Comparative Efficacy of Amoxicillin-Clavulanic Acid Versus Amoxicillin-Clavulanic Acid Plus Ciprofloxacin in Chemotherapy-Induced Fever in Adult Hematology Patients

The primary objective of this study is to demonstrate the **non-inferiority** of amoxicillin-clavulanate (AC) compared to the reference combination treatment of amoxicillin-clavulanate and ciprofloxacin (AC+C) in the empirical oral outpatient treatment of a first episode of chemotherapy-induced fever (CIF) in adult hematology patients. This is clinically relevant as it may offer a simpler and potentially less costly treatment option without compromising efficacy for patients experiencing CIF.

Secondary objectives include evaluating and comparing between randomized arms:

• Adherence to the study treatment
• Incidence of negative events such as change in antibiotic treatment, relapse, hospitalization, intensive care unit admission, and death
• Treatment efficacy in the subgroup of neutropenic patients (neutrophils < 500/mm³)
• Safety of treatment
• Incidence of bacteraemia in the subgroup of secondarily hospitalized patients
• Incidence of empiric treatment inefficiency against identified bacteria in the subgroup of secondarily hospitalized patients
• Identification of prognostic factors

The clinical trial involves **adult patients** aged 18 years and older, both male and female, who are being treated for **haematological disorders**. These disorders include lymphoma of all histological types, myelodysplasia treated with azacytidine, and acute myeloblastic leukaemia treated with non-intensive schemes. The study population is expected to experience neutropenia lasting less than 7 days due to chemotherapy regimens. Participants are required to provide written informed consent and must be capable of understanding study-related information and following protocol procedures. The trial does not include a vulnerable population, and the sponsor has not provided the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** of an empirical treatment with amoxicillin-clavulanate compared to the combination of amoxicillin-clavulanate and ciprofloxacin in the outpatient care of chemotherapy-induced fever in adult hematology patients. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment is being administered, thus minimizing bias. The trial is expected to commence on June 1, 2025, and conclude by December 31, 2027, with the primary objective of demonstrating the non-inferiority of amoxicillin-clavulanate compared to the reference combination treatment.

Participants will be involved in the study for a maximum of 30 days, with the treatment period lasting up to 7 days. The study will include several key visits: an initial screening visit to confirm eligibility, follow-up visits at 48 hours, Day 4, Day 14, and Day 30, and an end-of-study visit. The primary endpoint is clinical success, defined as the absence of fever 4 days after the first antibiotic dose without modification of the treatment. Secondary endpoints include fever recurrence, hospitalization rates, and adverse events, which will be monitored throughout the study duration.

Inclusion criteria require participants to be adults aged 18 years or older with specific hematological disorders, such as lymphoma or acute myeloblastic leukemia, where chemotherapy is expected to induce neutropenia lasting less than 7 days. Participants must provide written informed consent and be able to comply with study procedures. Conditions for early termination from the study include non-compliance with the protocol, withdrawal of consent, or any adverse event that poses a risk to the participant's health. The trial aims to provide valuable insights into the management of chemotherapy-induced fever, potentially influencing future treatment guidelines.

The clinical trial involves the use of two experimental medications: **Ciprofloxacin** and **Amoxicillin-clavulanate**. **Ciprofloxacin** is administered in the form of **ciprofloxacin hydrochloride** and **ciprofloxacin**, both of which are chemical substances. The pharmaceutical form is identified as PHF00134MIG, and the medication is administered orally. The maximum daily dose is 1 gram, with a total maximum dose of 7 grams over a treatment period of 7 days. The medication is classified under the ATC code J01MA02, indicating its use as an antibiotic agent. Participant compliance with the dosing schedule is monitored throughout the trial.

**Amoxicillin-clavulanate** is composed of **amoxicillin sodium** and **clavulanic acid**, both of which are chemical substances. The pharmaceutical form is designated as PHF00231MIG, and the medication is also administered orally. The maximum daily dose for this treatment is 3 grams, with a total maximum dose of 21 grams over a 7-day treatment period. This medication is classified under the ATC code J01CR02, indicating its role as an antibiotic agent with a beta-lactamase inhibitor. Compliance with the dosing schedule is similarly monitored to ensure adherence to the treatment protocol.

Both medications are used in the empirical oral outpatient treatment of chemotherapy-induced fever in adult hematology patients. The trial aims to demonstrate the non-inferiority of **amoxicillin-clavulanate** compared to the combination treatment of **amoxicillin-clavulanate** and **ciprofloxacin**. No non-experimental treatments, such as placebo or comparator treatments, are utilized in this study. The trial is designed to ensure rigorous monitoring of participant compliance and adherence to the prescribed dosing schedules.

The efficacy of the empirical treatment with Amoxicillin-clavulanate (AC) compared to the combination of Amoxicillin-clavulanate and **Ciprofloxacin** (AC+C) in the outpatient care of chemotherapy-induced fever in adult hematology patients will be assessed through a series of predefined endpoints. The primary endpoint is clinical success, defined as the achievement of apyrexia measured 4 days after the first antibiotic dose, without any modification of the antibiotic treatment. This will be evaluated using temperature measurements to confirm the absence of fever.

Secondary endpoints include a range of clinical, therapeutic, microbiological, and adverse event criteria. Clinical criteria involve monitoring for fever recurrence before Day 14, hospitalization for treatment failure, intensive care unit admission, and mortality rates, with specific timepoints for assessment at 48 hours (H48), Day 4, Day 14, and Day 30. Therapeutic criteria will assess the adequacy of empirical antibiotic treatment, treatment compliance, any modifications in antibiotic treatment, and the duration of antibiotic use, with evaluations at H48, Day 4, and Day 14. Microbiological criteria will focus on the presence of bacteraemia and the efficacy of empirical antibiotic treatment against identified bacteria, particularly **Pseudomonas aeruginosa**, assessed on Day 14.

Adverse events, including both adverse events (AE) and serious adverse events (SAE), will be collected at every follow-up visit. Evaluations will occur at H48 via phone call, at Day 14 through phone calls, review of medical charts, and retrospective collection of biological and microbiological data, and at Day 30 via phone call. Specific adverse events of interest include tendinous pain, joint pain, confusion, QT prolongation, cardiac rhythm disorders, allergy, and C. difficile colitis. These comprehensive assessments will ensure a thorough evaluation of the treatment's efficacy and safety profile.