Evaluation of Chronotherapeutics: Active Light Therapy and Prolonged-Release Melatonin in Major Depressive Episode with Insomnia

The primary objective of this study is to evaluate the **effectiveness** of two **chronotherapeutics**, either alone or in combination, on the reduction of depressive symptoms after 8 weeks of treatment in patients with Major Depressive Episode (MDE). This is clinically relevant as it aims to provide insights into the potential benefits of active light therapy and 2 mg prolonged-release melatonin in managing depressive symptoms, which could lead to improved treatment strategies for MDE with insomnia.

Secondary objectives include:

• Evaluating the effectiveness of the chronotherapeutics on the reduction of depressive symptoms at 1, 4, 8 weeks, and 3 months of treatment, using the MADRS scale.
• Assessing therapeutic response at 1, 4, 8 weeks, and 3 months of treatment, using the MADRS scale.
• Determining remission of depressive symptoms at 4, 8 weeks, and 3 months of treatment, using the MADRS scale.
• Improving sleep and circadian rhythms at 1, 4, 8 weeks, and 3 months of treatment, based on sleep and sleep-wake rhythm self-questionnaires and objective actigraphy parameters.
• Monitoring the longitudinal evolution of the MADRS score over time from baseline to 8 weeks and from baseline to 3 months.
• Measuring the time to therapeutic response from baseline to 3 months of treatment, using the MADRS scale.
• Evaluating the safety and tolerance of different combinations of chronotherapeutics.
• Assessing the patient's mood state and overall functioning at 1, 4, 8 weeks, and 3 months of treatment.

The clinical trial involves participants diagnosed with **Major Depressive Episode** (MDE) and comorbid **insomnia**. The study population includes both male and female subjects aged between 18 to 65 years. Participants are required to have a MADRS score of 20 or higher, indicating moderate MDE, and an ISI score of 8 or higher, indicating mild and clinically significant insomnia. The trial excludes individuals who have been exposed to antidepressants or light therapy in the month prior to inclusion. Participants are either receiving outpatient or inpatient care for the duration of the 8-week treatment. The sponsor has not provided information regarding the total number of participants. The trial does not involve a vulnerable population, and all participants must have the ability to understand and sign the informed consent. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the effectiveness of two **chronotherapeutics**, either alone or in combination, on the reduction of depressive symptoms in patients with a **Major Depressive Episode** (MDE) and comorbid **insomnia**. This is a multicenter, randomized, double-blind, placebo-controlled 2x2 factorial trial. The trial will involve the administration of active light therapy and 2 mg prolonged-release **melatonin** over an 8-week period. The primary endpoint is the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 8 weeks, adjusted for the baseline score. Secondary endpoints include therapeutic response, remission rates, subjective sleep quality, objective actigraphy parameters, and mood state assessments at various intervals.

Participants will be involved in the study for a total of 8 weeks, with the trial estimated to conclude by September 2027. The inclusion criteria require participants to be aged 18 to 65 years, diagnosed with MDE according to DSM-5 criteria, and have a MADRS score of 20 or higher. Additionally, participants must have comorbid insomnia with an Insomnia Severity Index (ISI) score of 8 or higher and must not have been exposed to antidepressants or light therapy in the month prior to inclusion. The study will exclude individuals who do not meet these criteria or who are unable to provide informed consent.

The sequence of study visits includes an initial screening and inclusion visit (Visit 0), where participants will be randomized into one of the four treatment arms. Follow-up visits will occur at weeks 1, 4, and 8, with clinical evaluations and assessments conducted at each visit. The end-of-study visit will coincide with the 8-week mark, where the primary endpoint will be assessed. Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the study protocol, or withdraw consent. The trial aims to provide valuable insights into the treatment of MDE with insomnia, potentially informing future therapeutic strategies.

The clinical trial involves the administration of **MELATONIN** in the form of **MELATONINE ARROW LP 2 mg**, a **prolonged-release tablet**. This experimental medication is designed for **oral use** and is administered at a dosage of 2 mg per day. The maximum treatment period is 8 weeks, with a total maximum dose of 112 mg. The active substance, melatonin, is of chemical origin and is intended to evaluate its effectiveness in reducing depressive symptoms in patients with Major Depressive Episode (MDE) with insomnia. The pharmaceutical form is specifically designed to release the active ingredient gradually, ensuring a sustained therapeutic effect over time.

The study also includes a **placebo** group, which receives the **PLACEBO DE MELATONINE ARROW LP 2 mg comprimé**. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the active treatment, mimicking the **prolonged-release tablet** form and **oral route** of administration, to ensure consistency in the study protocol.

The efficacy of the treatment in the clinical trial titled "CombiChronoS - Effectiveness of a Combination of Chronotherapeutics for the Treatment of Major Depressive Episode (MDE) with Insomnia" will be assessed using several parameters. The primary endpoint is the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 8 weeks, adjusted for the baseline score. This will be measured at Week 8 during a clinical evaluation visit, with the baseline score taken at Week 0 during the inclusion and randomization visit.

Secondary endpoints include the MADRS score at 1, 4, 8 weeks, and 3 months, with assessments of therapeutic response (defined as a 50% reduction in MADRS score) and remission (MADRS score ≤ 10). Subjective sleep quality will be evaluated at 1, 4, 8 weeks, and 3 months using sleep and sleep-wake rhythm self-questionnaires. Objective actigraphy parameters will be measured at 1, 4, and 8 weeks, including total sleep time, nocturnal awakenings, fragmentation index, sleep efficiency, and time spent in bed. Rhythm parameters such as relative amplitude, stability, and variability of sleep-wake rhythms, as well as L5 and M10 phase markers, will also be assessed.

Additional secondary endpoints include subjective sleep diary parameters at 1, 4, and 8 weeks, the slope of longitudinal evolution of the MADRS score, and the time to therapeutic response, with a maximum assessment period of 3 months. Side effects will be monitored using the PRISE-M questionnaire at 1, 4, and 8 weeks. Mood state and overall functioning will be evaluated using various questionnaires (YMRS, C-SSRS, QIDS-SR, GAG7, CGI) at 1, 4, 8 weeks, and 3 months.