E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Invasive fungal disease caused by Aspergillus species and Candida strains in patients with renal impairment as well as disease caused by rare moulds, yeats or dimorphic fungi. |
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E.1.1.1 | Medical condition in easily understood language |
Aspergillosis / Invasive Fungal Infections
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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 | 14.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10003486 |
E.1.2 | Term | Aspergillus infections |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049160 |
E.1.2 | Term | Candidaemia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 describe the safety and efficacy of isavuconazole in the treatment of invasive aspergillosis in patients with renal impairment or in patients with invasive fungal disease caused by rare moulds, yeasts or dimorphic fungi. |
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E.2.2 | Secondary objectives of the trial |
To determine clinical and mycological response rate by pathogen.
To evaluate the survival status at Day 42, 84, 120 and 180.
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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.
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. |
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E.3 | Principal inclusion criteria |
1. Patients and/or legal authorized representative(s), if applicable, who have been fully informed and have given voluntary written informed consent and HIPAA Authorization for US 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) who have given oral informed consent, and
HIPAA Authorization for US 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 the time of signing the informed consent form.
4. Female patients must be non-lactating and at no risk for pregnancy
5. Patients who fall into one of the following 5 subgroups:
a) Patients with proven, probable or possible invasive aspergillosis who have renal impairment ( including dialysis) OR
b) Patients meeting EORTC/MSG definition of proven or culture positive probable IFD caused by rare molds, yeasts, or dimorphic fungi, whether renally impaired or not (including dialysis), who require primary therapy for their IFD at the time of enrollment as defined in the body of the protocol.
OR
c) Patients who have proven or probable zygomycosis, whether they are renally impaired or not (including dialysis), who require primary therapy. Zygomycosis must be documented by culture or histology / cytology.
OR
d) Patients meeting EORTC/MSG definition of proven or culture positive probable IFD caused by rare molds, yeasts, or dimorphic fungi, whether renally impaired or not (including dialysis), who are refractory to current treatment defined as:
-clear documentation of progression of disease
-failure to improve clinically despite currently receiving at least 7 days of standard antifungal regimen
OR
e) Patients meeting EORTC/MSG definition of proven or culture positive probable IFD caused by rare molds, yeasts, or dimorphic fungi, whether renally impaired or not (including dialysis), who are intolerant to current treatment, for example:
-doubling of serum creatinine value to higher than the upper limit of normal (ULN) within 48 hours
or
-serum creatinine > 2.0 mg/ml and current treatment with polyene or IV voriconazole
or
-other significant drug-related adverse reaction(s) to the current antifungal agent, resulting in discontinuation of the treatment, e.g. persistence of visual disturbance, allergic reaction, phototoxicity or severe infusion reaction
or
-documented inability to achieve adequate blood levels of posaconazole, voriconazole or itraconazole. |
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E.4 | Principal exclusion criteria |
1. Women who are pregnant or breastfeeding.
2. Known history of allergy, hypersensitivity, or any serious reaction to the azole class of antifungals or to any component of the study medication.
3. Patients at high risk for QT prolongation
4. Patients with evidence of hepatic dysfunction with any of the following abnormalities at the time of enrollment:
Total bilirubin > 3 x upper limit of normal (ULN) OR
Alanine transaminase (ALT) or aspartate transaminase (AST) > 5 x ULN OR
Patients with known cirrhosis or chronic hepatic failure
5. Concomitant use of astemizole, cisapride, rifampin/rifampicin, rifabutin, ergot alkaloids, long acting barbiturates, ritonavir, efavirenz, carbamazepine, pimozide, quinidine, neostigmine,
terfenadine, ketoconazole, valproic acid or St. John’s Wort in the 5 days prior to first administration of study medication.
6. Patients with either chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis (ABPA).
7. Microbiological findings (e.g. virological) or other potential conditions that are temporally related and suggest a different etiology for the clinical features in the absence of evidence of
systemic fungal infection.
8. Advanced human immunodeficiency virus (HIV) infection with CD4 count < 50 or uncontrolled acquired immunodeficiency syndrome-defining condition.
9. Any known or suspected condition of the patient that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy
10. 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.
11. Patients previously enrolled in a phase III study with ISA.
12. Treatment with any investigational drug in any clinical trial 30 days prior to the first administration of study medication except open label protocols.
13. Patients who are unlikely to survive 30 days.
14. Patients with a body weight < 40 kg.
15. Patients who need primary therapy for invasive aspergillosis 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the overall outcome of treatment (clinical, mycological and radiological response) evaluated by DRC at Day 42 by subgroup (e.g. type of pathogen).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Overall outcome of treatment evaluated by Investigator at Day 42 by sub-group
Overall outcome at EOT and Day 84, assessed by DRC and Investigator by sub-group
Clinical response at Days 42, EOT, Day 84 and FU, assessed by DRC and Investigator by sub-group
Mycological response at Day 42, EOT, Day 84 and FU, assessed by DRC and Investigator by sub-group
Survival rate at Day 42, Day 84, Day 120 and Day 180 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall outcome of treatment evaluated by Investigator at Day 42 by sub-group
Overall outcome at EOT and Day 84, assessed by DRC and Investigator by sub-group
Clinical response at Days 42, EOT, Day 84 and FU, assessed by DRC and Investigator by sub-group
Mycological response at Day 42, EOT, Day 84 and FU, assessed by DRC and Investigator by sub-group
Survival rate at Day 42, Day 84, Day 120 and Day 180 |
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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 | No |
E.8.1.1 | Randomised | No |
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 | 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 | 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 | 23 |
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 | No |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
Chile |
Egypt |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Korea, Republic of |
Lebanon |
Mexico |
Poland |
Russian Federation |
South Africa |
Taiwan |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 |
E.8.9.2 | In all countries concerned by the trial months | 6 |