NAlmefene versus placebo in addition to treatment as usual on craving in Behavioural Addictions (NABAb)

The primary objective of this study is to assess the **efficacy** of nalmefene versus placebo as an add-on to treatment as usual for reducing the intensity of craving episodes in patients with **Behavioural Addictions**, specifically Gambling Disorder, Sexual Addiction, and Food Addiction, at the end of treatment at the maximum dosage tolerated. This is clinically relevant as it aims to provide an effective therapeutic option for managing craving episodes, which are a significant challenge in the treatment of these disorders.

Secondary objectives include:

• Comparing the two groups (Placebo vs Nalmefene) on the efficacy of nalmefene for reducing the frequency and duration of craving episodes at the end of treatment.
• Evaluating the efficacy of nalmefene for reducing craving intensity, frequency, and duration of craving episodes at 4 weeks after the end of treatment.
• Assessing the efficacy of nalmefene for reducing Behavioural Addictions episodes (frequency, duration, and intensity) at the end of treatment and 4 weeks after.
• Evaluating the overall clinical improvement as perceived by the clinician.
• Investigating the impact of nalmefene on the co-use of psychoactive substances (including nicotine) and daily life behaviors of interest (gambling, sex, food).
• Assessing the overall safety of nalmefene at the two dosages used (18 mg/d and then 36 mg/d).
• Investigating the link between the efficacy of treatment and polymorphisms in genes involved in pharmacodynamics and pharmacokinetics of nalmefene.
• Characterizing the profiles of responders/non-responders to treatment with nalmefene in terms of sociodemographic and clinical characteristics, especially psychiatric and addictive co-morbidities.

The clinical trial involves a study population comprising both **males and females** aged 18 years and older, diagnosed with **behavioural addictions** such as gambling disorder, sexual addiction, or food addiction. The total number of participants is not provided by the sponsor. Participants are either already receiving care or are newly initiating care in addictology departments. They must be capable of regularly assessing and reporting their craving episodes on a weekly diary. The trial includes individuals who have experienced at least one episode of craving with an intensity of 4 or higher on the Numerical Rating Scale (NRS) during the week prior to inclusion. Participants must provide written informed consent and be affiliated with the French social security system or be beneficiaries of such a system. Women participants are required to meet specific contraceptive measures or be post-menopausal, or have undergone irreversible surgical sterilization. The trial population is selected based on these criteria to ensure the efficacy of nalmefene versus placebo in reducing the intensity of craving episodes as an add-on to treatment as usual.

The clinical trial is designed to evaluate the efficacy of **nalmefene** versus placebo as an adjunct to standard treatment in reducing the intensity of craving episodes in patients with **behavioural addictions**, including gambling disorder, sexual addiction, and food addiction. This is a randomized, double-blind, placebo-controlled trial, with participants receiving either Selincro 18 mg film-coated tablets or a placebo. The trial is expected to run until June 30, 2027, with recruitment having commenced on September 15, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), current diagnosis of a behavioural addiction, and the ability to report craving episodes. Following the screening, participants will be randomized to receive either the active treatment or placebo. The trial includes regular follow-up visits to monitor the variation in the intensity, frequency, and duration of craving episodes, as well as overall clinical improvement, using tools like the Clinical Global Impression – Improvement scale. The end-of-study visit will assess the primary endpoint, which is the change in the averaged intensity of craving episodes from the start to the end of treatment.

The expected duration of participant involvement is up to five weeks, corresponding to the maximum treatment period. Participants may be withdrawn from the study early if they experience severe adverse effects, fail to comply with the study protocol, or withdraw consent. The trial aims to provide comprehensive data on the efficacy and safety of nalmefene in treating behavioural addictions, with secondary endpoints including the assessment of adverse side effects and the identification of genetic mutations associated with non-response to treatment.

The clinical trial involves the administration of **Selincro** 18 mg film-coated tablets as the experimental medication. Selincro is administered orally, with a maximum daily dose of 36 mg and a total maximum dose of 1134 mg over the treatment period. The pharmaceutical form is a film-coated tablet, and the medication is produced by H. Lundbeck A/S. The treatment period is set for a maximum of 5 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** for therapeutic use, which is administered in the form of capsules. Each placebo capsule contains 99.90 mg of cellulose microcrystalline and 0.10 mg of silica colloidal anhydrous. The placebo is designed to match the experimental medication in appearance and is also administered orally. The placebo is provided by ARROW Génériques. The use of a placebo allows for the assessment of the efficacy of Selincro by providing a comparator to measure against the active treatment.

The efficacy of nalmefene versus placebo as an add-on to treatment as usual for reducing the intensity of craving episodes in patients with **Behavioural Addictions** will be assessed in this clinical trial. The primary endpoint is the variation in the averaged intensity of craving episodes between the start and end of treatment. This will be measured using a Numerical Rating Scale (NRS) reported by patients on a weekly diary. Secondary endpoints include the variation in the averaged weekly frequency and duration of craving episodes, both during treatment and four weeks post-treatment. Additionally, overall clinical improvement will be evaluated using the Clinical Global Impression – Improvement (CGI-I) scale and the GGI – Efficacy Index (CGI-EI).

Data collection will involve patient-reported outcomes, with craving episodes documented weekly. The trial will also assess the variation in the use of psychoactive substances and daily life behaviors, such as gambling, sex, and food, from the start of treatment to four weeks after its conclusion. The study will further explore the number, type, and severity of self-reported adverse side effects at dosages of 18 mg/d or 36 mg/d. Genetic mutations associated with non-response to nalmefene treatment will be identified using a Next-Generation Sequencing (NGS) panel. Sociodemographic, medical, and clinical data, including psychiatric and addictive co-morbidities, will be assessed using the Mini International Neuropsychiatric Interview – Simplified (MINI-S).