| 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 | 14.1 |
| 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 |
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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 |
| Compare global clinical response of POS vs VOR in the first-line treatment of invasive aspergillosis at Week 6 in those subjects with proven or probable invasive aspergillosis (FAS population). The hypothesis to be tested is that the proportion of subjects achieving the overall clinical response at week 6 in the treatment group POS not inferior to those in the treatment group VOR. |
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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 FAS population
Evaluate all-cause mortality for POS vs. VOR at Week 6 in ITT population |
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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 |
| Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| 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 [110 lb]. Subjects may be of either sex and of any race/ethnicity.
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. 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 aspergillosisIA 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.
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.
8. The subject must have the ability to transition to oral study therapy during the course of the study or be willing to receive the entire 12-week study treatment course intravenously.
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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 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 immediately prior to randomization.
5. The subject is taking mold-active antifungal prophylaxis and the IA infection is considered to be a breakthrough. A breakthrough IA infection is one that develops after the initiation of 13 days or more of preventative systemic antifungal therapy.
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Global clinical response of POS vs VOR in the first-line treatment of invasive aspergillosis at Week 6 in those subjects with proven or probable invasive aspergillosis (FAS population) |
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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) |
Evaluate of all-cause mortality for POS vs VOR at Week 6 in FAS population
Evaluate of global clinical response for POS vs VOR at Week 12 in FAS population
Evaluate of all-cause mortality for POS vs. VOR at Week 12 in FAS population
Evaluate the time to global clinical response for POS vs. VOR in the FAS population.
Evaluate the time to death (all causes) for POS vs. VOR in the FAS population.
Evaluate mortality due to IA at Weeks 6 and Week 12 for POS vs. VOR in the FAS population.
Evaluate the all-cause mortality and global clinical response at Weeks 6 and 12 in subjects with a diagnosis of possible, probable, or proven IA receiving POS vs. VOR (Intention to Treat [ITT] population).
Evaluate the safety and tolerability of POS and VOR by analyzing Tier 1 Safety events and all adverse events.
Evaluate the safety of POS compared to VOR therapy in the All-Patients-as-Treated (APaT) population.
Evaluate the pharmacokinetic profile of POS and VOR, and the exposure-response (efficacy and safety endpoints) relationships of POS and VOR in a subset of subjects. |
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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 | 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 | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| 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 | 11 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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