E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients diagnosed with moderate or severe alcohol use disorder |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10080021 |
E.1.2 | Term | Alcohol use disorder |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate the efficacy of oral AD04 0.33 mg administered BID in conjunction with brief psychosocial counselling for a period of 24 weeks in reducing alcohol consumption among currently consuming subjects with AUD having selected genotypes at the serotonin transporter and receptor genes. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the safety and tolerability of oral AD04 0.33 mg BID treatment in subjects with AUD having selected genotypes at the serotonin transporter and receptor genes. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study: A blood sample will be collected from approximately 100 subjects as part of a pharmacokinetic (PK) sub-study. PK sample collection may be relegated to a subset of Investigative sites selected by the sponsor. PK data from about 50 of the samples (those from the subjects that were randomized to AD04) will be included in a PK modeling simulation analysis to assess the recommended dose in adolescent subjects with AUD. |
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E.3 | Principal inclusion criteria |
1. The subject has signed the Informed Consent Form. 2. The subject has breath alcohol concentration (BAC) of 0.00% at the Screening and < 0.02 % at the Baseline visit. 3. The subject has moderate to severe diagnosis of AUD as measured by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria. 4. Males and females aged 18 and over. 5. Able to provide Timeline Follow-back Method (TLFB) alcohol consumption information for the 28-day period prior to Screening Visit. 6. A subject is eligible for participation in the study if he/she had: a. ≥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, b. 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, c. ≤14 consecutive abstinent days in the 4 weeks preceding the Screening Visit. 7. 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 8. Expressed a wish to reduce or stop alcohol consumption. 9. Willingness to participate in behavioral and medicinal treatments for AUD. 10. 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. 11. Able to read and understand, and complete the rating scales and questionnaires accurately, follow instructions, and make use of the behavioral treatments. 12. 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 an adequate methods of contraception, 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 permanently prior to baseline. 13. The subject, if male and has a female partner of childbearing potential, must use a condom as a contraceptive method up to the safety follow-up visit. |
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E.4 | Principal exclusion criteria |
1. Patients with withdrawal symptoms requiring additional medication for withdrawal. 2. 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-stress disorder, panic disorder or eating disorders. 3. 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. 4. 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. 5. The subject is currently participating or has recently (4 weeks prior to the Baseline Visit) participated in a treatment program for alcohol use disorders. 6. Any subject who has suicidal thoughts as evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS). 7. The subject has a clinically significant untreated and unstable illness. 8. The subject has clinically significant abnormal vital signs. 9. 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. 10. Serum potassium, magnesium or calcium levels that are below or>10% above the central laboratory's reference range, If serum potassium, magnesium, or calcium is below lower normal range, subject is allowed to take a supplement and be re-assessed before baseline. 11. The subject with elevated liver function tests or diagnosis of hepatic failure, esophageal variceal disease or any other clinically significant hepatic disease. 12. 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 13. The subject reports treatment at Baseline with any of the prohibited medications. 14. Previous or current abuse of benzodiazepines. 15. The subject has a history of allergic reactions or other known intolerance to ondansetron or other 5-HT3 antagonists. 16. 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 17. The subject received in-patient or out-patient treatment for alcohol use disorder within the 28 days prior to the Baseline Visit. 18. As of the Baseline Visit, the subject is compelled to participate in an alcohol treatment program to maintain his/her liberty. 19. As of Baseline Visit, the subject is sharing a household with a subject randomized to any investigational trial of ondansetron. 20. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for analysis of efficacy is the change from baseline in the monthly percent of (heavy) drinking days (PHDD) in Study Months 5 and 6 combined, where (heavy) drinking is defined as the consumption of ≥ 60 g alcohol/day (if male) or ≥ 40 g alcohol/day (if female). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The key secondary endpoints for analyses of efficacy are: • Change from baseline in total alcohol consumption (TAC) during Study Months 5 and 6. • Change from baseline in PHQ-9 total score at Week 24 Other secondary endpoints for analyses of efficacy will include: • Proportion of subjects with a significant categorical shift from baseline in the modified DRL at Study Month 6 o for subjects at Very High Risk at baseline: Shift to Medium Risk or below o for subjects at High Risk at baseline: Shift to Low Risk or below o for subjects at Medium Risk at baseline: Shift to Very Low Risk or below o for subjects at Low Risk at baseline: Shift to abstinence The modified DRL is defined below, incorporating a "very low" drinking level patterned after the U.S. Dietary Guidelines of 2 standard drinks per day for men and 1 standard drink per day for women, adjusted for this analysis by the different definition of a standard drink (U.S. standard drink is 14 g/day, this protocol uses 10 g/day): • Abstinence: TAC of 0 g/day • Very low risk: TAC of 1-20 g/day for men; 1-10 g/day for women • Low risk: TAC of >20 to 40 g/day for men; >10 to 20 g/day for women • Medium risk: TAC of >40 to 60 g/day for men; >20 to 40 g/day for women • High risk: TAC of >60 to 100 g/day for men; >40 to 60 g/day for women • Very high risk: TAC of >100 g/day for men; >60 g/day for women • Responder analysis based on the number of subjects with no risk alcohol consumption during Study Months 5 and 6. Endpoints for assessing tolerability: • WHOQOL-BREF Endpoints for assessing safety: • Treatment-emergent adverse events (TEAEs) • Treatment-emergent serious adverse events (SAEs) • Treatment-emergent clinically significant laboratory abnormalities • Treatment-emergent clinically significant changes in vital signs • Treatment-emergent clinically significant changes in ECGs • Treatment-emergent potentially clinically significant changes in cardiac conduction parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Analyses of efficacy: • Months 5 and 6 • PHQ-9 total score at Week 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |