E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Invasive Aspergillus infection |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022881 |
E.1.2 | Term | Invasive bronchopulmonary aspergillosis |
E.1.2 | System Organ Class | 100000004862 |
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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 |
Evaluate if the survival in patients with a triazole susceptible IA can be improved when the initial therapy consists of triazole and echinocandin combination therapy instead of triazole monotherapy. |
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E.2.2 | Secondary objectives of the trial |
1. Evaluate if the survival in patients with an IA in whom azole resistance was not detected can be improved by starting triazole/echinocandin combination therapy compared to the local standard of care.
2. Evaluate if a triazole/echinocandin combination therapy improves the overall quality of life and if it is a cost-effective intervention
3. Evaluate the outcome of patients in which a triazole-resistant A. fumigatus is detected in relation to the initial antifungal therapy they had received (i.e. triazole monotherapy or combination therapy).
4. Evaluate the outcome of patients in which resistance testing is unsuccessful in function of the antifungal therapy they received.
5. Evaluate if the baseline serum galactomannan value and the serum galactomannan kinetics are predictive of overall 6-week mortality.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18 years or older 2. Have started or will start voriconazole or isavuconazole (or posaconazole if voriconazole or isavuconazole cannot be given as per treating physician’s decision) as antifungal therapy on the baseline visit. 3. For all patients: presence of one of the EORTC/MSG host factors as defined in appendix 1 or being admitted to the ICU with influenza 4. For non-ICU patients or ICU patients without influenza: Meet the EORTC/MSG clinical criterion 5. For non-ICU patients or ICU patients without influenza: Meet the mycological criterion or fulfil inclusion criterion 7 6. For ICU patients with influenza we consider an isolated positive sputum culture for Aspergillus spp. insufficient as a mycological criterion. Therefore, in these patients only one of the following mycological criteria are acceptable; Serum galactomannan >=0.5, BAL galactomannan >=1.0 or Aspergillus spp. cultured in BAL fluid. 7. Please note that patients with AML or ALL receiving intensive treatment regimens for induction/remission, refractory or relapsed disease OR patients receiving systemic immunosuppressive therapy for GVHD can be included before the mycological criterion is fulfilled on condition that they fulfill the EORTC/MSG lung CT radiology criteria (halo sign, well-described nodule, cavity as described in appendix 1) at the time of inclusion and as long as the mycological test results are expected to become available within 96 and no later than 7 days after inclusion. If these test results turn out to be negative, the patient will be withdrawn from the study and further treatment is at physician’s discretion. |
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E.4 | Principal exclusion criteria |
1. Known history of allergy, hypersensitivity or serious reaction to triazole or echinocandin antifungals; 2. Patients with chronic invasive aspergillosis or a chronic non-invasive aspergillus infection (e.g. aspergilloma) defined as the clinical or radiological sign of infection being present for >28 days. 3. Receipt of itraconazole, voriconazole, posaconazole or isavuconazole as prophylaxis for at least 7 days in the 14 days preceding the date of the first radiological signs of the Aspergillus infection. Patients in which the most recent serum level of the triazole given as prophylaxis was subtherapeutic can be included (*). 4. Receipt of echinocandin prophylaxis for >96 hours in the preceding 7 days 5. Receipt of systemic antifungal treatment with an echinocandin, a triazole (except fluconazole) or amphotericin B for the current episode of invasive aspergillosis for a duration of > 96 hours. 6. For patients in the Netherlands only: Diagnostic testing to exclude triazole resistance will not be possible (sputum cultures are negative and BAL sampling will not be performed) 7. ICU patients only: Patients with a sequential organ failure assessment (SOFA) score >11 at the time of screening for the study are excluded. If randomization is done >24 hours after screening the calculation should be repeated before the patient can be randomized (appendix 3) 8. ICU patients only: Patients in which weaning from the ventilator or ECMO system is deemed unlikely due to irreversible lung damage 9. Patients with any condition which, in the opinion of the investigator, could affect patient safety, preclude evaluation of response (e.g. because survival beyond 6 weeks is unlikely due to the underlying disease status) 10. Patient previously included in this study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival 6 weeks after the start of antifungal therapy in the MITT population |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When the relevant data are available. |
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E.5.2 | Secondary end point(s) |
1. Overall survival 6 weeks after the start of antifungal therapy in the ITT population 2. Overall aspergillus attributable mortality 12 weeks after the start of antifungal therapy(*). 3. Overall survival 12 weeks after the start of antifungal therapy in the MITT population 4. Overall survival 6 weeks after the start of therapy in the subgroup of patients in the MITT population with a positive serum galactomannan test at baseline. 5. Overall survival 6 weeks after the start of therapy in the subgroup of non-ICU patients who fulfill the EORTC/MSG probable or proven definition (MITT population). 6. Overall survival 6 weeks after the start of therapy in the subgroup of non-ICU patients with an underlying haematological disease (MITT population) 7. Overall survival 6 weeks after the start of therapy in the subgroup of non-ICU patients without an underlying haematological disease (MITT population) 8. Overall survival 6 weeks after the start of therapy in patients that started with triazole monotherapy and in which triazole resistance is detected during follow-up 9. Overall survival 6 weeks after the start of therapy in patients that started with triazole-anidulafungin combination therapy and in which triazole resistance is detected during follow-up 10. In the subgroup of patients with a positive serum galactomannan; Kinetics of serum galactomannan levels with combination versus monotherapy 11. Outcome of patients in which resistance testing was unsuccessful 12. Time to hospital discharge (in the MITT subgroup of patients admitted to the hospital at baseline) 13. Time to hospital discharge (in the ITT subgroup of patients admitted to the hospital at baseline) 14. Cost-effectivity of azole-anidulafungin combination therapy |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
When the relevant data are available. |
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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 | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
treatment with azole which is regular treatment |
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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 | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |