Evaluation of Nitrous Oxide and Oxygen as Adjunctive Therapy to Antidepressants in Treating Depressive Symptoms in Neurocognitive Disorder Patients

The primary objective of this study is to compare the changes in **depressive symptomatology** at 4 weeks after baseline between the MEOPA group and the placebo group (medical air) in a population of nursing-home residents with neurocognitive disorders and significant depressive symptoms, resistant to at least one conventional antidepressant. This is clinically relevant as it aims to evaluate the efficacy of MEOPA as an add-on therapy to conventional antidepressants, potentially offering a new therapeutic option for this challenging patient population.

Secondary objectives include:

• Comparing changes in baseline depressive symptomatology at 8 weeks between the two groups.
• Comparing changes in baseline clinical global impression at 8 weeks between the two groups.
• Comparing changes in baseline psychobehavioural symptoms at 8 weeks between the two groups.
• Comparing changes in perceived well-being from baseline to 8 weeks between the two groups.
• Evaluating the safety profile of MEOPA specific to this use.

The clinical trial involves a **population** of nursing-home residents aged 60 and over, both male and female, who have been diagnosed with a major neurocognitive disorder according to DSM-V for at least six months. Participants exhibit significant depressive symptoms, as indicated by an NPI depression score of 4 or higher, and have shown resistance to at least one well-tolerated antidepressant, as assessed by the MGH-ATRQ scale. The study population is considered vulnerable due to their age and health conditions. Participants are required to have a Mini-Mental State Examination (MMSE) score of 20 or less out of 30. The trial does not provide specific information on the total number of participants, as this data was not disclosed by the sponsor. All participants must be affiliated with a social security scheme and have provided consent, either personally or through a family or legal representative. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study aims to compare changes in depressive symptomatology between a group receiving MEOPA and a placebo group, focusing on individuals who have not responded to conventional antidepressants.

The clinical trial is designed to evaluate the **efficacy** of EMONO as an add-on therapy to conventional antidepressants for treating depressive symptoms in nursing-home residents with neurocognitive disorders. This study is a **randomized**, controlled trial with a double-blind design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The trial is expected to commence recruitment in April 2024 and conclude by June 2026, with a total duration of approximately 26 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of major neurocognitive disorder, and resistance to at least one conventional antidepressant. Following successful screening, participants will be randomized to receive either the investigational product, KALINOX 50%/50% (a combination of **nitrous oxide** and **oxygen**), or the comparator, Medical Air (a combination of **nitrogen** and **oxygen**), both administered via **inhalation**. The maximum treatment period for KALINOX is 15 hours, while Medical Air is limited to 1 hour.

Study visits will occur at baseline (S1) and at weeks 1, 2, 3, 4, and 8, with assessments including the CORNELL depression severity scale, GDS scale, CGI-S and CGI-I scales, and the NPI scale for psychobehavioural disorders. The primary endpoint is the change in the CORNELL depression severity scale between week 4 and baseline. Secondary endpoints include various scales measured at specified intervals and the collection of adverse events at all visits. The end-of-study visit will occur at week 8, marking the conclusion of participant involvement.

Participants are expected to be involved in the study for a maximum of 8 weeks. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the use of **KALINOX 50%/50%**, a **medicinal gas, compressed** formulation, as the experimental treatment. This product contains a combination of **nitrous oxide** and **oxygen** as active substances. The gas is administered via **inhalation**. The maximum daily dose is limited to 1 hour, with a total treatment period not exceeding 15 days. The product is manufactured by Air Liquide Santé International and is authorized for use in France. The trial aims to assess the efficacy of KALINOX as an add-on therapy to conventional antidepressants for treating depressive symptoms in nursing-home residents with neurocognitive disorders.

The comparator treatment in this study is **Medical Air**, also a **medicinal gas, compressed** formulation, consisting of **nitrogen** and **oxygen**. This product is administered through **inhalation** as well. The maximum daily dose is set at 1 hour, with a total treatment period of up to 8 hours. Medical Air is produced by BOC Gases Ireland Ltd and is authorized for use in Ireland. It serves as the placebo group in the trial, allowing for a comparison of changes in depressive symptomatology between the MEOPA group and the placebo group.

The efficacy of the investigational treatment in this clinical trial will be assessed by evaluating changes in depressive symptomatology among nursing-home residents with neurocognitive disorders. The primary endpoint for efficacy assessment is the change in the CORNELL depression severity scale between baseline (S1) and one week after the last administration of the investigational product or placebo (S4). Secondary endpoints include measurements using the CORNELL scale and the GDS scale at weeks 1, 2, 3, 4, and 8, as well as the CGI-S and CGI-I scales at the same timepoints. Additionally, the NPI scale will be used to assess the frequency and severity of the 12 most frequent psychobehavioral disorders in this population at weeks 1, 4, and 8. The EVIBE visual analogue scale will be employed to measure well-being at weeks 1, 2, 3, 4, and 8. Adverse events will be collected at all study visits to ensure comprehensive safety monitoring.