Clinical trial NCT05845398: Phase 1b Study of DCR-AUD in Healthy Volunteers
Official title: A Phase 1b, Double-blind, Placebo-controlled, Repeat-dose, Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of DCR-AUD in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alcohol Use Disorder
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2023-05-06
Enrollment: 16
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized 3 to 1 to DCR-AUD or placebo.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to test the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of of repeat doses of DCR-AUD in adult healthy volunteers who are social drinkers.

The main questions it aims to answer are:

* Are repeat doses of DCR-AUD safe and well-tolerated in healthy adults who are social drinkers?
* How does the drug behave inside the human body and how it is removed from the human body?
* What are the symptoms the drug may cause with alcohol consumption?

Participants will:

* Receive multiple doses of DCR-AUD.
* Have assessment visits through Week 24.
* Participate in up to 10 Ethanol Interaction Assessments (EIAs) to see how the body is affected by DCR-AUD.

Researchers will compare the groups of participates who receive study drug with the group of participants who receive placebo to see if the study drug is safe and tolerable and whether the study drug has any real effect.


Eligibility criteria: Inclusion Criteria:

1. 21 to 65 years, inclusive, at the time of signing informed consent.
2. Overtly healthy volunteers, as determined by medical evaluation including medical history, physical examination, and laboratory testing.
3. No diagnosis of AUD within the preceding 12 months per Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
4. Social drinkers who consume, on average, 5 to 20 drinks per week for men or 5 to 14 drinks per week for women over the 4 weeks prior to Screening, and not more than 8 drinks in a single day.
5. No evidence of overt or sub-clinical hepatic pathology, as manifest by serologic tests demonstrating hepatic inflammation or compromised hepatic synthetic function (i.e., AST, ALT, GGT, total bilirubin \< 1.5 times the ULN at Screening and Day -1).
6. eGFR ≥ 60 mL/min/1.73 m2 at Screening.
7. No history of significant adverse reaction(s) to alcohol. Participant should be expected to tolerate the amount of alcohol administered during EIAs.
8. Willing to participate in up to 10 EIAs.
9. Has a negative test for SARS-CoV-2 infection on Day -1.
10. Systolic BP in the range of 80 to 140 mmHg and diastolic BP in the range of 50 to 95 mmHg at Screening. If out of range, BP may be repeated once at the discretion of the Investigator.
11. Male or female

    * 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 (see Section 10.4).
    * 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 (see Section 10.4), beginning at consent and the first Screening visit and for at least 24 weeks after the last dose of study intervention.
12. BMI within the range 18.0 to 32.0 kg/m2 (inclusive).
13. 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 metabolism of study intervention or with the clinical and laboratory assessments in this study. 2. History of serious, persistent medical conditions, including liver, gastrointestinal, pulmonary, renal, or cardiovascular abnormalities. 3. History of suicidal attempt at any time or an answer of "yes" on any of the following items in the C-SSRS at Screening:

1. Items 1 or 2 of the Suicidal Ideation section, if ideation occurred in the previous 12 months.
2. Items 4 or 5 of the Suicidal Ideation section, in lifetime.
3. Any item of the Suicidal Behavior section of the C-SSRS, in lifetime. 4. Any history of severe or recent clinically significant depression, anxiety, bipolar disorder, schizophrenia, or other neuropsychiatric disorder that, in the judgement of the Investigator, represents a safety risk to the participant were they to participate in the trial, as informed by the participant's medical history and/or responses to the MINI Screen Questionnaire. 5. History of substance use disorder (SUD) or illicit drug use (excluding cannabis) within the preceding 12 months. 6. History of alcohol withdrawal symptoms including delirium tremens or alcohol-related seizures. 7. 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:

a. Poorly controlled or unstable hypertension. b. Diabetes mellitus treated with insulin or hypoglycemic agents (including metformin) or HbA1C \> 7%. Asthma requiring hospital admission within the preceding 12 months. NOTE: Persons with clinically stable asthma who have not been hospitalized in the prior year and are treated only with orally inhaled medications are not excluded. d. Currently poorly controlled endocrine conditions, except for hypothyroidism that is stable (no treatment change in prior 6 months). e. Significant infection or known systemic inflammatory process ongoing at Screening.

f. History of chronic or recurrent UTI, or UTI within 1 month prior to Screening.

8. History of malignancy within the preceding 5 years requiring treatment, with the exception of excised low grade basal cell skin neoplasms. 9. History of any concomitant medical condition for which alcohol consumption is prohibited or advised against by the participant's physician or health care provider.

10. SARS-CoV-2 infection in the 14 days prior to randomization. 11. Clinically significant illness within the 7 days prior to the first administration of study intervention. History of multiple drug allergies or a history of allergic reaction to an oligonucleotide based therapy.

13. Use of prescription medications (except for hormonal replacement/contraceptive medication for women and inhaled medication 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). 14. Receipt of any vaccine (including COVID-19) within 14 days prior to the first administration of study intervention. 15. Regular use of OTC medications, including NSAID (periodic or occasional NSAID use to control temporary pain is not exclusionary). 16. Previously participated in Dicerna Study DCR-AUD-101. 17. 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. 18. Clinically significant abnormalities in vital signs at Screening: pulse rate (\< 40 bpm or \> 90 bpm), respiratory rate, or temperature. 19. 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. 20. Positive urine drug test at Screening or Day -1. Tests positive for cannabis are not exclusionary. 21. 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. 22. Safety laboratory test result at Screening considered clinically unacceptable for study participation by the Investigator. 23. 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. 24. Scheduled for an elective surgical procedure during the conduct of this study.

25. 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.

Life Style Considerations:

1. Study participants are to refrain from drinking alcohol for 24 hours prior to each EIA and must have a negative breath-alcohol test on the day of the study visit.
2. Study participants will be advised to avoid consuming more than 4 drinks during any drinking session outside of in-clinic EIAs.
3. Study participants will be instructed to stop drinking at the onset of any ethanol reaction symptoms during outside drinking sessions.
4. Tobacco/nicotine use is not restricted.
5. Study participants are to refrain from using cannabis for 24 hours prior to each EIA and must have a negative urine-drug test on the day of the study visit.
6. Study participants should abstain from strenuous exercise for 24 hours before each blood collection for clinical laboratory tests. Participants may participate in light recreational activities (e.g., walking at a pace \< 3 miles per hour, shopping, watering plants) in that 24-hour time period.
7. For each EIA study visit, participants will be required to fast for at least 3 hours and then will be fed a standardized meal in the clinic prior to administration of ETOH for the EIA.

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 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)
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: Six Symptom Responses During Ethanol Interactions Assessments (EIAs)
timeFrame: Day -1 (baseline), Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168
measure: AUC0-last: Area Under the Plasma Concentration Curve From Time Zero to the Last Quantifiable Concentration of DCR-AUD
timeFrame: Day 1, Day 29 and Day 57
measure: Cmax: Maximum Observed Plasma Concentration of DCR-AUD
timeFrame: Day 1, Day 29 and Day 57
measure: Tmax: Time to Reach the Maximum Plasma Concentration of DCR-AUD (Cmax)
timeFrame: Day 1, Day 29 and Day 57
measure: Cmax: Maximum Observed Plasma Concentration of Acetaldehyde
timeFrame: Day -1 (baseline), Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168
measure: AUC0-4: Area Under the Concentration Time Curve From Time 0 to Fixed Time 4 of Acetaldehyde
timeFrame: Day -1, Day 14, Day 28, Day 42, Day 56, Day 70, Day 84, Day 112, Day 140 and Day 168
measure: Change From Baseline in Heart Rate
timeFrame: Baseline, Day 169
measure: Change From Baseline in Facial Skin Temperature
timeFrame: Baseline, Day 169
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Parexel Los Angeles Early Phase Clinical Unit
state: California
Study officials:
affiliation: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
name: John Hanrahan, MD, MPH
role: STUDY_DIRECTOR
affiliation: Parexel
name: Lev G. Gertsik, MD
role: PRINCIPAL_INVESTIGATOR
References: