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Study of DCR-AUD in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT05021640
Recruitment Status : Recruiting
First Posted : August 25, 2021
Last Update Posted : November 8, 2021
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

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

Condition or disease Intervention/treatment Phase
Alcohol Use Disorder (AUD) Drug: DCR-AUD Drug: Placebo for DCR-AUD Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
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.
Primary Purpose: Treatment
Official Title: A Phase 1, Double-blind, Placebo-controlled, Single-ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of DCR-AUD in Healthy Volunteers
Actual Study Start Date : September 21, 2021
Estimated Primary Completion Date : September 10, 2022
Estimated Study Completion Date : September 10, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1 DCR-AUD
Single dose, subcutaneous administration of 80 mg of DCR-AUD (HV)
Drug: DCR-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).
Other Name: DCR-A1203

Placebo Comparator: Cohort 1 DCR-AUD Placebo
Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose
Drug: Placebo for DCR-AUD
0.9% saline for injection
Other Name: Placebo

Experimental: Cohort 2 DCR-AUD
Single dose, subcutaneous administration of 240 mg of DCR-AUD (HV)
Drug: DCR-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).
Other Name: DCR-A1203

Placebo Comparator: Cohort 2 DCR-AUD Placebo
Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose
Drug: Placebo for DCR-AUD
0.9% saline for injection
Other Name: Placebo

Experimental: Cohort 3 DCR-AUD
Single dose, subcutaneous administration of 480 mg of DCR-AUD (HV)
Drug: DCR-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).
Other Name: DCR-A1203

Placebo Comparator: Cohort 3 DCR-AUD Placebo
Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose
Drug: Placebo for DCR-AUD
0.9% saline for injection
Other Name: Placebo

Experimental: Cohort 4 (OPTIONAL) DCR-AUD
Single dose, subcutaneous administration of 960 mg of DCR-AUD (HV)
Drug: DCR-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).
Other Name: DCR-A1203

Placebo Comparator: Cohort 4 (OPTIONAL) DCR-AUD Placebo
Single dose, subcutaneous administration of Placebo for DCR-AUD (HV), volume to match active single dose
Drug: Placebo for DCR-AUD
0.9% saline for injection
Other Name: Placebo




Primary Outcome Measures :
  1. Incidence and severity of AEs, SAEs, and DLTs as assessed by CTCAE v5.0. [ Time Frame: 24 weeks ]
    Adverse events will be defined as treatment-emergent AEs if they have a start date on or after the administration of study intervention during the treatment period. Frequency and percentages will be used to summarize AEs, SAEs, AEs of special interest, and AEs by relationship. Laboratory values will be reported by CTCAE grade and summarized, if applicable.

  2. Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings. [ Time Frame: 24 weeks ]
    To evaluate the safety and tolerability of single doses of DCR-AUD administered to adult HVs.


Secondary Outcome Measures :
  1. Plasma area under the concentration curve (AUC). [ Time Frame: 24 weeks ]
    Measured to characterize plasma pharmacokinetics (PK) of a single dose of DCR-AUD in adult HVs.

  2. Plasma maximum observed concentration (Cmax). [ Time Frame: 24 weeks ]
    Measured to characterize plasma pharmacokinetics (PK) of a single dose of DCR-AUD in adult HVs.

  3. Plasma time to maximum concentration (Tmax). [ Time Frame: 24 weeks ]
    Measured to characterize plasma pharmacokinetics (PK) of a single dose of DCR-AUD in adult HVs.

  4. Plasma acetaldehyde levels. [ Time Frame: 24 weeks ]
    Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group.

  5. Plasma acetate levels. [ Time Frame: 24 weeks ]
    Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group.

  6. Plasma ethanol levels. [ Time Frame: 24 weeks ]
    Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group.

  7. Heart rate. [ Time Frame: 24 weeks ]
    Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group.

  8. Facial skin temperature. [ Time Frame: 24 weeks ]
    Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group.

  9. Subjective feelings of alcohol intoxication or intolerance using the Subjective Effects of Alcohol Scale (SEAS). [ Time Frame: 24 weeks ]
    Measured to evaluate the PD effects of ALDH2 reduction by DCR-AUD during serial EIAs for the expanded group.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 21 to 65 years of age, inclusive, at the time of signing the informed consent.
  • Overtly healthy, as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
  • Social drinkers of modest amounts (≤ 2 drinks/day and ≤ 3 days/week) who are able to refrain from drinking alcohol during the outpatient portion of the trial.
  • 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.
  • Willing to participate in repeated low-dose EIAs followed by an overnight clinic stay.
  • Has a negative test for SARS-CoV-2 infection on Day -1 and prior to admission to the clinical unit.
  • Systolic BP in the range of 90 to 140 mmHg and diastolic BP in the range of 55 to 95 mmHg.
  • 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.
  • 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, beginning at consent and the first Screening visit and for at least 24 weeks after the last dose of study intervention.
  • BMI within the range 18.0 to 32.0 kg/m2 (inclusive).
  • 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 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. NOTE: Persons with clinically stable asthma who have not been hospitalized in the prior year and are treated with orally inhaled medications only are not excluded.
  • History of suicidal attempt as an adult or suicide ideation in the past year that resulted in pharmacologic treatment or hospitalization. Specifically: Answer of "yes" on items 4 or 5 of the Suicidal Ideation section of the C-SSRS at screening if ideation occurred in the past 6 months. Answer of "yes" on any item of the Suicidal Behavior section of the C-SSRS, except for the Non-Suicidal Self-injurious Behavior if this behavior occurred in the previous 2 years.
  • 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 subject were they to participate in the trial, as informed by the participant's medical history and/or responses to the MINI Screen Questionnaire.
  • History of delirium tremens or alcohol-related seizures.
  • History of significant adverse reaction(s) to alcohol.
  • 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:

    1. Poorly controlled or unstable hypertension.
    2. Clinically significant abnormalities in vital signs: pulse rate (< 40 or > 90 bpm), respiratory rate, or temperature.
    3. 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.
    4. Diabetes mellitus treated with insulin or hypoglycemic agents (including metformin) or HbA1C > 7%.
    5. Asthma requiring hospital admission within the preceding 12 months.
    6. Currently poorly controlled endocrine conditions, except for hypothyroidism that is stable (no treatment change in prior 6 months).
    7. Significant infection or known systemic inflammatory process ongoing at Screening.
    8. History of chronic or recurrent UTI, or UTI within 1 month prior to Screening.
  • History of malignancy within the preceding 3 years requiring treatment, with the exception of excised low grade basal cell skin neoplasms.
  • 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.
  • Clinically significant illness within the 7 days prior to the administration of study intervention.
  • History of multiple drug allergies or a history of allergic reaction to an oligonucleotide-based therapy.
  • Use of prescription medications (except for hormonal replacement/contraceptive medication for women and inhaled medical 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).
  • Receipt of any vaccine (include COVID-19) within 14 days prior to administration of study intervention.
  • Regular use of OTC medications, including NSAID (Periodic or occasional NSAID use to control temporary pain is not exclusionary).
  • 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.
  • 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.
  • Had laboratory-confirmed SARS-CoV-2 infection in the 14 days prior to randomization.
  • Liver function test results (AST, ALT, GGT, total bilirubin) above the normal range.
  • Safety laboratory test result considered clinically unacceptable for study participation by the Investigator.
  • 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.
  • Scheduled for an elective surgical procedure during the conduct of this study.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05021640


Contacts
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Contact: Vice President Clinical Operations 1-617-621-8097 ext 0440 sshergill@dicerna.com

Locations
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United States, California
Parexel Los Angeles Early Phase Clinical Unit Recruiting
Glendale, California, United States, 91206
Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc.
Parexel
Investigators
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Study Director: John Hanrahan, MD, MPH Dicerna Pharmaceuticals, Inc.
Principal Investigator: Lev G. Gertsik, MD Parexel
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Responsible Party: Dicerna Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT05021640    
Other Study ID Numbers: DCR-AUD-101
First Posted: August 25, 2021    Key Record Dates
Last Update Posted: November 8, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alcoholism
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders