Clinical trial NCT05021640: Study of DCR-AUD in Healthy Volunteers
Official title: A Phase 1, Double-blind, Placebo-controlled, Single-ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alcohol Use Disorder (AUD)
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2021-08-25
Enrollment: 36
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From Day 1 up to 24 Weeks
measure: Number of Participants With Severity Grades of TEAEs
timeFrame: From Day 1 up to 24 Weeks
measure: Number of Participants With Dose-limiting Toxicities (DLTs) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
timeFrame: From Day 1 up to 24 Weeks
measure: Number of Participants With Change From Baseline in Clinically Significant Abnormal Vital Signs
timeFrame: From Baseline (Day -1) up to 24 weeks
measure: Number of Participants With Change From Baseline in Clinically Significant Abnormal Electrocardiogram (ECG) Findings
timeFrame: From Baseline (Day -1) up to 24 weeks
measure: Number of Participants With Change From Baseline in Clinically Significant Abnormal Laboratory Values
timeFrame: From Baseline (Day -1) up to 24 weeks
measure: Number of Participants With Change From Baseline in Clinically Significant Physical Examination Findings
timeFrame: From Baseline (Day -1) up to 24 weeks
Secondary outcomes:
measure: AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD
timeFrame: Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose
measure: Cmax: Maximum Observed Plasma Concentration of DCR-AUD
timeFrame: Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose
measure: Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax)
timeFrame: Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose
measure: t1/2: Apparent Terminal Elimination Half-life of DCR-AUD
timeFrame: Day 1: Predose, at 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72 hours post dose; Day 15: Once Post dose
measure: Fe%0-72: Urinary Cumulative Excretion as % of Unchanged DCR-AUD up to 72 Hours
timeFrame: At time interval between 0- 4 hours, 0- 8 hours, 0-12 hours, 0-24 hours, 0-48 hours, 0-72 hours
measure: CLR: Renal Clearance of the DCR-AUD From Plasma
timeFrame: Day 1: 0-4, 4-8, 8-12, 12-24, 24-48, and 48-72-hours post-dose
measure: Six Symptom Responses During Ethanol Interactions Assessments (EIAs)
timeFrame: Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169
measure: Cmax: Maximum Observed Plasma Concentration of Acetaldehyde
timeFrame: Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169
measure: AUC0-2.5: Area Under the Concentration Time Curve From Time 0 to Fixed Time 2.5 of Acetaldehyde
timeFrame: Day -1, Day 4, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 169
measure: Change From Baseline in Heart Rate
timeFrame: Baseline (Day -1), Day 169
measure: Change From Baseline in Facial Skin Temperature
timeFrame: Baseline (Day -1), Day 169
measure: Change From Baseline in Subjective Effects of Alcohol Scale (SEAS) Score
timeFrame: Baseline (Day -1), Day 169
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Parexel Los Angeles Early Phase Clinical Unit
state: California
Study officials:
affiliation: Novo Nordisk A/S
name: Clinical Transparency (dept. 1452)
role: STUDY_DIRECTOR
References: