Etude de phase II évaluant la capacité d'un agoniste des récepteurs 5-HT4, le prucalopride (Resolor©), à accélérer l'efficacité thérapeutique d'un antidépresseur de type ISRS: preuve de concept clinique.

The primary objective is to evaluate the efficacy of prucalopride, a 5-HT4 receptor agonist, in accelerating therapeutic response at 6 weeks when combined with escitalopram, a selective serotonin reuptake inhibitor (SSRI), in patients with major depressive disorder. This objective addresses the clinically significant delay in antidepressant onset of action, which typically requires several weeks before therapeutic benefits are observed.

The secondary objectives include:

• Evaluation of changes in mood dimension

• Assessment of changes in anxiety dimension using various psychometric instruments

• Evaluation of prucalopride tolerability

• Assessment of prucalopride treatment impact on emotional cognitive bias known to occur in depression

• Evaluation of treatment adherence

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population consisted of adults aged **18 to 65 years**, including both male and female subjects. Participants were required to have a diagnosis of **major depressive disorder** according to **DSM-5** criteria, confirmed through structured clinical assessment using the **Structured Clinical Interview for DSM-5 (SCID-V)**, with a baseline **Hamilton Depression Rating Scale (HDRS-21)** score of 19 or higher, indicating moderate to severe depression. Subjects were selected based on the clinical indication for initiating treatment with the **selective serotonin reuptake inhibitor (SSRI) escitalopram** as part of standard care at the time of enrollment. Female participants of childbearing potential were required to have a negative urine pregnancy test at inclusion and maintain effective contraception throughout the study duration. All participants were required to be affiliated with or beneficiaries of a social security system. The trial did not include vulnerable populations.

This phase II clinical trial evaluates the capacity of **prucalopride succinate**, a **5-HT4 receptor agonist**, to accelerate the therapeutic efficacy of **escitalopram**, a selective serotonin reuptake inhibitor (**SSRI**), in patients with **major depressive disorder**. The study represents a proof-of-concept investigation examining the combination of two marketed products, with prucalopride being used outside its approved indication. The trial employs a **randomized**, **placebo-controlled** design comparing participants receiving escitalopram plus prucalopride against those receiving escitalopram plus placebo. The primary objective is to assess the efficacy of prucalopride on improvement of response to escitalopram treatment at 6 weeks in patients presenting with major depressive disorder.

Eligible participants include individuals aged 18 to 65 years who meet **DSM-5** diagnostic criteria for major depressive disorder, confirmed by a structured clinical interview (**SCID-V**), with a **Hamilton Depression Rating Scale** 21-item (**HDRS-21**) severity score of 19 or greater at screening. Participants must be initiating escitalopram treatment as part of standard care at the time of study enrollment. Female participants of childbearing potential must have a negative urine pregnancy test at inclusion and maintain effective contraception throughout the study duration. All participants must be affiliated with or beneficiaries of a social security system.

The investigational medicinal products include prucalopride succinate capsules administered at a maximum daily dose of 1 mg, escitalopram 10 mg film-coated tablets administered at a maximum daily dose of 10 mg, and matching placebo capsules for prucalopride. All products are administered via **oral route**. The maximum treatment period for all products is 6 weeks, with total cumulative doses of 42 mg for prucalopride and 420 mg for escitalopram over the treatment duration.

The study visit schedule includes a screening visit at Day 0 (J0) and follow-up visits at Day 3 (J3), Day 7 (J7), Day 14 (J14), Day 28 (J28), and an end-of-study visit at Day 42 (J42). At the screening visit, baseline assessments include confirmation of diagnosis, HDRS-21 scoring, and pregnancy testing for applicable participants. Follow-up visits involve repeated assessments of depressive symptoms using HDRS-21, **Montgomery-Åsberg Depression Rating Scale** (**MADRS**), **Clinical Global Impressions-Severity** (**CGI-S**), and **Visual Analogue Scale for Depression** (VAS-D). Anxiety dimensions are evaluated using the **State-Trait Anxiety Inventory** (**STAI**) and **Patient Health Questionnaire-9** (**PHQ-9**) at each follow-up visit. Additional assessments include emotional facial recognition testing and emotional memory testing at J0, J7, and J42, as well as **Medication Adherence Rating Scale** (**MARS**) at J7 and J42. Adverse events, particularly fatigue, gastrointestinal disturbances, and headache, are recorded at each visit. Treatment adherence is monitored through capsule counting of returned unused medication and collection of empty blister packs.

The primary endpoint is the mean change in HDRS-21 score between Day 0 and Day 42, compared between the escitalopram plus prucalopride group and the escitalopram plus placebo group. Secondary endpoints include evaluation of mood dimensions and anxiety dimensions at multiple time points throughout the study, assessment of adverse events, cognitive testing results, and adherence measures. The estimated recruitment start date is July 2025, with an estimated study completion date of September 2026. Total participant involvement duration is 42 days (6 weeks). Conditions that may lead to early termination from the study are not explicitly specified in the protocol documentation.

The experimental medication **Prucalopride** is administered as a **capsule** formulation for **oral use**. The active substance is **prucalopride succinate**, which is of chemical origin. The maximum daily dose is **1 mg**, with a maximum total dose of **42 mg** over the treatment period. The treatment duration is **6 weeks**. This investigational product is manufactured by Centre Hospitalier Universitaire de Grenoble and is not an authorized medicinal product.

**Escitalopram** is administered as a **film-coated tablet** for **oral use** under the trade name ESCITALOPRAM ARROW LAB 10 mg. The active substance is escitalopram, also known as **(S)-citalopram**, which is of chemical origin. The maximum daily dose is **10 mg**, with a maximum total dose of **420 mg** over the treatment period. The treatment duration is **6 weeks**. This product is an authorized medicinal product in France with marketing authorization number 65483098, manufactured by Arrow Generiques. The product is classified under **ATC code N06AB10**.

A **placebo** formulation matching Prucalopride is included in the study, administered as a capsule for oral use. The placebo contains no active dose of prucalopride succinate, with a maximum daily dose of **0 mg** and maximum total dose of **0 mg**. The placebo treatment duration is **6 weeks**. This placebo product is manufactured by Centre Hospitalier Universitaire de Grenoble to maintain blinding in the study design.

Efficacy will be assessed through evaluation of depressive symptom improvement in patients with **major depressive disorder**. The primary endpoint consists of the mean change in HDRS-21 score between Day 0 and Day 42, which will be compared between the group treated with Escitalopram plus Prucalopride and the group treated with Escitalopram plus placebo.

Secondary efficacy parameters include assessment of mood dimensions at Day 3, Day 7, Day 14, Day 28, and Day 42 using multiple validated instruments: the Hamilton Depression Rating Scale-21 (HDRS-21), the Montgomery-Åsberg Depression Rating Scale (MADRS), the Clinical Global Impressions-Severity (CGI-S), and the Visual Analogue Scale-Depression (VAS-D). Anxiety dimensions will be evaluated at the same timepoints using the State-Trait Anxiety Inventory (STAI) and the Patient Health Questionnaire (PHQ-9). Additional assessments include emotional facial recognition testing and emotional memory testing at Day 0, Day 7, and Day 42. The collection of adverse events, particularly fatigue, gastrointestinal disorders, and headache, will be performed at each visit. Treatment adherence will be monitored through the MARS score at Day 7 and Day 42, as well as by counting returned unused capsules and empty blisters.