A Phase 1, Double-blind, Placebo-controlled, Single-ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in Healthy Volunteers
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Masking Description
Participants, Investigators, site staff, the CRO staff, and the Sponsor Medical Monitor will be blinded to the randomization. Other members of the Sponsor staff will be unblinded for the duration of the study. Complete details will be presented in the Study Blinding Plan.
Eligibility Criteria
- Ages
- 21 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- Not provided
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.
- •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
- •History of delirium tremens or alcohol-related seizures.
- •History of significant adverse reaction(s) to alcohol.
- •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.
- •History of multiple drug allergies or a history of allergic reaction to an oligonucleotide based therapy
Arms & Interventions
Cohort 2: DCRAUD 240 mg
Participant received a single dose of DCR-AUD 240 mg, subcutaneous injection on Day 1.
Intervention: DCR-AUD (Drug)
Cohort 1: DCRAUD 80 mg
Participant received a single dose of DCR-AUD 80 mg, subcutaneous injection on Day 1.
Intervention: DCR-AUD (Drug)
Cohort 3: DCR-AUD 480 mg
Participant received a single dose of DCR-AUD 480 mg, subcutaneous injection on Day 1.
Intervention: DCR-AUD (Drug)
Cohort 4: DCR-AUD 960 mg
Participant received a single dose of DCR-AUD 960 mg, subcutaneous injection on Day 1.
Intervention: DCR-AUD (Drug)
Pooled Placebo
Participant received a single dose of DCR-AUD matching placebo, subcutaneous injection on Day 1.
Intervention: Placebo for DCR-AUD (Drug)
Outcomes
Primary Outcomes
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame: 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
Time Frame: 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 life-threatening; 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 Dose-limiting Toxicities (DLTs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
Time Frame: From Day 1 up to 24 Weeks
DLT is defined as an AE of greater than or equal to (\>=) 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.
Number of Participants With Change From Baseline in Clinically Significant Abnormal Vital Signs
Time Frame: 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) Findings
Time Frame: 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
Time Frame: 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
Time Frame: 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 Outcomes
- AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD(Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose)
- Cmax: Maximum Observed Plasma Concentration of DCR-AUD(Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose)
- Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax)(Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose)
- t1/2: Apparent Terminal Elimination Half-life of DCR-AUD(Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose)
- Fe%0-72: Urinary Cumulative Excretion as % of Unchanged DCR-AUD up to 72 Hours(At time interval between 0- 4 hours, 0- 8 hours, 0-12 hours, 0-24 hours, 0-48 hours, 0-72 hours)
- CLR: Renal Clearance of the DCR-AUD From Plasma(Day 1: 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72-hours post-dose)
- Six Symptom Responses During Ethanol Interactions Assessments (EIAs)(Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169)
- Cmax: Maximum Observed Plasma Concentration of Acetaldehyde(Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169)
- AUC0-2.5: Area Under the Concentration Time Curve From Time 0 to Fixed Time 2.5 of Acetaldehyde(Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169)
- Change From Baseline in Heart Rate(Baseline (Day -1), Day 169)
- Change From Baseline in Facial Skin Temperature(Baseline (Day -1), Day 169)
- Change From Baseline in Subjective Effects of Alcohol Scale (SEAS) Score(Baseline (Day -1), Day 169)