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Alcohol Use DisorderPhase 3ONWARDNCT04101227

Study to Evaluate AD04 in Adults With Alcohol Use Disorder (AUD) and Selected Serotonin Transporter Polymorphisms

A Phase 3 study testing AD04 (ondansetron), Companion Diagnostic for Genetic Testing and Brief Psychological Counseling in people with Alcohol Use Disorder, run by Adial Pharmaceuticals at 25 sites in 7 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Randomized, multi-center, double-blind, parallel-group, placebo-controlled study. Eligible subjects will be randomized to receive either 0.33 mg AD04 or placebo orally twice-daily for 24 weeks in conjunction with brief psychological counseling. Randomization will be stratified by: 1. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Alcohol Use Disorder
What is being tested?
AD04 (ondansetron), Companion Diagnostic for Genetic Testing and Brief Psychological Counseling
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
302 participants
Where
25 sitesin 7 countries
Study dates
1 Feb 2020to 18 Mar 2022
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The subject has signed the Informed Consent Form.
  • The subject has breath alcohol concentration (BAC) of 0.00% at the Screening and < 0.02 % at the Baseline visit.
  • The subject has moderate to severe diagnosis of AUD as measured by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.
  • Males and females aged 18 and over.
  • Able to provide Timeline Follow-back Method (TLFB) alcohol consumption information for the 28-day period prior to Screening Visit.
  • A subject is eligible for participation in the study if he/she had:
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  • ≥6 HDDs (HDD is defined as a day with alcohol consumption of 60 g or more for males and 40 g or more for females) in the 4 weeks prior to the Baseline Visit,
  • an average alcohol consumption at the medium risk level (defined by the WHO "International guide for monitoring alcohol consumption and related harm" as >40 grams of ethanol/day for males and >20 grams of ethanol/day for females) for the 4 weeks prior to the Screening Visit,
  • ≤14 consecutive abstinent days in the 4 weeks preceding the Screening Visit.
  • Willingness to provide a blood sample for DNA analysis at the Screening visit. The blood sample collected for DNA testing contains at least one of the following genotypes as measured by Adial's validated method:
  • rs4795541-LL genotype of the insertion-deletion polymorphism (5'-HTTLPR) in the 5'-regulatory region and rs1042173-TT SNP in the 3'-untranslated region of SLC6A4 gene that encodes the serotonin transporter
  • rs1150226-AG SNP in HTR3A, the gene that encodes subtype A of the serotonin-3 receptor
  • rs1176713-GG SNP in HTR3A, the gene that encodes subtype A of the serotonin-3 receptor
  • rs17614942-AC in HTR3B, the gene that encodes subtype B of the serotonin-3 receptor
  • Expressed a wish to reduce or stop alcohol consumption.
  • Willingness to participate in behavioral and medicinal treatments for AUD.
  • Has had a stable residence in the 28 days prior to the Baseline Visit in the study and has no plans to move in the next 9 months. A stable residence is a domicile in which an individual can operate as if it were his or her own homestead and does not include shelters or halfway houses.
  • Provides contact information for 2 individuals who can be used to contact the subject.
  • Able to read and understand, and complete the rating scales and questionnaires accurately, follow instructions, and make use of the behavioral treatments.
  • The subject, if female must:
  • have a negative urine pregnancy test prior to the initiation of treatment and agree not to try to become pregnant during the study
  • use two adequate methods of contraception [intrauterine device, oral contraceptives, progesterone implanted rods, or regular medroxyprogesterone acetate injections in addition to condom or diaphragm, or double barrier method (condom or diaphragm + spermicide)], or
  • be post-menopausal having had the last natural menstruation at least 24 months prior to the Screening Visit, or
  • have had a hysterectomy or been surgically sterilized prior to baseline.

Who cannot join

  • Patients with withdrawal symptoms requiring additional medication for withdrawal. If present at Screening/Baseline Visit, subjects must complete a medically supervised detoxification program prior to being able to enroll in the study.
  • Subjects with diagnosis of any of the following concomitant psychiatric disorders: non-treated, unstable schizophrenia, bipolar disorder, other psychotic disorder during the lifetime of the subject. Recent (within last 12 months) diagnosis of a major depressive disorder, post traumatic stress disorder, panic disorder or eating disorders. Subjects with nicotine use disorder, phobic or other anxiety disorders (other than post-traumatic stress disorder or panic disorder) can be included.
  • The subject reports current or recent (within 8 weeks prior to Baseline Visit) treatment with antipsychotics or antidepressants medications, which can have an effect on serotonin receptor or transporter actions.
  • The subject has been treated with any investigational medicinal product within 30 days or 5 half-lives (whichever is longer) prior to the Baseline Visit.
  • The subject is currently participating or has recently (4 weeks prior to the Baseline Visit) participated in a treatment program for alcohol use disorders.
  • Any subject who has suicidal thoughts as evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS) (i.e., has any suicidal ideation of type 4 or 5 on the C-SSRS in the last month).
Show all 25Show fewer
  • The subject has a clinically significant untreated and unstable illness, for example, hepatic or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, infectious, neoplastic, or metabolic disturbance.
  • The subject has clinically significant abnormal vital signs.
  • The subject has a clinically abnormal ECG at the Screening/Baseline Visit, clinically significant cardiovascular disease requiring regular or intensive clinical monitoring, a current history of arrhythmias, or a current or past history of clinically significant QT prolongation, including:
  • QTcF > 450 ms (one ECG at screening and average of 3 12-lead measurements at baseline)
  • serum potassium, magnesium or calcium levels outside the central laboratory's reference range
  • receiving medications (within the last 7 days prior to the Baseline Visit) that have the potential of prolonging the QT interval or may require such medications during the course of the study
  • clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia or indwelling pacemaker
  • complete left bundle branch block
  • history of Long QT Syndrome or an immediate family member with this condition
  • The subject with elevated liver function tests or diagnosis of hepatic failure, esophageal variceal disease or any other clinically significant hepatic disease. The clinical evidence may include any of the following: prolonged prothrombin time (International Normalized Ratio, INR≥1.7) with bilirubin > 10% above the upper limit, and/or serum glutamic oxaloacetic transaminase (SGOT), and/or serum glutamic pyruvic transaminase (SGPT) and/or lactate dehydrogenase (LDH) > 3x the upper limit of normal at screening.
  • The subject reports treatment, either current or within 28 days prior to the Baseline Visit, with any medications having a potential effect on alcohol consumption and related behaviors or mood. These include opiate antagonists (e.g., naltrexone, Vivitrol®, Selincro®), glutamate antagonists (e.g., acamprosate), anticonvulsants (e.g., topiramate), serotonin reuptake inhibitors (e.g., fluoxetine), serotonin antagonists (e.g., buspirone), other antidepressants (e.g., tricyclic antidepressants or monoamine oxidase inhibitors), dopamine antagonists (e.g., haloperidol), and disulfiram (Antabuse®). Note benzodiazepines are allowed if used chronically.
  • Previous or current abuse of benzodiazepines.
  • At Baseline Visit, the subject's urine contains prescription and non-prescription drugs with abuse potential or other psychotropic agents not otherwise specified, including herbal agents such as St John's Wort that could interfere with the drug treatment.
  • The subject has a history of allergic reactions or other known intolerance to ondansetron or other 5-HT3 antagonists.
  • Female subjects of childbearing potential who have a positive pregnancy test at Screening/Baseline Visit or are pregnant, breast feeding and who are unwilling to adhere to an acceptable form of contraception or meet the other criteria for inclusion as specified for females in the inclusion criteria (See Inclusion Criteria, Item # 13).
  • The subject received in-patient or out-patient treatment for alcohol use disorder within the 28 days prior to the Baseline Visit.
  • As of the Baseline Visit, the subject is compelled to participate in an alcohol treatment program to maintain his/her liberty.
  • As of Baseline Visit, the subject is sharing a household with a subject randomized to any investigational trial of ondansetron.
  • Any other condition or therapy that in the investigator's opinion may pose a risk to the subject, prevent the subject from completing the required study procedures or interfere with the study objectives.

Trial locations and contacts

25 sites in 7 countries.

25 sites in 7 countries

Bulgaria7 sites

  • Mental Health Centre Prof. Dr. Ivan Temkov Burgas EOOD Department for treatment of Emergency Psychiatric conditions

    Burgas

  • State Psychiatric Hospital

    Kardzhali

  • UMHAT Dr. Georgi Stranski Second Psychiatric Clinic

    Pleven

  • Ambulatory for Group Practice for Specialized Psychiatric Help - Philipopolis OOD

    Plovdiv

  • Medical Center Intermedica OOD

    Sofia

  • State Psychiatric Hospital for Treatment of drug addiction and alcoholism

    Sofia

  • Diagnostic-Consultative Center Mladost-М Varna

    Varna

Other trials in Bulgaria

Finland6 sites

  • Addiktum klinikka Helsinki

    Helsinki, 00120

  • Savon psykiatripalvelu

    Kuopio

  • Mentalcare

    Oulu

  • Satakunnan Psykiatripalvelu Oy

    Pori

  • Satakunnan Psykiatripalvelu Oy

    Tampere

  • Addiktum Oy

    Turku

Other trials in Finland

Croatia3 sites

  • Clinical Hospital Center Split

    Split

  • Polyclinic Neuron

    Zagreb

  • University Psychiatric Hospital Vrapče Klinika za psihijatriju Vrapče

    Zagreb

Other trials in Croatia

Latvia3 sites

  • Liepaja Regional Hospital Addictive disorder department

    Liepāja

  • M&M Centrs

    Riga

  • Strenci Psychoneurological Hospital

    Strenči

Other trials in Latvia

Poland3 sites

  • Centrum Medyczne Luxmed Sp. z. o. o.

    Lublin

  • NZOZ Prywatna Klinika Psychiatryczna

    Tuszyn

  • Clinical Research Group Sp. z.o.o

    Warsaw

Other trials in Poland

Sweden2 sites

  • Ladulaas Kliniska Studier

    Borås

  • ClinSmart Sweden AB

    Uppsala

Other trials in Sweden

Estonia1 site

  • West Tallinn Central Hospital, Haabersti Health Center

    Tallinn

Other trials in Estonia

About this study

Official title: Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of AD04 (Ondansetron) in Adults With Alcohol Use Disorder (AUD) and Selected Polymorphisms in the Serotonin Transporter and Receptor Genes

Randomized, multi-center, double-blind, parallel-group, placebo-controlled study. Eligible subjects will be randomized to receive either 0.33 mg AD04 or placebo orally twice-daily for 24 weeks in conjunction with brief psychological counseling. Randomization will be stratified by:

  1. Level of alcohol consumption prior to enrollment in the study (heavy drinkers averaging <10 drinks per day of drinking or very heavy drinkers averaging ≥10 drinks per day of drinking), and
  2. Gender (male or female).
Read the detailed description

Target enrollment of subjects with AUD who regularly engage in risk alcohol consumption (i.e. >6/day or more heavy alcohol consumption in the 4 weeks preceding the screening visit), and have selected genotypes (LL/TT genotype and/or 1, 2 or 3 of the SNPs on the genes for the 5-HT3 receptor subunits: rs1150226-AG or rs1176713-GG in the gene that encodes the 5-HT3A receptor subunit, and rs17614942-AC in the gene that encodes the 5-HT3B receptor subunit), and who are eligible to participate in the study based on meeting the remaining study inclusion/exclusion criteria. Eligible subjects will be randomized to receive either 0.33 mg AD04 or placebo BID for 24 weeks.

The trial will have a 16-week grace period to enable medication effects to be optimal for comparison with placebo. The grace period starts immediately after beginning of study drug treatment, in which consumption of alcohol is not counted as a failure. All primary and secondary efficacy endpoints will be assessed during the last 8 weeks of treatment (i.e. weeks 17-24). The primary measure of efficacy, incidence risk alcohol consumption, will be assessed over the last 8 weeks of treatment. The secondary measure of efficacy evaluating the incidence of risk alcohol consumption over the last 4 weeks of treatment, important because it has been used commonly to validate efficacy for regulatory agencies such as the European Medicines Agency, was also calculated. To enhance study feasibility, subjects will be evaluated every week during the first 8 weeks of treatment and every other week for the remaining 16 weeks of the treatment period.

Being tested
AD04 (ondansetron), Matching placebo, Companion Diagnostic for Genetic Testing, Brief Psychological Counseling
Medical subject headings
Alcoholism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AD04 (ondansetron)Drug

    AD04 (ondansetron) 0.33 mg, orally (p.o.) twice a day (BID)

  • Matching placeboDrug

    Matching placebo to AD04 (ondansetron), orally (p.o.) twice a day (BID)

  • Companion Diagnostic for Genetic TestingDevice

    Companion Diagnostic for Genetic Testing

  • Brief Psychological CounselingBehavioural

    Brief Psychological Counseling

Study groups in NCT04101227
Study groupRoleWhat they receive
Treatment ArmExperimentalAD04 (ondansetron)
Receives: Drug: AD04 (ondansetron); Device: Companion Diagnostic for Genetic Testing; Behavioral: Brief Psychological Counseling
Placebo ArmPlacebo comparatorMatching Placebo
Receives: Drug: Matching placebo; Device: Companion Diagnostic for Genetic Testing; Behavioral: Brief Psychological Counseling

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change from baseline in the percentage of monthly heavy drinking days (PHDD)

    Change from baseline in the percentage of monthly HDDs, where (heavy) drinking is defined as the consumption of ≥ 60 g alcohol/day (if male) or ≥ 40 g alcohol/day (if female).

    Measured: Weeks 16 to 24

Secondary outcomes (10)

  1. Change from baseline in the primary efficacy endpoint at each study month

    Change from baseline in PHDD at each study month.

    Measured: Weeks 4, 8, 12, 16, 20, and 24

  2. Change from baseline in AUD symptoms and clinical status

    AUD symptoms and clinical status (<2 symptoms, Mild, Moderate, or Severe) based on DSM-5 criteria at Baseline, weeks 12 and 24 visits

    Measured: Weeks 12 and 24

  3. Change from baseline in Drinking Risk Levels (DRL), 1-level shift

    Proportion of subjects with a 1-level categorical shift from baseline in modified DRL

    Measured: Week 24

  4. Change from baseline in Drinking Risk Levels (DRL), 2-level shift

    Proportion of subjects with a 2-level categorical shift from baseline in modified DRL

    Measured: Week 24

  5. Change from baseline in total alcohol consumption (TAC)

    Change from baseline in total alcohol consumption (TAC), defined as the mean daily alcohol consumption expressed in g/day

    Measured: Weeks 16 to 24

  6. Change from baseline in the Patient Health Questionnaire-9 (PHQ-9)

    Change from baseline in the PHQ-9 calculated as the difference from baseline to Week 24.

    Measured: Week 24

  7. Change from baseline in risk alcohol consumption responders

    The number of subjects with no risk alcohol consumption will be calculated

    Measured: Weeks 16 to 24

  8. Change from baseline in percent reduction in monthly total alcohol consumption (TAC)

    Proportion of subjects with ≥10%, ≥20%, ≥30%, ≥40%, ≥50%, ≥60%, ≥70%, ≥80%, and ≥90% reduction from baseline in monthly TAC

    Measured: Weeks 20 to 24

  9. Change from baseline in the percent of non-drinking days (PNDD)

    Change from baseline in the percent of non-drinking days (PNDD)

    Measured: Weeks 16 to 24

  10. Change from baseline in drinks per drinking day (DDD)

    Change from baseline in the monthly drinks per drinking day (DDD)

    Measured: Weeks 16 to 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Sep 2019
  2. Study start1 Feb 2020
  3. Primary completion18 Feb 2022
  4. Study completion18 Mar 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
302 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04101227
Sponsor's protocol ID
AD04-301
Acronym
ONWARD
Status last verified
Apr 2024
First submitted
23 Sep 2019
Last updated
17 Apr 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing AD04 (ondansetron), Companion Diagnostic for Genetic Testing and Brief Psychological Counseling in people with Alcohol Use Disorder, run by Adial Pharmaceuticals at 25 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 25 sites in Bulgaria, Finland, Croatia, Latvia, Poland and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change from baseline in the percentage of monthly heavy drinking days (PHDD) (time frame: Weeks 16 to 24). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04101227.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Apr 2024.

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