Evaluation of Oral Vancomycin for Prophylaxis of Clostridium difficile Infections in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

The primary objective of this study is to evaluate the effectiveness of primary prophylaxis with oral **vancomycin** in preventing **Clostridium difficile** infections in patients hospitalized for allogeneic hematopoietic stem cell transplantation (HCT). This is clinically relevant as **Clostridium difficile** infections can lead to significant morbidity in this vulnerable patient population, and effective prophylaxis could improve patient outcomes and reduce healthcare-associated complications.

Secondary objectives include:

• Evaluating the impact of primary prophylaxis with oral vancomycin on the prevention of **Clostridium difficile** infections after stopping prophylaxis until week 12.
• Assessing the prevention of **Clostridium difficile** infections in patients hospitalized for HCT allogeneic transplantation up to week 5, in terms of cumulative incidence.
• Investigating the prevention of **Clostridium difficile** infections in hospitalized patients diagnosed by PCR detection of the toxigenic strain.
• Evaluating the severity of **Clostridium difficile** infections occurring under treatment.
• Identifying risk factors for the occurrence of **Clostridium difficile** infection, including type of packaging, antibiotics received, presence of toxigenic strain on day 0 of treatment, and microbiota composition.
• Analyzing the profile of bacterial infections occurring during treatment with vancomycin or placebo.
• Assessing the impact of the treatment on the intestinal microbiota.
• Monitoring the emergence of vancomycin-resistant enterococcus (VRE).
• Observing the occurrence of nosocomial clusters of **Clostridium difficile** infection up to week 12.
• Evaluating the occurrence of acute or chronic graft-versus-host disease (GVHD) at month 12.
• Monitoring relapse of hematological disease.
• Assessing mortality linked to the transplant procedure at 1 month.
• Evaluating overall survival at month 12.
• Assessing treatment tolerance.

The clinical trial involves **patients hospitalized for allogeneic hematopoietic stem cell transplantation**. The study population includes both male and female participants aged 15 years and older. Participants are required to have been hospitalized for less than 72 hours to receive an allograft of hematopoietic stem cells, regardless of the indication and packaging. The trial does not focus on a vulnerable population. Participants of childbearing age must use effective contraception throughout the study and for one month after the end of treatment. All participants must have given consent for participation and be beneficiaries of health insurance. The sponsor has not provided information regarding the total number of participants in the trial. 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 primary prophylaxis with **oral vancomycin** in preventing **Clostridium difficile infections** in patients hospitalized for allogeneic hematopoietic stem cell transplantation. This is a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know who is receiving the treatment or placebo, thus minimizing bias. The trial is expected to run from October 27, 2022, to October 27, 2026, with participant involvement lasting up to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥15 years), hospitalization status, and consent. Follow-up visits will occur throughout the study, including assessments at weeks 2, 5, and 12, to monitor the occurrence of **Clostridium difficile infections** and other health parameters. The end-of-study visit will take place at 12 months, or earlier if the participant experiences a relapse of the hematological disease or other significant events.

Participants may be withdrawn from the study early if they experience severe adverse effects, withdraw consent, or if the study is terminated for any reason. The primary endpoint is the occurrence of **Clostridium difficile infection** between inclusion and discharge from hospitalization or the end of treatment. Secondary endpoints include the time to infection, risk factors, severity factors, and microbiota composition, among others. The study aims to provide valuable insights into the prevention of **Clostridium difficile infections** in this vulnerable patient population.

The clinical trial involves the administration of **Vancomycin**, specifically the product "Vancomycine Viatris 500 mg poudre pour solution pour perfusion." This experimental medication is provided in the form of a powder intended for the preparation of a solution for infusion. The active substance in this formulation is vancomycin, a chemical compound classified under the ATC code J01XA01. The product is authorized in Belgium under the marketing authorization number BE395421 and is manufactured by VIATRIS GX. The route of administration for this medication is oral use, although it is typically prepared as a solution for infusion. The dosing schedule and frequency of administration are determined by the study protocol, and participant compliance is monitored throughout the trial.

The study also includes a **placebo** control, which is a solution of NaCl 0.9% intended for oral use. This placebo is designed to mimic the administration of the experimental medication without containing the active substance, vancomycin. The placebo serves as a comparator treatment to evaluate the effectiveness of the experimental medication in preventing **Clostridium difficile** infections in patients undergoing allogeneic hematopoietic stem cell transplantation. The placebo is administered following the same route and frequency as the experimental medication to ensure blinding and maintain the integrity of the double-blind study design.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the occurrence of **Clostridium difficile** infection between inclusion and discharge from hospitalization or the end of treatment with vancomycin or placebo, defined by diarrhea with more than three unformed stools per day, detection of **Clostridium difficile** (CD) and free toxin in the stools by enzyme immunoassay, without evidence for another etiology of diarrhea, or the presence of pseudomembranous colitis at endoscopy, colectomy, or autopsy.

Secondary endpoints include several parameters: the occurrence of **Clostridium difficile** infection between inclusion and week 12, time to infection, risk factors for infection, severity factors, microbiologically documented bacterial infections during treatment, acquisition of vancomycin-resistant Enterococcus, and study of the intestinal microbiota at various timepoints (inclusion, week 2, week 5, and week 12). Additional secondary endpoints involve the occurrence of nosocomial clusters of **Clostridium difficile** infection, acute or chronic graft-versus-host disease (GVHD) grade 2-4 at month 12, time to relapse of hematological disease, mortality rate linked to the transplant procedure at week 5, and the delay between inclusion and death or last news up to month 12. The proportion of adverse effects during protocol monitoring will also be evaluated.