E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076734 |
E.1.2 | Term | Chemotherapy induced neutropenia |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To establish the non-inferiority of amoxicillin-clavulanate alone versus the combination of amoxicillin-clavulanate with ciprofloxacin to treat febrile neutropenia in low-risk patients (MASCC score ≥21 and neutropenia expected duration ≤ 7 days) during cancer chemotherapy. |
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E.2.2 | Secondary objectives of the trial |
1. To describe pharmacokinetics (PK) of amoxicillin-clavulanate and ciprofloxacin in febrile neutropenic patients. 2. To assess the relevance of French current dosage regimen of amoxicillin-clavulanate regimen and ciprofloxacin in febrile neutropenic patients. 3. To evaluate the impact of tested regimen on MDR bacteria emergence. 4. To evaluate the occurrence of Clostridium difficile colitis. 5. To evaluate the documented infections with bacteria resistant to the studied regimen. 6.To evaluate the safety of amoxicillin-clavulanate alone versus combination with ciprofloxacin in the global population of the study. 7. To evaluate the safety of amoxicillin-clavulanate alone versus combination with ciprofloxacin in outpatients. 8. To evaluate the tolerance of amoxicillin-clavulanate alone versus combination with ciprofloxacin. 9. To evaluate time to fever resolution. 10. To evaluate survival at day 30 after randomization.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patient ≥ 18 years old. - Treated for a solid cancer or a hematological malignancy. - Presented with low-risk febrile neutropenia (low risk is defined by MASCC score ≥ 21) due to chemotherapy with an expected duration of neutropenia ≤ 7 days. - Neutropenia is defined by an absolute neutrophil count ≤500/mm3. - Fever is defined by temperature ≥ 38.3° or ≥ 38° twice during a 1-hour interval. - Patient affiliated to an appropriate health insurance. - Signing informed consent
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E.4 | Principal exclusion criteria |
- Hypersensitivity to the active substances: amoxicillin-clavulanic, ciprofloxacin, penicillins, to other quinolones or to one of the excipient - History of severe immediate hypersensitivity reaction to another beta-lactam - History of jaunditis/hepatic impairment related to amoxicillin/clavulanic -Concomitant administration of ciprofloxacin and tizanidine. - Clinical signs of focal infection including history of untreated dental abscess. - Signs of sepsis or organ failure. - Severe immune deficiency other than the current cancer, except controlled-HIV infection. - Gastrointestinal symptoms requiring intravenous treatment (mucositis, vomiting,...). - Known aminotransferase serum levels > 5 x normal values - Know renal insufficiency defined as creatinine clearance of < 30 mL/min (MDRD). - Antibiotherapy within 24h before enrollment. Prophylactic use of amoxicillin is an exclusion criterium whereas prophylactic use of trimethoprim–sulfamethoxazole (cotrimoxazole) and penicillin G (Oracilline®) are not and will be considered in the analysis. - History of infection or colonization due to bacteria resistant to experimental drugs in the previous year - Can be enrolled in the study only once. - Patients not benefiting from a Social Security scheme or not benefiting from it through a third party. - Persons benefiting from enhanced protection, namely minors, persons deprived of their liberty by a judicial or administrative decision, persons staying in a health or social institution, adults under legal protection, and finally patients in emergencies. - Pregnant or breastfeeding women, women at age to procreate and not using effective contraception.
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E.5 End points |
E.5.1 | Primary end point(s) |
Comparison of antibiotic therapy success rate in both arms. The success rate is defined by the proportion of patients receiving the tested regimen: - with resolution of fever ≤72h after the start of antibiotics - AND without any modification of the antibiotic regimen (route, dosage, combination), - AND without fever recurrence in 48h following the discontinuation of antibiotics
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
48h following the discontinuation of antibiotics |
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E.5.2 | Secondary end point(s) |
1. Evaluation of population PK parameters for amoxicillin- clavulanate and ciprofloxacin in febrile neutropenic patients 2. Probability of target attainment for PK-PD index relevant to each antibiotic (T>MIC, AUC/MIC) using Monte Carlo simulations 3. Percentage of patients with ESBL and/or MRSA colonization/infection occurring during the follow-up study period in patients without known previous colonization, assessed at the end of the follow-up period by (i) history of infection with MRSA or ESBL since the end of studied antibiotic treatment, (ii) positivity of nasal swab for MRSA and/or rectal swab for ESBL during follow-up period. 4. Percentage of patients having developed microbiologically documented Clostridium difficile colitis at D30 and D90 after the first dose of antibiotic in both arms. 5. Percentage of documented infections with amoxicillin-clavulanate and/or ciprofloxacin-resistant bacteria 6. Comparison of serious complication rates in both arms • admission to ICU whatever the reason • respiratory failure necessitating invasive or non-invasive ventilation, or high flow nasal oxygen therapy • septic shock: patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia • death 7. Comparison of the frequency of outpatient readmission to hospital in both arms. 8. Number of adverse events (AE) and serious AE (SAE) reported in both arms. 9. Comparison of time to resolution of fever in both arms 10. Comparison of survival through D30 after randomization in both arms
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 / 2: 2 days 3/5/6/7/8/9: 90 days max 4: 30 and 90 days 10: 30 days |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS+3 months for analysis |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | |