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 |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003488 |
E.1.2 | Term | 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 |
To compare the all-cause mortality for posaconazole
(POS) compared to voriconazole (VOR) in the first line treatment of invasive
aspergillosis (IA) at Week 6 in all randomized subjects who received at least one dose of study treatment (in the ITT [Intention To
Treat] population). The hypothesis to be tested is that the all-cause mortality at Week 6 in the POS
treatment group is non-inferior to that in the VOR treatment group. |
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E.2.2 | Secondary objectives of the trial |
Evaluate all-cause mortality for POS vs VOR at Week 6 in FAS population
Evaluate global clinical response for POS vs VOR at Week 12 in FAS population
Evaluate all-cause mortality for POS vs. VOR at Week 12 in both the FAS and ITT populations
To evaluate the global clinical response for POS vs. VOR at Week 6 in the FAS population |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Each subject must be willing and able to provide written informed consent for the trial. The legal representative (e.g. parent or guardian) for a subject under the age of legal consent or who otherwise is unable to provide independent consent may provide written informed consent for the subject. Each subject of the age of assent must be willing and able to provide assent in addition to consent from the legal representative to participate in the trial.
2. Each subject must be ≥13 years of age weighing >40 kg [88 lb] and ≤150 kg [330 lb] at the time of randomization. Each subject between 13 and 14 years of age must weigh ≥ 50 kg [110lb]. Subjects may be of either sex and of any race/ethnicity. For those sites that do not have the ability to enroll adolescents, subjects must be greater than ≥18 years of age.
3. Each subject must meet the criteria for proven, probable, or possible invasive aspergillosisIA as per 2008 EORTC/MSG disease definitions at the time of randomization. Proven IA will include those subjects with
the demonstration of fungal elements (by cytology, microscopy, or culture) in diseased tissue (sterile sampling). Probable IA includes subjects with at least 1 host factor, clinical criteria, as well as mycological criteria including both direct and indirect (i.e., detection of serum, or BAL fluid Aspergillus galactomannan antigen by sandwich EIA) methods. If using the galactomannan test for diagnosis, a positive test results is defined as a cut-off index of ≥ 1.0 for both serum and BAL. Two positive test results will qualify the subject for meeting the criteria as probable IA. For subjects receiving piperacillin/tazobactam within 72 hours of serum galactomannan sampling, serum galactomannan criteria for probable IA will not meet the criteria for probable IA. Possible IA includes subjects with at least 1 host factor and clinical criteria but without mycological criteria. See Appendix 3 for tables of diagnostic criteria.
4. Each subject with possible invasive aspergillosis IA at time of randomization must be willing or be in process of an ongoing diagnostic work up which is anticipated to result in a mycological diagnosis of proven or probable IA within 7 days post-randomization. In the event this does not result in mycological diagnosis of proven or probable IA, the patient must be willing to continue on study therapy and remain in the study.
5. Each subject must have a central catheterline (e.g., central venous catheter, peripherally-inserted central catheter, etc.) in place or planned to be in place prior to beginning IV study therapy. Subjects without central catheter access must be clinically stable and able to receiving oral study therapy.
6. Each subject must have acute invasive aspergillosisIA defined as duration of clinical syndrome of <30 days.
7. Each subject must be willing to adhere to dosing, study visit schedule, and mandatory procedures as outlined in the protocol. The subject must be willing to continue on study therapy for up to 12 weeks and remain in the study through the 1 month follow-up visit.
8. The subject must have the ability to transition to oral study therapy during the course of the study. |
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E.4 | Principal exclusion criteria |
1. The subject has chronic (>1 month duration) IA, relapsed/recurrent IA, or refractory IA which has not responded to prior antifungal therapy.
2. The subject has chronic pumonary sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis (ABPA).
3. The subject has a known mixed invasive mold fungal infection including Zygomycetes, and/or a known invasive Aspergillus fungal infection in which either study drug may not be considered active.
4. The subject has received any systemic (oral, intravenous, or inhaled) antifungal therapy for this infection episode for 4 or more consecutive days (>96 hours) immediately prior to randomization.
5. The subject has developed the current episode of IA infection (possible, probable, or proven infection ) during the receipt of more than 13 days of an azole or polyene antifungal agent given for prophylaxis that is considered to be a mold-active antifungal agent (including itraconazole, posaconazole, voriconazole, isavuconazole, inhaled or systemic amphotericin or lipid-associated amphotericin). Any duration of echinocandin antifungal use is allowed (prior to randomization).
6. The subject has received POS or VOR as empirical treatment for this infection for 4 days (96 hours) or more within the 15 days immediately prior to randomization.
19. The subject is on artificial ventilation or receiving acute Continuous positive airway pressure (CPAP)/ Bilevel Positive Airway Pressure (BPAP) at the time of randomization. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary Endpoint is related to the Primary Trial Objective. The Primary endpoint for the trial is the All-Cause mortality at week 6 post randomization in the ITT. |
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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) |
Key secondary endpoints include the global clinical response at Week 6 and Week 12 in the FAS population, all-cause mortality at Week 6 and Week 12 in the FAS population and all-cause mortality at Week 12 in the ITT population. All will be evaluated using a similar methodology as that for the primary analysis.
Other secondary endpoints: Other endpoints (i.e., time to global clinical response in the FAS population; time to death [all causes] in the FAS population; and mortality due to IA at Weeks 6 and 12 in the FAS population) will also be analyzed. Global clinical response Weeks 6 and 12 in subjects with possible, probable, or proven IA subjects (ITT population) will also be assessed as a secondary endpoint.
Survival will be assessed using a Kaplan Meier estimates and will be compared between the two arms using the Log-Rank test. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 6 and Week 12 of therapy, end of study |
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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 | No |
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Other analyses: Sparse pharmacokinetic (steady state trough) sampling will be performed on all subjects throughout the treatment period. Data regarding food intake relative to posaconazole tablet administration will be collected and the effect of food on the steady state pharmacokinetics of posacoanzole tablet will be evaluated. |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.2.3 | Other | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
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 |
China |
Colombia |
Estonia |
France |
Germany |
Greece |
Guatemala |
India |
Ireland |
Israel |
Italy |
Korea, Republic of |
Lithuania |
Malaysia |
Mexico |
Peru |
Poland |
Portugal |
Russian Federation |
Singapore |
Spain |
Switzerland |
Taiwan |
Turkey |
United Kingdom |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |