| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Invasive fungal disease caused by Aspergillus species or other filamentous fungi. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003488 |
| E.1.2 | Term | Aspergillosis |
|
| 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 |
Primary Objective:
- To compare overall outcome following primary treatment with isavuconazole versus
voriconazole (VRC) in patients with IFD caused by Aspergillus species or other
filamentous fungi. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
- To compare the effects of treatment on:
- Overall outcome at EOT and Day 84
- Response in patients with mycologically confirmed pulmonary disease
- Response in the subpopulations defined by the stratification variables
- Mycological response
- Survival rate.
- To characterize the safety of treatment with isavuconazole
- To characterize the pharmacokinetics (PK) of BAL4815 and cleavage product BAL8728. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
In selected sites with appropriate facilities and equipment the PK of BAL4815 and cleavage product BAL8728 will be evaluated in patients treated with isavuconazole.
Seven plasma samples including samples from at least 10 patients aged < 42 years and 10 patients aged > 65 years will be collected on Day 7 or 14 for PK profiling |
|
| E.3 | Principal inclusion criteria |
1. Patients and/or legally authorized representative(s), if applicable, who have been fully informed and have given voluntary written informed consent.
or
patients unable to write and/or read but who fully understand the oral information given by the Investigator (or nominated representative) who have given oral informed consent witnessed in writing by an independent person.
2. Ability and willingness to comply with the protocol.
3. Male and female patients aged ≥ 18 years.
4. Female patients must be non-lactating and at no risk for pregnancy for one of the following reasons:
- Postmenopausal for at least 1 year
- Post-hysterectomy and/or post-bilateral ovariectomy
- If of childbearing potential, having a negative urine or serum human chorionic
gonadotropin (hCG) pregnancy test at the screening visit and be using a highly effective method of birth control throughout the course of the study. Reliable sexual abstinence throughout the course of the study is acceptable as a highly effective method of birth control for the purposes of this study.
5. Patients must have proven or probable IFD caused by Aspergillus species or other
filamentous fungi as defined below.
NB1: Patients fulfilling the criteria for possible IFD as defined below will be eligible for
enrollment; if, however, it is not possible to confirm IFD by culture, histology/ cytology or galactomannan (GM) antigen within the 7 days after the first administration of study medication will be withdrawn from the study.
NB2: Patients with neutropenia or allogeneic BMT and LRT disease are eligible to remain in the study even in the absence of mycological criteria. However, the enrollment of these types of patients will be limited to a maximum of 120 randomized.
Please refer to the protocol for additional information on the inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or breastfeeding.
2. Known history of allergy, hypersensitivity to or any serious reaction to the azole class of
antifungals or to any component of the study medication.
3. Patients for whom VRC is contra-indicated, including cardiovascular findings.
4. Patients at high risk for QT/QTc prolongation e.g.
• a family history of long QT syndrome, or
• other known pro-arrythmic conditions.
5. Evidence of moderate to severe hepatic or renal dysfunction with any of the following abnormal laboratory parameters at the screening visit:
- Total bilirubin ≥ 3 times the upper limit of normal (ULN)
- Alanine transaminase or aspartate transaminase ≥ 5 times ULN
- Calculated creatinine clearance < 50 mL/minutes
6. Concomitant use of astemizole, cisapride, rifampicin, rifabutin, ergot alkaloids, long acting barbiturates, carbamazepine, pimozide, quinidine, neostigmine or terfenadine, in the 5 days prior to first administration of study medication. 7. Patients with any other invasive fungal infection other than Aspergillus species or other filamentous fungi and patients with Zygomycetes or Scedosporium prolificans infection not expected to respond to voriconazole treatment.
8. Patients with either chronic aspergillosis, aspergilloma, or ABPA.
9. Microbiological (e.g. virological) findings or other potential conditions that are temporally related and suggest an different etiology of the clinical features.
10. Patients who have received more than 4 cumulative days of systemic antifungal therapy other than fluconazole within the 7 days prior to the first administration of study medication.
11. Chronic granulomatous disease, severe combined immunodeficiency, advanced human immunodeficiency virus infection with CD4 count < 200 or acquired immunodeficiency
syndrome-defining condition, body weight < 40 kg.
12. Any known or suspected condition of the patient that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy (e.g. neutropenia not expected to resolve, patients with endocarditis, osteomyelitis, meningitis, uncontrolled malignancy (treatment refractory, palliative therapy only) with life expectancy of less than 30 days).
13. Patients with a concomitant medical condition that, in the opinion of the investigator, may be an unacceptable additional risk to the patient should he/she participate in the study.
14. Patients previously enrolled in a phase III study with isavuconazole.
15. Treatment with any investigational drug in any clinical trial within 30 days prior to the first administration of study medication except unblinded phase III trials.
16. Patients who are unlikely to survive longer than 5 days or patients on mechanical ventilation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Primary Endpoint
- Overall outcome (clinical, mycological and radiological response) at Day 42.
Secondary Endpoints
- Overall outcome at EOT and Day 84 (if different from EOT / if applicable)
- Response at Day 42, EOT and Day 84 (if different from EOT / if applicable) in
patients with mycologically confirmed pulmonary disease
- Overall outcome in the subpopulations defined by the stratification variables
Isavuconazole Water-Soluble Azole
Clinical Study Protocol WSA-CS-004
Amendment Final/ Confidential
BAP00647
9 - Mycological response at Day 42, EOT and Day 84 (if different from EOT / if
applicable)
- Survival rate at Day 42 and Day 84. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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