Evaluation of Perioperative Selective Digestive Decontamination with Colistin Sulfate, Tobramycin, and Amphotericin B in Resectable Esophageal Carcinoma

The primary objective of this study is to evaluate the effect of **Selective Decontamination of the Digestive tract (SDD)** on infectious complications following esophagectomy, with a specific focus on the prevention of pneumonia. This is clinically relevant as pneumonia is a common and serious postoperative complication in patients undergoing esophagectomy for **esophageal cancer**, potentially impacting recovery and overall outcomes.

Secondary objectives include evaluating additional benefits such as the reduction of other infectious complications, including anastomotic leakage, and assessing overall health and wellbeing during the recovery period. The study will also consider the risks associated with SDD and utilize the outcomes for a cost-effectiveness analysis.

The clinical trial focuses on individuals diagnosed with **esophageal cancer**, specifically primary esophageal adenocarcinoma or squamous cell carcinoma, located in the mid or distal esophagus or at the gastro-esophageal junction. Participants are scheduled for transthoracic esophagectomy with curative intent or esophageal reconstruction with a gastric or jejunal interposition. The study population includes both male and female subjects aged 18 years and older. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their ability to provide written informed consent and their scheduled surgical procedures. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial details.

The clinical trial is designed to evaluate the effect of **selective decontamination of the digestive tract (SDD)** on infectious complications following esophagectomy, with a focus on preventing pneumonia in patients with **esophageal cancer**. This is a randomized, multicenter, double-blind, controlled trial. The trial will commence on January 15, 2024, and is expected to conclude by March 15, 2027. Participants will be randomly assigned to receive either the investigational treatment or a control, with both groups receiving standard care. The investigational treatment involves the administration of an oral suspension containing **colistin sulfate** and **tobramycin**, with the addition of **amphotericin B** mixed with the suspension.

The trial will include several study visits. The initial visit will be a screening visit to confirm eligibility based on criteria such as a diagnosis of primary esophageal adenocarcinoma or squamous cell carcinoma, age of 18 years or older, and the ability to provide written informed consent. Following the screening, participants will undergo a baseline assessment before the surgical procedure. Post-surgery, follow-up visits will occur at regular intervals to monitor for postoperative complications, including pneumonia, and to assess secondary endpoints such as the incidence of other infectious complications, anastomotic leakage, and overall mortality within 90 days post-surgery. The end-of-study visit will occur six months after surgery to evaluate long-term outcomes, including quality of life and healthcare costs.

Participant involvement is expected to last approximately six months, encompassing the preoperative period, the surgical procedure, and the postoperative follow-up. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that necessitate discontinuation of the investigational treatment. The primary endpoint is the cumulative incidence of postoperative pneumonia within 30 days after surgery, defined by specific clinical and microbiological criteria. Secondary endpoints include the incidence of all postoperative infectious complications, anastomotic leakage, re-operation rates, length of hospital stay, and quality of life assessments. The trial aims to provide robust data on the efficacy of SDD in reducing postoperative infections and improving patient outcomes following esophagectomy.

The clinical trial involves the administration of **Basis voor SDD suspensie**, an **oral suspension** containing the active substances **colistin sulfate** and **tobramycin**. This formulation is designed for oral administration and is provided in a liquid suspension form. The maximum daily dose is 20 ml, with a total maximum dose of 130 ml over a treatment period of 7 days. The suspension is classified as a nonabsorbable antibiotic, and its administration is intended to selectively decontaminate the digestive tract. The dosing schedule requires careful monitoring to ensure participant compliance, with the oral route being the sole method of administration.

In addition to the Basis voor SDD suspensie, the trial also includes the use of **Amphotericin B**, a macrocyclic, polyene antifungal antibiotic. This substance is also administered orally and is provided in a form that requires mixing with an equal amount of the SDD basis suspension. The maximum daily dose for Amphotericin B is 2000 mg, with a total maximum dose of 13000 mg over the same 7-day treatment period. The combination of Amphotericin B with the SDD suspension is intended to enhance the decontamination process, and the dosing regimen is structured to ensure optimal therapeutic outcomes while maintaining participant safety. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the cumulative incidence of postoperative **pneumonia** within 30 days after surgery. Pneumonia will be defined by specific criteria, including a positive sputum culture or the presence of a new progressive radiographic infiltrate, along with at least two clinical features such as fever greater than 38.5°C, leukocytosis, or leukopenia, and purulent secretions.

Secondary endpoints include the cumulative incidence of all postoperative infectious complications within 30 days, as recorded in the Dutch Upper Gastrointestinal Cancer Audit (DUCA). These complications encompass postoperative pneumonia, Clostridium difficile infection, urinary tract infection, wound infection or abscess requiring intervention, central line infection, intra-thoracic or intra-abdominal abscess, generalized sepsis, and other infections necessitating antibiotics. Additionally, the cumulative incidence of anastomotic leakage within 30 days post-esophagectomy, all-cause mortality within 90 days, the rate of re-operation within 30 days, and the postoperative length of stay in the ICU and hospital will be evaluated. Quality of life will be assessed at 30 days, 3 months, and 6 months post-surgery using validated questionnaires such as the EORTC OG25, QLQC30, and EuroQoL-5D-5L. Furthermore, direct and indirect costs will be estimated up to 6 months post-surgery using the medical consumption and productivity cost questionnaires developed by the iMTA.