered. An SAE is defined as any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly /birth defect, is the other important medical event.
Time frame: From Day 1 up to 24 Weeks
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DCR-AUD | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 11 Participants |
| DCR-AUD | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 3 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Secondary
AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde
Area under the concentration time curve from time 0 to fixed time 4 of acetaldehyde levels was measured to evaluate the pharmacodynamic effects of ALDH2 reduction by DCR-AUD during serial EIAs.
Time frame: Day -1, Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168
Population: PP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo and have at least 1 postdose PD assessment. Here, number analysed signifies participants with available data for each specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day -1 | 47.8 Micromolar*hours (μM*h) | Standard Deviation 20.3 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 42 | 81.8 Micromolar*hours (μM*h) | Standard Deviation 52.9 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 14 | 48.2 Micromolar*hours (μM*h) | Standard Deviation 43.1 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 28 | 93.2 Micromolar*hours (μM*h) | Standard Deviation 68.6 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 56 | 131 Micromolar*hours (μM*h) | Standard Deviation 81.8 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 70 | 135 Micromolar*hours (μM*h) | Standard Deviation 88.9 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 84 | 135 Micromolar*hours (μM*h) | Standard Deviation 52.4 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 112 | 187 Micromolar*hours (μM*h) | Standard Deviation 75.9 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 140 | 228 Micromolar*hours (μM*h) | Standard Deviation 85.1 |
| DCR-AUD | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 168 | 334 Micromolar*hours (μM*h) | Standard Deviation 93.9 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 112 | 57.5 Micromolar*hours (μM*h) | Standard Deviation 63.6 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 70 | 78.3 Micromolar*hours (μM*h) | Standard Deviation 51.2 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 42 | 21.6 Micromolar*hours (μM*h) | Standard Deviation 10.7 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day -1 | 65.8 Micromolar*hours (μM*h) | Standard Deviation 48 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 168 | 69.4 Micromolar*hours (μM*h) | Standard Deviation 70 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 14 | 62.1 Micromolar*hours (μM*h) | Standard Deviation 11.6 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 84 | 49.5 Micromolar*hours (μM*h) | Standard Deviation 45.6 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 28 | 32.0 Micromolar*hours (μM*h) | Standard Deviation 24.6 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 140 | 56.8 Micromolar*hours (μM*h) | Standard Deviation 63.5 |
| Placebo | AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde | Day 56 | 54.4 Micromolar*hours (μM*h) | Standard Deviation 48.9 |
Secondary
AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD
AUC0-last is defined as the area under the plasma concentration curve from time zero to the last quantifiable concentration of DCR-AUD.
Time frame: Day 1, Day 29 and Day 57
Population: Pharmacokinetic Population (PKP): All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD and have at least 1 postdose PK assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DCR-AUD | AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD | Day 1 | 44100 hour*nanogram per millilitre (h*ng/ mL) | Geometric Coefficient of Variation 16.3 |
| DCR-AUD | AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD | Day 29 | 41000 hour*nanogram per millilitre (h*ng/ mL) | Geometric Coefficient of Variation 16.9 |
| DCR-AUD | AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD | Day 57 | 66200 hour*nanogram per millilitre (h*ng/ mL) | Geometric Coefficient of Variation 27 |
Secondary
Change From Baseline in Facial Skin Temperature
Change in facial skin temperature was measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs.
Time frame: Baseline, Day 169
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DCR-AUD | Change From Baseline in Facial Skin Temperature | -0.05 degree celsius | Standard Deviation 0.555 |
| Placebo | Change From Baseline in Facial Skin Temperature | 0.03 degree celsius | Standard Deviation 0.704 |
Secondary
Change From Baseline in Heart Rate
Heart rate is measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIA. Heart rate was monitored by telemetry during the EIAs.
Time frame: Baseline, Day 169
Population: SP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DCR-AUD | Change From Baseline in Heart Rate | 1.9 beats per minute (beats/min) | Standard Deviation 9.09 |
| Placebo | Change From Baseline in Heart Rate | 4.3 beats per minute (beats/min) | Standard Deviation 8.1 |
Secondary
Cmax: Maximum Observed Plasma Concentration of Acetaldehyde
Maximum observed plasma concentration of acetaldehyde levels was measured to evaluate the pharmacodynamic effects of ALDH2 reduction by DCR-AUD during serial EIAs.
Time frame: Day -1 (baseline), Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168
Population: PP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo and have at least 1 postdose PD assessment. Here, number analysed signifies participants with available data for each specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 14 | 21.6 Micromolar (μM) | Standard Deviation 14.1 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 28 | 40.2 Micromolar (μM) | Standard Deviation 27.9 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 42 | 34.0 Micromolar (μM) | Standard Deviation 19.9 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 56 | 53.9 Micromolar (μM) | Standard Deviation 29.6 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 112 | 80.3 Micromolar (μM) | Standard Deviation 37.8 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 168 | 132 Micromolar (μM) | Standard Deviation 48.6 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day -1 (baseline) | 19.8 Micromolar (μM) | Standard Deviation 5.71 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 70 | 58.6 Micromolar (μM) | Standard Deviation 46.3 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 84 | 62.9 Micromolar (μM) | Standard Deviation 23 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 140 | 98.3 Micromolar (μM) | Standard Deviation 40.7 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 140 | 21.9 Micromolar (μM) | Standard Deviation 16.2 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 14 | 24.3 Micromolar (μM) | Standard Deviation 3.51 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 112 | 25.3 Micromolar (μM) | Standard Deviation 21.7 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 28 | 15.1 Micromolar (μM) | Standard Deviation 6.88 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 168 | 30.6 Micromolar (μM) | Standard Deviation 24.1 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 42 | 12.6 Micromolar (μM) | Standard Deviation 3.51 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 70 | 36.3 Micromolar (μM) | Standard Deviation 23.8 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 56 | 26.7 Micromolar (μM) | Standard Deviation 14.9 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day 84 | 20.7 Micromolar (μM) | Standard Deviation 13.8 |
| Placebo | Cmax: Maximum Observed Plasma Concentration of Acetaldehyde | Day -1 (baseline) | 28.3 Micromolar (μM) | Standard Deviation 17.1 |
Secondary
Cmax: Maximum Observed Plasma Concentration of DCR-AUD
Cmax is defined as maximum observed plasma concentration of DCR-AUD is presented.
Time frame: Day 1, Day 29 and Day 57
Population: PKP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD and have at least 1 postdose PK assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of DCR-AUD | Day 1 | 2530 nanogram per millilitre (ng/mL) | Geometric Coefficient of Variation 28.1 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of DCR-AUD | Day 29 | 2280 nanogram per millilitre (ng/mL) | Geometric Coefficient of Variation 32.3 |
| DCR-AUD | Cmax: Maximum Observed Plasma Concentration of DCR-AUD | Day 57 | 1900 nanogram per millilitre (ng/mL) | Geometric Coefficient of Variation 26.3 |
Secondary
Six Symptom Responses During Ethanol Interactions Assessments (EIAs)
The degree of aldehyde dehydrogenase 2 (ALDH2) reduction was measured by quantitative assessment of 6 symptom (flushing, headache, palpitations, light-headedness, nausea, and vomiting) responses during EIAs. Each of 6 symptoms was assessed at each of the 4 time points during each EIA. Composite score at each time point was the sum of severity ratings for each of the 6 symptoms. Peak composite score (of the 3 post-alcohol initiation composite scores at each EIA test) was used as the subject's peak score for that EIA test. The point system was as follows: 0 point = symptom not present, 1 point = mild severity of symptom, 2 points = moderate severity of symptom and 3 points = severe severity of symptom. Participants were given a composite score, which was the sum of the scores of all 6 symptoms (highest possible score is 18).
Time frame: Day -1 (baseline), Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168
Population: Pharmacodynamic Population (PP): All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD or placebo and have at least 1 postdose PD assessment. Here, number analysed signifies participants with available data for each specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day -1 (baseline) | 0.3 Score on a scale | Standard Deviation 0.65 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 42 | 0.9 Score on a scale | Standard Deviation 1.08 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 56 | 1.1 Score on a scale | Standard Deviation 1.14 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 84 | 1.1 Score on a scale | Standard Deviation 1.24 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 140 | 0.8 Score on a scale | Standard Deviation 1.06 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 14 | 0.4 Score on a scale | Standard Deviation 0.67 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 28 | 0.8 Score on a scale | Standard Deviation 0.75 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 70 | 1.0 Score on a scale | Standard Deviation 1.21 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 112 | 0.9 Score on a scale | Standard Deviation 1.22 |
| DCR-AUD | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 168 | 0.8 Score on a scale | Standard Deviation 0.87 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 112 | 0 Score on a scale | Standard Deviation 0 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 28 | 0.5 Score on a scale | Standard Deviation 0.58 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 42 | 0.8 Score on a scale | Standard Deviation 0.96 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 56 | 0.3 Score on a scale | Standard Deviation 0.5 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 140 | 0.3 Score on a scale | Standard Deviation 0.5 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 84 | 0 Score on a scale | Standard Deviation 0 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 70 | 0 Score on a scale | Standard Deviation 0 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day -1 (baseline) | 0.5 Score on a scale | Standard Deviation 0.58 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 168 | 0.3 Score on a scale | Standard Deviation 0.5 |
| Placebo | Six Symptom Responses During Ethanol Interactions Assessments (EIAs) | Day 14 | 0 Score on a scale | Standard Deviation 0 |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax)
Tmax is defined as time to reach the maximum plasma concentration (Cmax) of DCR-AUD.
Time frame: Day 1, Day 29 and Day 57
Population: PKP: All participants randomized to study intervention and who receive at least 1 dose of DCR-AUD and have at least 1 postdose PK assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| DCR-AUD | Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax) | Day 1 | 4.95 Hours |
| DCR-AUD | Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax) | Day 29 | 4.99 Hours |
| DCR-AUD | Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax) | Day 57 | 3.98 Hours |