| 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 | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003488 |
| E.1.2 | Term | Aspergillosis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 all cause mortality thourgh Day 42 following priamry 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 |
To compare the effects of treatment on:
- All cause mortality rate at Day 42 and Day 84
- Overall outcome at Day 42, end of treatment (EOT) and Day 84
- Overall outcome at Day 42, EOT and Day 84 in patients with mycologically confirmed
lower respiratory tract disease (LRTD)
- Overall outcome and mycological response at Day 42, EOT and Day 84 in the
subpopulations defined by the stratification variable
- Mycological response at Day 42, EOT and Day 84
• To characterize the safety and tolerance of treatment with ISA |
|
| 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 ISA.
Seven plasma samples from approximately 25 patients aged < 42 years and approximately 25 patients aged > 65 years will be collected on Day 7 or preferrably on Day 14 for PK profiling.
If PK data permits within the sub-study, an assessment of the route of administration will be assessed. Additionally, time above the minimum inhibitory concentration (MIC) should also be captured. |
|
| E.3 | Principal inclusion criteria |
1. Patients and/or legally authorized representative(s), if applicable, who have been fully informed and who have
given voluntary written informed consent and HIPAA
Authorization for U.S. sites, or equivalent privacy language as per national
regulations Or patients unable to write and/or read but who fully understand the oral information given by the investigator (or nominated representative), and who have given oral informed consent and HIPAA Authorization
for U.S. sites, or equivalent privacy language as per national regulations, witnessed in writing by an independent person.
2. Ability and willingness to comply with the protocol.
3. Male and female patients aged ≥ 18 years, at time of signing the informed consent form.
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 with proven, probable or possible IFD caused by Aspergillus species or other filamentous fungi as defined in the protocol.
Refer to the protocol for the criteria for Proven Invasive Fungal Disease, Probable Invasive Fungal Disease and Possible Invasive Fungal Disease. |
|
| 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, such as:
• Baseline prolongation of QTcF interval >/= 500 msec
• Risk factors for Torsade de Pointes (e.g. uncompensated heart failure, abnormal potassium or magnesium levels that cannot be corrected, any unstable cardiac condition during the last 30 days, or a family history or long QT syndrome);
The use of concomitant medications that prolong the QT/QTc interval.
5. Patients with evidence of persistent moderate to severe hepatic dysfunction at the time of randomization, defined as (may be rechecked using local laboratory:
• Total bilirubin ≥ 3 times the upper limit of normal (ULN) or
• Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 5 times ULN or
• Patients with known cirrohisis or chronic hepatic failure.
6. Concomitant use of sirolimus, efavirenz, ritonavir, astemizole, cisapride,
rifampin/rifampicin, rifabutin, ergot alkaloids, long acting barbiturates,
carbamazepine, pimozide, quinidine, neostigmine, terfenadine, ketoconazole,
valproic acid or St. John’s Wort 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/ Mucormycosis or Scedosporium prolificans infection notexpected to respond to voriconazole treatment.
8. Patients with either chronic aspergillosis, aspergilloma or Allergic Bronchopulmonary Aspergillosis (ABPA).
9. Microbiological (e.g. virological) findings or other potential conditions that are temporally related and suggest a different etiology of the clinical features in the absence of evidence of systemic aspergillosis infection.
10. Patients who have been administered more than 4 cumulative days of itraconazole, voriconazole, or posaconazole, for any reason, within the 7 days prior to the first administration of study medication.
- Patients with applicable host factors who develop new evidence of IFD
while on prophylactic therapy, for at least 14 days, with either an
amphotericin B product or an echinocandin, will be eligible for enrollment.
- Prior use of fluconazole of any duration and for any reason will be eligible
for enrollment.
11. 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, for
example, neutropenia not expected to resolve, patients with fungal endocarditis,
fungal osteomyelitis, fungal meningitis, palliative therapy only for underlying
condition.
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 open label protocols.
16. Patients who are unlikely to survive longer than 30 days or patients on mechanical ventilation.
17. Patients with a body weight ≤ 40 kg.
18. Patients with evidence of moderate to severe renal dysfunction with any of the
following:
• Calculated creatinine clearance (CLcr) < 50 mL/minute at screening, or
• Currently on dialysis during administration of study medication. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| All cause mortality through Day 42. |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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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