Study of DCR-AUD in Healthy Volunteers

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05021640

Enrollment

Registered

2021-08-25

Start date

2021-09-21

Completion date

2022-12-31

Last updated

2024-12-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alcohol Use Disorder (AUD)

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.

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 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).

DRUGPlacebo for DCR-AUD

0.9% saline for injection

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, 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

Sex/Gender

ALL

Age

21 Years to 65 Years

Healthy volunteers

Yes

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

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 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	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	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	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
Cmax: Maximum Observed Plasma Concentration of Acetaldehyde	Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169	Maximum plasma concentration of acetaldehyde was measured to evaluate the pharmacodynamic effects of ALDH2 reduction by DCR-AUD during serial EIAs days.
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	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.
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	AUC0-last is defined as the area under the plasma concentration curve from time zero to the last quantifiable concentration of DCR-AUD.
Change From Baseline in Facial Skin Temperature	Baseline (Day -1), Day 169	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.
Change From Baseline in Subjective Effects of Alcohol Scale (SEAS) Score	Baseline (Day -1), Day 169	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.
Change From Baseline in Heart Rate	Baseline (Day -1), 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.
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	Cmax is defined as maximum observed plasma concentration of DCR-AUD during a dosing interval.
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	Tmax is defined as time to reach the maximum plasma concentration (Cmax) of DCR-AUD.
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	t1/2 is defined as apparent terminal elimination half-life of DCR-AUD.
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	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.
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	Renal clearance of the DCR-AUD from plasma is reported in this outcome measure.
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	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).

Countries

United States

Participant flow

Pre-assignment details

In this trial 36 healthy participants were randomized to four ascending-dose cohorts (80 milligram \[mg\], 240 mg, 480 mg, 960 mg) and placebo.

Participants by arm

Arm	Count
Cohort 1: DCR-AUD 80 mg Participant received a single dose of DCR-AUD 80 mg, subcutaneous injection on Day 1.	6
Cohort 2: DCR-AUD 240 mg Participant received a single dose of DCR-AUD 240 mg, subcutaneous injection on Day 1.	6
Cohort 3: DCR-AUD 480 mg Participant received a single dose of DCR-AUD 480 mg, subcutaneous injection on Day 1.	6
Cohort 4: DCR-AUD 960 mg Participant received a single dose of DCR-AUD 960 mg, subcutaneous injection on Day 1.	6
Pooled Placebo Participant received a single dose of DCR-AUD matching placebo, subcutaneous injection on Day 1.	12
Total	36

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Lost to Follow-up	0	0	0	0	1

Baseline characteristics

Characteristic	Cohort 1: DCR-AUD 80 mg	Cohort 2: DCR-AUD 240 mg	Cohort 3: DCR-AUD 480 mg	Cohort 4: DCR-AUD 960 mg	Pooled Placebo	Total
Age, Continuous	51.3 years STANDARD_DEVIATION 10.29	36.3 years STANDARD_DEVIATION 12.26	34.2 years STANDARD_DEVIATION 14.44	32.8 years STANDARD_DEVIATION 4.88	41.3 years STANDARD_DEVIATION 12.19	39.6 years STANDARD_DEVIATION 12.48
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	3 Participants	2 Participants	4 Participants	3 Participants	14 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	3 Participants	4 Participants	2 Participants	9 Participants	22 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants	1 Participants	1 Participants	4 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	1 Participants	1 Participants	3 Participants	7 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	4 Participants	4 Participants	3 Participants	8 Participants	24 Participants
Sex: Female, Male Female	3 Participants	4 Participants	5 Participants	4 Participants	8 Participants	24 Participants
Sex: Female, Male Male	3 Participants	2 Participants	1 Participants	2 Participants	4 Participants	12 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 6	0 / 6	0 / 6	0 / 12
other Total, other adverse events	4 / 6	5 / 6	4 / 6	2 / 6	9 / 12
serious Total, serious adverse events	0 / 6	0 / 6	0 / 6	0 / 6	0 / 12

Outcome results

Primary

Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG) Findings

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