| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003488 |
| E.1.2 | Term | Aspergillosis |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 (complete and partial response) of POS vs VOR in the first-line treatment of invasive aspergillosis at Week 6 in those patients with proven or probable invasive aspergillosis (Full Analysis Set [FAS] population) |
|
| 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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient:
1. Must be willing and able to provide written informed consent for the trial. The legal representative (e.g. parent or guardian) for a patient under the age of legal consent or who otherwise is unable to provide independent consent may provide written informed consent for the patient. Each patient 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. Must be ≥18 years of age weighing >40 kg [88 lb] and ≤150 kg [330 lb] at the time of randomisation. Patients may be of either sex and of any race/ethnicity.
3. Must meet the criteria for proven, probable, or possible IA as per 2008 EORTC/MSG disease definitions at the time of randomisation.
4. With possible IA at time of randomisation 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-randomisation. 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. 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. Must have acute IA defined as duration of clinical syndrome of <30 days.
7. Must be willing to adhere to dosing, study visit schedule, and mandatory procedures as outlined in the protocol.
8. Must have the ability to transition to oral study therapy during the course of the study.
9. Female participants of child-bearing potential must be using a medically
accepted method of birth control before beginning study-drug treatment and
agree to continue its use for 30 days after stopping the medication, or have been surgically sterilized (e.g., hysterectomy or tubal ligation.
10. To participate in the pharmacogenetic analysis, the participant must be willing to give written informed consent for the pharmacogenetic testing and able to adhere to dose and visit schedules.
11.Participant is not taking prohibited antifungal prophylaxis or treatment as defined by the protocol. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded if they:
1. Have chronic (>1 month duration) IA, relapsed/recurrent IA, or refractory IA which has not responded to prior antifungal therapy.
2. Have sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis (ABPA).
3. Have 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. Have received any systemic (oral, intravenous, or inhaled) antifungal therapy for this infection episode for 4 or more consecutive days immediately prior to randomisation.
5.The patient has developed the current episode of IA infection (possible,
probable, or proven infection) during the receipt of more than 13 days of
antifungal prophylaxis that is considered to be a mold-active antifungal agent
(including itraconazole, posaconazole, voriconazole, isavuconazole, inhaled or
systemic amphotericin or lipid-associated amphotericin, and echinocandin
agents).
6. Have received POS or VOR as empirical (experimental)treatment for this infection for 4 days (96 hours) or more within the 15 days immediately prior to randomisation.
7. Have received any treatment specifically listed in Table 2 (page 49 of the protocol) which is more recent than the indicated washout period prior to randomisation.
8. Have any condition that, in the opinion of the investigator, may interfere with optimal participation in the study, i.e., any condition requiring the use of prohibited drugs or unstable medical conditions other than the hematological disorder such as cardiac or neurologic disorder or impairment expected to be unstable or progressive during the course of this study (e.g., seizures or demyelinating syndromes, acute myocardial infarction within 3 months of study entry, myocardial ischemia, or unstable congestive heart failure, unstable arrhythmias, atrial fibrillation with ventricular rate <60/min, or history of
torsades de pointes, symptomatic ventricular or sustained arrhythmias, unstable electrolyte abnormalities [e.g., ≥ Grade 2 hypokalemia or hypomagnesemia]).
9. Have known hypersensitivity or other serious adverse reaction to any azole antifungal therapy, or to any other ingredient of the study medication used.
10. The female patient is pregnant, intends to become pregnant, or is nursing at the time of randomisation.
11. Have any known history of Torsade de Pointes, unstable cardiac arrhythmia or proarrhythmic conditions, or a history of recent myocardial infarction within 90 days of study entry.
12. Have QTc (either Fridericia or Bazett’s correction) interval ≥ 500 msec on electrocardiogram performed at screening or baseline.
13. Have significant liver dysfunction (defined as total bilirubin > 1.5 times upper limit of normal AND AST or ALT > 3 times upper limit of normal with normal alkaline phosphatase [ALP] on screening labs) at the time of randomisation.
14. Have hepatic cirrhosis or a Child-Pugh score of C (severe hepatic impairment) at the time of randomisation. See Appendix 4 for Child-Pugh Classification.
15. The patient has severe renal insufficiency (estimated creatinine clearance <20 mL/min) or on haemodialysis at the time of randomisation or is likely to require dialysis during the study.
16. Have a known hereditary problem of galactose intolerance, Lapp lactase deficiency, or glucosegalactose malabsorption.
17. Have acute symptomatic pancreatitis within 6 months of study entry or has a diagnosis of chronic pancreatitis at the time of randomisation.
18. Have an active skin lesion consistent with squamous cell carcinoma at the time of randomisation, or a current or prior history of malignant melanoma within 5 year of study entry.
19. Are on artificial ventilation or receiving acute Continuous positive airway pressure (CPAP)/ Bilevel Positive Airway Pressure (BPAP) at the time of randomisation.
20. Have known or suspected Gilbert’s disease at the time of randomisation.
21. Require treatment with other medications that cannot be stopped and for which there is a known contraindication to co-administration of one or more of the study drugs.
22. Are not expected to survive for at least 1 week post-randomisation.
23. Have prior enrollment in this study. The patient must not have prior enrollment in other POS studies within 90 days of study entry.
24. Or a family member is among the personnel of the investigational or sponsor staff directly involved with this trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Global clinical response of POS versus VOR in the first-line treatment of IA at Week 6 in those participants with proven or probable invasive aspergillosis (known as the FAS population). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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 participantss 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 participants.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 6 and Week 12 of therapy, end of study |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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 | 21 |
Print
