| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| 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 |
| To compare all cause mortality at 6 weeks in patients with hematologic malignancy or with allogeneic HSCT with a diagnosis of proven or probable IA receiving voriconazole and anidulafungin in combination versus voriconazole monotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare (global response) and (mortality due to IA) at 6 weeks;
• To compare all cause mortality at 6 weeks and 12 weeks in patients with hematologic malignancyor with allogeneic HSCT with a diagnosis of possible, proven or probable IA (ITT population) receiving the combination of voriconazole and anidulafungin to voriconazole monotherapy;
• To compare time to death due to (IA ) and (all causes) in patients mentioned in third bullet
• To compare the safety and tolerability of voriconazole monotherapy to that of voriconazole in combination with anidulafungin;
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Immunocompromised state due to either:
Receipt of allogeneic hematopoietic stem cell transplantation after myeloablative or
non-myeloablative conditioning; or,
Hematologic malignancy (excluding subjects with progressive hematologic disease
who have not responded (or are not likely to respond) to treatment);
2. Diagnosis of proven or probable or possible invasive aspergillosis (based on a modified version of the revised EORTC/MSG consensus definitions);
NOTE: Subjects enrolled with possible IA will be required to have a proven or
probable diagnosis established based on tests done within 7 days of enrollment (See
Section 6.6).
Proven invasive aspergillosis is defined as:
Histopathologic, cytopathologic, or direct microscopic examination of a needle
aspiration or biopsy showing hyphal forms with evidence of associated tissue damage (either microscopically or as an infiltrate or lesion by imaging);
or,
Recovery of Aspergillus species by culture from a sample obtained by a sterile
procedure from normally sterile and clinically or radiologically abnormal site
consistent with an infectious disease process, excluding BAL, cranial sinus cavity,
and urine.
Probable invasive aspergillosis is defined by at least:
One host factor; and;
One clinical criterion; and;
One microbiologic criterion.
Possible invasive aspergillosis is defined by at least:
One host factor; and;
One clinical criterion.
3. Male or female greater than or equal to 16 years of age;
4. For women of childbearing potential, patient has had a negative pregnancy test.
5. Evidence of a personally signed and dated informed consent document in accordance with local regulatory and legal requirements indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
6. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Known history of allergy, hypersensitivity or serious reaction to azole or echinocandin antifungals;
2. Female patients who are pregnant or lactating;
3. Patients with sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis
(ABPA);
4. Patients with chronic invasive aspergillosis with a duration of symptoms or radiological finding for more than 4 weeks prior to study entry;
5. Patients who are receiving and cannot discontinue the following drugs at least 24 hours prior to randomization: terfenadine, astemizole, cisapride, pimozide or quinidine (because of the possibility of QT prolongation);
6. Patients receiving any of the following medications: sirolimus, rifampin, rifabutin,
carbamazepine, long-acting barbiturates (eg, phenobarbital, mephobarbital), ritonavir, efavirenz, or ergot alkaloids (eg, ergotamine, dihydroergotamine);
7. There are other potentially clinically relevant interactions between voriconazole and some commonly prescribed drugs. While these drugs have not been contraindicated, advice on monitoring or dosage adjustments is made.
8. Receipt of systemic antifungal treatment for the current episode of invasive aspergillosis for a duration of greater than 96 hours.
NOTE: Patients receiving mold-active prophylaxis may be enrolled provided that they meet criteria for proven or probable IA at the time of enrollment.
9. Severe liver dysfunction (defined as total bilirubin >10x upper limit of normal, or AST, ALT, or alkaline phosphatase >5x upper limit of normal). Local laboratory results may be used to qualify individuals for enrollment. However, if laboratory values drawn at the Baseline visit exceed the above limits for exclusion, the medical monitor must be contacted without delay to discuss continuation of study treatment;
10. Patients on artificial ventilation;
11. Patients with any condition which, in the opinion of the investigator, could affect patient safety, preclude evaluation of response, or make it unlikely that the proposed course of therapy can be completed;
12. Patients who are receiving, or are likely to receive, any Phase I investigational drug. Patients receiving Phase II or Phase III investigational drugs may be enrolled only with the prior approval of the medical monitor. Patients receiving investigational drugs that are currently licensed for other indications may be enrolled;
13. The inclusion of a patient more than once in this trial is not permissible;
14. Patients not expected to survive for at least 5 days or who have a Karnofsky score <20 (See Appendix 4);
15. Patients with a high likelihood of death due to factors unrelated to aspergillosis (eg, due to relapsed malignancy, severe graft versus host disease, other underlying diseases, etc.) within 30 days following planned enrollment (investigator's discretion);
16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study;
17. Concomitant administration of systemic agents active against Aspergillus species is not permissible. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is all cause mortality, measured 6 weeks after IA diagnosis in subjects with proven or probable IA. |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Anidulafungin is double blinded but Voriconazole is not blinded at all |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Anidulafungin and Voriconzaole is a combination versus Voriconazole alone |
|
| 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 | 74 |
| 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
|
| The End of the Trial is the Last Visit Last Subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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