Study of DCR-AUD in Healthy Volunteers

Dicerna Pharmaceuticals, Inc., a Novo Nordisk company36 enrolled

Overview

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

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Alcohol Use Disorder (AUD)

Interventions

DCR-AUDDRUG

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).

Placebo for DCR-AUDDRUG

0.9% saline for injection

Eligibility

Sex: ALLMin age: 21 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion criteria * Male and female participants, between 21 and 65 years of age (inclusive), who were social drinkers of modest amounts of alcohol (less than or equal to (≤) 2 drinks/day, ≤ 3 days/week) and would be able to refrain from drinking alcohol during the outpatient portion of the trial * Overtly healthy, as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. * 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. * Had a negative test for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection on Day -1 and prior to admission to the clinical unit. * Systolic BP in the range of 90 to 140 millimetre(s) of mercury (mmHg) and diastolic BP in the range of 50 to 95 mmHg, and body mass index (BMI) within the range of 18.0 to 32.0 kilogram per square meter (kg/m\^2) (inclusive). 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

Locations (1)

Parexel Los Angeles Early Phase Clinical Unit

Glendale, California, United States

Outcomes

Primary Outcomes

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

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 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.

Time frame: From Day 1 up to 24 Weeks

Number of Participants With Dose-limiting Toxicities (DLTs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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: 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

Cmax is defined as maximum observed plasma concentration of DCR-AUD during a dosing interval.

Time frame: 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)

Tmax is defined as time to reach the maximum plasma concentration (Cmax) of DCR-AUD.

Time frame: 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

t1/2 is defined as apparent terminal elimination half-life of DCR-AUD.

Time frame: 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

Urinary cumulative excretion as % of DCR-AUD at each interval collection (0- 4 hours, 0- 8 hours, 0-12 hours, 0-24 hours, 0-48 hours, 0-72 hours) is reported in this outcome measure.

Time frame: 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

Renal clearance of the DCR-AUD from plasma is reported in this outcome measure.

Time frame: 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)

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, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169

Cmax: Maximum Observed Plasma Concentration of Acetaldehyde

Maximum plasma concentration of acetaldehyde was measured to evaluate the pharmacodynamic effects of ALDH2 reduction by DCR-AUD during serial EIAs days.

Time frame: 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

Area under the concentration time curve from time 0 to fixed time 2.5 of acetaldehyde was measured to evaluate the pharmacodynamic effects of ALDH2 reduction by DCR-AUD during serial EIAs days.

Time frame: Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169

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 -1), Day 169

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 for the expanded group. Facial skin temperature was measured using a surface scanning thermometer.

Time frame: Baseline (Day -1), Day 169

Change From Baseline in Subjective Effects of Alcohol Scale (SEAS) Score

Subjective feelings of alcohol intoxication or intolerance is measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs. Participants' subjective experience of the effects of alcohol was assessed using the SEAS. The SEAS is a 14-item tool that allows participants to rate the subjective effects of alcohol. Participants rated the extent to which they were feeling (high/low arousal positive: relaxed, wobbly, lively, secure, woozy, fun, calm, dizzy, mellow, funny, talkative and high/low arousal negative: demanding, rude and aggressive) on an 11-point scale from (0 = not at all, 10 = extremely). higher values represent more effects.

Time frame: Baseline (Day -1), Day 169