| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A pattern of alcohol use that involves problems controlling drinking, increased tolerance to alcohol and withdrawal symptoms when alcohol is stopped. |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
| 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 |
|
| 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 |
| To assess whether treatment with naltrexone hydrochloride nasal spray reduces drinking in patients with alcohol use disorder |
|
| E.2.2 | Secondary objectives of the trial |
To assess the time needed for naltrexone hydrochloride nasal spray to reduce drinking by 2 levels (WHO drinking risk levels) in patients with alcohol use disorder that is maintained until the end of the trial.
To assess the effect of naltrexone hydrochloride nasal spray on day with no heavy drinking, abstinence from alcohol, grams of ethanol per day, percentage of days with no heavy drinking and percentage of drinking days in patients with alcohol use disorder.
To assess the time needed for naltrexone hydrochloride nasal spray to reduce drinking by 1 level (WHO drinking risk levels) in patients with alcohol use disorder that is maintained until the end of the trial.
To assess the effect naltrexone hydrochloride nasal spray on average number of drinks consumed per day for days when two doses of the spray are used.
To assess the effect of naltrexone hydrochloride nasal spray on alcohol craving, nicotine use (for smokers) and positive and negative effects in patients with alcohol use dis |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged 18 to 70 years
2. Provided written, informed consent prior to any study specific procedure being conducted.
3. Diagnosis of alcohol use disorder of at least moderate severity (AUD-MS or F10.20) according to
DSM-5 or ICD-10 (as appropriate) prior to Screening (within the previous 6 months).
4. Seeking treatment for AUD and desire to reduce or stop drinking.
5. Drinking at WHO High Risk or Very High-Risk Drinking Level for the 28 days prior to Baseline
based on the TimeLine Followback Interview. The WHO Cut-offs for High Risk drinking are as
follows: If male, reporting at least 60 grams of ethanol per day and if female, reporting at least
40 grams of ethanol per day, on average in the 4 weeks prior to consent.
6. Stable housing at Screening and for the duration of the study.
7. Plan to remain in the area throughout the study period and able to attend all sessions.
|
|
| E.4 | Principal exclusion criteria |
1. More than 7 consecutive days of abstinence immediately prior to Baseline.
2. Moderate to severe drug use disorder in the past 12 months, as defined by DSM-5, other than alcohol, caffeine or nicotine, relative to Screening.
3. Any history of neurological condition considered by the Investigator to be clinically significant in the context of the study.
4. Known allergic reaction to naltrexone.
5. Known allergic reaction to excipients of IMP and placebo.
6. Subject is taking any prohibited medication (opioids, any medication delivered intranasally).
7. Opioid use 4 weeks prior to Screening.
8. Positive urine drug test for opioids at Screening or Baseline.
9. Taking any medications prescribed for depression or anxiety. SSRIs or SNRIs at a stable dose for 8 weeks prior to Screening are permitted.
10. Any behavioural treatment for AUD within the past 4 weeks prior to Screening.
11. Have used another investigational drug in the past 8 weeks or 5 half-lives, whichever is longer, prior to Screening.
12. EtG Test at Screening and/or Baseline that is inconsistent with self-reported drinking on the prior day (i.e., a negative test (< 500ng/ml) when participant reports heavy drinking on the prior day).
13. Have used naltrexone, nalmefene, topiramate, acamprosate, disulfiram; gabapentin, varenicline, baclofen in the past 3 months prior to Screening or intend to use these medications.
14. Significant nasal rhinitis or other conditions that restrict nasal airflow or abnormal nasal anatomy, at Screening and/or Baseline.
15. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless surgically sterile must use effective contraception (either combined oestrogen and progestogen containing hormonal contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], progestogen only hormonal contraception associated with inhibition of ovulation [oral, injectable, implantable], IUD, IUS, vasectomised partner, sexual abstinence [only considered an acceptable method of contraception when it is in line with the subjects’ usual and preferred lifestyle], combination of male condom with either cap, diaphragm or sponge with spermicide [double barrier methods]), and willing and able to continue contraception for 1 month after the last administration of IMP. Women using oral contraception must have started using it at least 2 months prior to Screening. Women are not considered to be of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels that have been confirmed to be in the “postmenopausal range”, or have had a surgical bilateral oophorectomy (with or without hysterectomy) or bilateral tubal ligation at least six weeks before the Screening visit. In case of oophorectomy alone, the reproductive status of the woman should have been confirmed by follow up hormone level assessment.
16. Women who are pregnant or breastfeeding at Screening or Baseline.
17. Subject with concurrent disease considered by the Investigator to be clinically significant in the context of the study.
18. Severe mental illness and/or a history or evidence of organic brain disease or dementia considered by the Investigator to be clinically significant in the context of the study, that would compromise the participant’s ability to comply with the study protocol.
19. At risk of alcohol withdrawal syndrome as indicated by any of the following: a) score >10 on the CIWA-Ar; b) history of seizures other than childhood febrile seizures; c) history of seizures, delirium, or hallucinations during alcohol withdrawal; d) history of medical detoxification in the past 4 weeks prior to Screening.
20. Subjects with any laboratory tests from samples taken at Screening considered to be clinically significant by the Investigator, including elevation of liver enzymes (AST, ALT) 4-times the upper reference range or bilirubin 2 times the upper reference range.
21. Current suicidal ideation (yes to either question 1 or 2 on the C-SSRS) at Screening or Baseline.
22. History of suicidal behaviour in the past 5 years; considered by the Investigator to be clinically significant in the context of the study, prior to Screening.
23. On probation or parole, at Screening.
24. BMI (calculated as weight in kilograms divided by the square of height in meters) less than 15 or greater than 39.99 or weight less than 45 kg, at Screening.
25. Subject is deemed unlikely to be able to comply with the requirements of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects showing an improvement in WHO Drinking Risk Level consisting of a 2-level reduction from Baseline to end of treatment. WHO Drinking Risk Level will be evaluated in the 28 days prior to the Baseline and end of treatment visits. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 16 based on the last 28 days of the study. |
|
| E.5.2 | Secondary end point(s) |
• Time to a 2-level risk reduction in WHO Drinking Risk Level that is maintained until the end of treatment.
• Proportion of subjects with No Heavy Drinking days, by month.
• Number of consecutive days abstinent during treatment, by month.
• Mean total alcohol grams per day, by month.
• Percentage heavy drinking days, by month.
• Percentage of drinking days, by month.
• Number of drinks consumed on days when the extra as needed dose was taken, by month.
• The proportion of subjects showing an improvement in WHO Drinking Risk Level consisting of a 1 level reduction from Baseline (28 days prior) to the final 28 days of treatment.
• Alcohol craving by month (MACE).
• Change in nicotine use from Baseline to Week 16.
• PANAS by month. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Time to a 2-shift risk reduction in WHO Risk Drinking Category that is maintained until the end of treatment -week 16
• Total alcohol grams per day-weeks 4, 8, 12, 16
• Proportion of subjects with 'No Heavy Drinking'-weeks 4, 8, 12, 16
• Consecutive days abstinent during treatment- weeks 4, 8, 12, 16
• Percentage heavy drinking days-weeks 4, 8, 12, 16
• Percentage of drinking days-weeks 4, 8, 12, 16
• Number of drinks consumed on days when the extra as needed dose was taken -weeks 4, 8, 12, 16
• Proportion of patients showing an improvement in WHO Drinking Risk Level consisting of a 1-level reduction from baseline to the final 28 days of treatment -week 16
• Alcohol craving -weeks 4, 8, 12, 16
• Positive and Negative Affect Score -weeks 4, 8, 12, 16
• Nicotine use – weeks 4, 8, |
|
| 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 | No |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | No |
| 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
|
| The end of the trial is the last patient follow-up call (28 days after the last patient Week 16 Visit). |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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