Evaluation of Diazepam and Oxazepam Stabilization Versus Tapering in Benzodiazepine-Dependent Patients Undergoing Opioid Agonist Therapy

The primary objective of this study is to evaluate the impact of a 24-week prescribed stable dose of **diazepam** or **oxazepam** compared to a 20-week tapering regimen on illicit benzodiazepine use in patients with benzodiazepine dependence undergoing opioid agonist therapy (OAT). This is clinically relevant as it aims to determine the most effective strategy for reducing illicit benzodiazepine use, which is a significant concern in patients with comorbid dependencies to benzodiazepines and opioids.

Secondary objectives include assessing the impact of a stable dose of benzodiazepines on various health and behavioral outcomes:

• Mental health
• Physical health
• Quality of life
• Cognitive function
• Comorbid substance use
• Criminal activity

The clinical trial involves participants with **comorbid dependencies to benzodiazepines and opioids**. The study population includes both male and female adults aged 18 years and older. Participants are required to have a diagnosis of opioid dependence according to ICD-10 and be undergoing opioid agonist therapy (OAT). Additionally, they must have a benzodiazepine dependence as per ICD-10, with a minimum duration of five years, and have used benzodiazepines 5-7 days a week during the last month at a minimum dose equivalent to 15 mg of diazepam per day or higher. Previous attempts at tapering benzodiazepines, either outpatient or inpatient, are also necessary. Participants must be capable of providing signed informed consent. The sponsor has not provided information regarding the total number of participants. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted.

The clinical trial is designed to evaluate the impact of a 24-week prescribed stable dose of **diazepam** or **oxazepam** versus a 20-week tapering regimen on illicit benzodiazepine use in patients with benzodiazepine dependence undergoing opioid agonist therapy (OAT). This is a randomized, double-blind, controlled trial with an estimated duration from September 1, 2022, to December 31, 2027. The trial involves adult participants (≥ 18 years) with a diagnosis of opioid dependence according to ICD-10, who are currently receiving OAT, and have a comorbid benzodiazepine dependence as per ICD-10 criteria. The primary endpoint is the difference in the illegal index, which measures the use of illicit benzodiazepines through supervised urinary tests at week 24 compared to baseline. Secondary endpoints include mental health symptoms, reaction time, health-related quality of life, treatment satisfaction, retention rate in OAT, use of other illicit substances, and instances of violent behavior or overdose.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on clinical assessment by a medical doctor. Follow-up visits will occur regularly to monitor progress, adherence to the treatment regimen, and collect data for endpoint assessments. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining queries are addressed. The expected length of participant involvement is up to 24 weeks, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or adverse events that necessitate discontinuation. The trial aims to provide valuable insights into the management of benzodiazepine dependence in the context of OAT, contributing to improved therapeutic strategies for this patient population.

The clinical trial involves the administration of several **benzodiazepine** formulations, each with specific characteristics. The first experimental medication is **Sobril 15 mg tabletter**, containing the active substance **oxazepam**. This medication is provided in tablet form and is administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 16,800 mg over a treatment period of 24 weeks. The pharmaceutical product is manufactured by Pfizer AS and is not a pediatric formulation.

Another experimental treatment is **Sobril 25 mg tabletter**, also containing **oxazepam**. Similar to the 15 mg formulation, it is administered orally in tablet form. The dosing regimen allows for a maximum daily intake of 100 mg, with a cumulative maximum dose of 16,800 mg over the 24-week period. This product is also produced by Pfizer AS and is not intended for pediatric use.

**Sobril 10 mg tabletter** is another formulation used in the trial, containing **oxazepam** as the active ingredient. It is administered orally in tablet form, with a maximum daily dose of 100 mg and a total maximum dose of 16,800 mg over the course of 24 weeks. This formulation is also manufactured by Pfizer AS and is not a pediatric formulation.

The trial also includes **Stesolid, tabletter**, which contains the active substance **diazepam**. This medication is provided in tablet form and administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 16,800 mg over the 24-week treatment period. The product is manufactured by Actavis Group PTC EHF and is not a pediatric formulation.

Lastly, **Valium 5 mg tabletter** is used in the trial, containing **diazepam** as the active substance. It is administered orally in tablet form, with a maximum daily dose of 30 mg and a total maximum dose of 5,040 mg over the 24-week period. This product is manufactured by Atnahs Pharma Netherlands B.V. and is not intended for pediatric use.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial aims to assess the impact of a stable dose of **diazepam** or **oxazepam** over 24 weeks compared to a 20-week tapering schedule on illicit benzodiazepine use in patients undergoing opioid agonist therapy.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the difference in the illegal index, which measures the use of illicit benzodiazepines. This will be assessed by supervised urinary tests conducted weekly or monthly, comparing results at week 24 to baseline. The illegal index is defined as the proportion of positive tests and is considered a continuous measure.

Secondary endpoints include several parameters evaluated at baseline and week 24. These include mental health symptoms scores using the Hopkins Symptom Checklist (SCL-10), reaction time, health-related quality of life scores using EQ-5D-5L, and satisfaction with treatment using a Visual Analogue Scale (VAS). Additionally, retention rate in opioid agonist therapy (OAT), use of other illicit substances and alcohol, violent behavior based on the Brøset Violence Checklist (BVC), and the number of non-fatal overdoses and deaths will be assessed. These secondary endpoints will be measured through a combination of self-reports, urinary tests, and validated scales.