Study of DCR-AUD in Healthy Volunteers

Study Overview
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Brief Summary
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DCR-AUD will be evaluated for safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers.

Detailed Description
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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.

Official Title
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A Phase 1, Double-blind, Placebo-controlled, Single-ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in Healthy Volunteers

Conditions
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Alcohol Use Disorder (AUD)

Intervention / Treatment
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* Drug: DCR-AUD
* Drug: Placebo for DCR-AUD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 21 to 65 years of age, inclusive, at the time of signing the informed consent. Overtly healthy, as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. 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. 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. Willing to participate in repeated low-dose EIAs followed by an overnight clinic stay. Has a negative test for SARS-CoV-2 infection on Day -1 and prior to admission to the clinical unit. Systolic BP in the range of 90 to 140 mmHg and diastolic BP in the range of 50 to 95 mmHg. 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. 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, beginning at consent and the first Screening visit and for at least 24 weeks after the last dose of study intervention. BMI within the range 18.0 to 32.0 kg/m2 (inclusive). 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 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 with orally inhaled medications only are not excluded. 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 past 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. 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 subject were they to participate in the trial, as informed by the participant's medical history and/or responses to the MINI Screen Questionnaire. History of delirium tremens or alcohol-related seizures. History of significant adverse reaction(s) to alcohol. 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: Poorly controlled or unstable hypertension. Clinically significant abnormalities in vital signs: pulse rate (< 40 or > 90 bpm), respiratory rate, or temperature. 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. Diabetes mellitus treated with insulin or hypoglycemic agents (including metformin) or HbA1C > 7%. Asthma requiring hospital admission within the preceding 12 months. Currently poorly controlled endocrine conditions, except for hypothyroidism that is stable (no treatment change in prior 6 months). Significant infection or known systemic inflammatory process ongoing at Screening. History of chronic or recurrent UTI, or UTI within 1 month prior to Screening. History of malignancy within the preceding 3 years requiring treatment, with the exception of excised low grade basal cell skin neoplasms. History of substance use disorder (SUD), including alcohol (AUD) or illicit drug use (excluding cannabis) within the preceding 12 months. Nicotine use is permitted. History of any concomitant medical condition for which alcohol consumption is prohibited or advised against by the participant's physician or health care provider. Clinically significant illness within the 7 days prior to the administration of study intervention. History of multiple drug allergies or a history of allergic reaction to an oligonucleotide-based therapy. Use of prescription medications (except for hormonal replacement/contraceptive medication for women and inhaled medical 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). Receipt of any vaccine (include COVID-19) within 14 days prior to administration of study intervention. Regular use of OTC medications, including NSAID (Periodic or occasional NSAID use to control temporary pain is not exclusionary). 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. 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. Had laboratory-confirmed SARS-CoV-2 infection in the 14 days prior to randomization. Liver function test results (AST, ALT, GGT, total bilirubin) above the normal range. Safety laboratory test result considered clinically unacceptable for study participation by the Investigator. 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. Scheduled for an elective surgical procedure during the conduct of this study. 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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 DCR-AUD<br>Single dose, subcutaneous administration of 80 mg of DCR-AUD (HV) | Drug: DCR-AUD<br>* 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).<br>* Other names: DCR-A1203;|
| Placebo Comparator: Cohort 1 DCR-AUD Placebo<br>Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose | Drug: Placebo for DCR-AUD<br>* 0.9% saline for injection<br>* Other names: Placebo;|
| Experimental: Cohort 2 DCR-AUD<br>Single dose, subcutaneous administration of 240 mg of DCR-AUD (HV) | Drug: DCR-AUD<br>* 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).<br>* Other names: DCR-A1203;|
| Placebo Comparator: Cohort 2 DCR-AUD Placebo<br>Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose | Drug: Placebo for DCR-AUD<br>* 0.9% saline for injection<br>* Other names: Placebo;|
| Experimental: Cohort 3 DCR-AUD<br>Single dose, subcutaneous administration of 480 mg of DCR-AUD (HV) | Drug: DCR-AUD<br>* 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).<br>* Other names: DCR-A1203;|
| Placebo Comparator: Cohort 3 DCR-AUD Placebo<br>Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose | Drug: Placebo for DCR-AUD<br>* 0.9% saline for injection<br>* Other names: Placebo;|
| Experimental: Cohort 4 (OPTIONAL) DCR-AUD<br>Single dose, subcutaneous administration of 960 mg of DCR-AUD (HV) | Drug: DCR-AUD<br>* 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).<br>* Other names: DCR-A1203;|
| Placebo Comparator: Cohort 4 (OPTIONAL) DCR-AUD Placebo<br>Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose | Drug: Placebo for DCR-AUD<br>* 0.9% saline for injection<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of AEs, SAEs, and DLTs as assessed by CTCAE v5.0. | 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. | 24 weeks | 
| Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings. | To evaluate the safety and tolerability of single doses of DCR-AUD administered to adult HVs. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma area under the concentration curve (AUC). | Measured to characterize plasma pharmacokinetics (PK) of a single dose of DCR-AUD in adult HVs. | 24 weeks | 
| Plasma maximum observed concentration (Cmax). | Measured to characterize plasma pharmacokinetics (PK) of a single dose of DCR-AUD in adult HVs. | 24 weeks | 
| Plasma time to maximum concentration (Tmax). | Measured to characterize plasma pharmacokinetics (PK) of a single dose of DCR-AUD in adult HVs. | 24 weeks | 
| Plasma acetaldehyde levels. | Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group. | 24 weeks | 
| Plasma acetate levels. | Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group. | 24 weeks | 
| Plasma ethanol levels. | Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group. | 24 weeks | 
| Heart rate. | Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group. | 24 weeks | 
| Facial skin temperature. | Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group. | 24 weeks | 
| Subjective feelings of alcohol intoxication or intolerance using the Subjective Effects of Alcohol Scale (SEAS). | Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group. | 24 weeks |