Efficacy of Citalopram in Patients with Reflux Hypersensitivity or Functional Heartburn Unresponsive to Proton Pump Inhibitors: A Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of citalopram 20 mg as an 8-week add-on treatment in patients with **reflux hypersensitivity** or **functional heartburn** who exhibit an incomplete response to proton pump inhibitor (PPI) therapy. This is clinically relevant as it addresses the need for effective treatment options in patients who do not fully respond to standard PPI therapy, potentially improving symptom management and quality of life in individuals with **gastro-esophageal reflux disease**.

Secondary objectives include assessing the predictive value of reflux assessment, esophageal sensitivity evaluation, and questionnaire results on the primary outcome. These assessments aim to identify potential predictors of treatment response, which could guide personalized treatment strategies in the future.

The clinical trial focuses on individuals diagnosed with **gastro-esophageal reflux disease** (GERD) who exhibit reflux hypersensitivity or functional heartburn and have shown an incomplete response to proton pump inhibitor (PPI) therapy. The study population includes both male and female participants aged between 18 to 65 years. Participants are required to have a history of typical GERD symptoms during PPI treatment, occurring at least three times per week for a duration of 12 weeks. Additionally, they must have been on a daily PPI regimen for 12 weeks prior to inclusion, with at least 8 weeks of twice-daily therapy. The trial does not involve a vulnerable population. Participants' lifestyle considerations include the requirement for sexually active women of childbearing potential to use medically acceptable contraception methods. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **citalopram** 20 mg as an add-on treatment for patients with reflux hypersensitivity or functional heartburn who exhibit an incomplete response to proton pump inhibitor (PPI) therapy. This study is structured as a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to span a duration of approximately eight weeks, with participant involvement extending over this period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age between 18 to 65 years, a history of typical gastro-esophageal reflux disease (GERD) symptoms during PPI treatment, and specific pH-impedance values. Following successful screening, participants will be randomized to receive either the active treatment or placebo. Subsequent follow-up visits will be scheduled to monitor treatment adherence, assess changes in reflux episodes, and evaluate secondary endpoints such as changes in symptom severity and esophageal sensitivity. The end-of-study visit will conclude the trial, where final assessments will be conducted to gather comprehensive data on the primary and secondary endpoints.

The expected length of participant involvement is eight weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The primary endpoint of the trial is the change in the number of reflux episodes, while secondary endpoints include changes in volume exposure of reflux, esophageal sensitivity, and symptom severity. The trial aims to provide valuable insights into the potential benefits of citalopram as an adjunctive therapy for patients with GERD-related conditions.

The clinical trial involves the administration of **Citalopram**, a selective serotonin reuptake inhibitor (SSRI), as the experimental medication. The pharmaceutical form of Citalopram used in this study is a film-coated tablet, specifically branded as Citalopram Viatris 20 mg filmomhulde tabletten. The active substance in this medication is Citalopram, with a maximum daily dose of 20 mg. The route of administration is oral, and the medication is to be taken once daily. The treatment period for Citalopram is set for a maximum of 16 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** as a non-experimental treatment to serve as a control. The placebo is manufactured by Laboratoria Wolfs, Zwijndrecht, and is presented in tablet form. Each placebo tablet weighs 488 mg and contains the following inactive ingredients: lactose monohydrate (320 mg), carmellose sodium (10 mg), corn starch (70 mg), cellulose microcrystalline (55 mg), silicium dioxide anhydrous (20 mg), and magnesium stearate (13 mg). The placebo is administered orally, mirroring the administration route of the experimental medication, to maintain blinding in the trial. The frequency and duration of placebo administration are identical to those of the Citalopram treatment, ensuring consistency in the study protocol.

The efficacy of citalopram in the treatment of **reflux hypersensitivity** or functional heartburn with incomplete proton pump inhibitor (PPI) response will be assessed through a placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the change in the number of reflux episodes. Secondary endpoints include changes in volume exposure of reflux, the number of reflux episodes with a high proximal extent, esophageal sensitivity, symptom severity, and the predictive value of reflux assessment, esophageal sensitivity assessment, and a reflux questionnaire.

Measurements will be collected at specified intervals throughout the trial, with the main objective being to assess the efficacy of an 8-week add-on treatment with citalopram 20 mg. The trial will involve the use of validated scales and patient-reported outcomes to ensure accurate and reliable data collection. The analysis will focus on comparing the changes in the specified endpoints between the citalopram and placebo groups to determine the treatment's efficacy.