| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of proven or probable invasive aspergillosis (IA) and rare molds such as Scedosporium or Fusarium species. |
|
| E.1.1.1 | Medical condition in easily understood language |
| A fungal infection caused by the fungus aspergillus or scedosporium or fusarium in people who have weak immune systems. |
|
| 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 |
|
| 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 | 10059045 |
| E.1.2 | Term | Scedosporium infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 | 10051919 |
| E.1.2 | Term | Fusarium infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 evaluate the safety and tolerability of voriconazole as primary treatment of invasive aspergillosis and rare molds such as Scedosporium or Fusarium species in immunocompromised pediatric subjects from 2 to <18 years of age. |
|
| E.2.2 | Secondary objectives of the trial |
| To describe the response to therapy with voriconazole as treatment of invasive aspergillosis and rare molds such as Scedosporium or Fusarium species in immunocompromised pediatric subjects from 2 to <18 years of age. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be eligible for enrollment into the study:
1. Immunocompromised with clinically compatible illness.
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 assessed again to determine if they have a proven or probable diagnosis based on tests done within 7 days of first dose of study drug.
Proven IA 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 bronchoalveolar lavage (BAL), cranial sinus cavity, and urine.
Probable IA is defined by at least:
One host factor; and
One clinical criterion; and
One microbiologic criterion.
Possible IA is defined by at least:
One host factor; and
One clinical criterion.
Note: CT scan or other radiological assessment done as standard of care within five days of enrollment in the study can be used as the Baseline radiological measure. Mycology and histopathology specimens taken as standard of care within ten days prior enrollment into the study (Day 1) are acceptable as the Baseline specimens.
3. Subjects with a diagnosis of infection due to Scedosporium or Fusarium species are eligible for enrollment.
4. Male or female from 2 to <18 years of age.
5. Females of childbearing potential must have a negative pregnancy test PLUS adequate contraception as determined by the investigator for the duration of the trial.
6. Documented informed consent by the subject or legal guardian and assent of the
child, as appropriate, in accordance with local regulatory and legal requirements.
Assent will be required (as applicable) for children per local regulations and for those
who, in the investigator’s judgment, are able to comprehend.
7. 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 enrolled in the trial:
1. History of allergy, hypersensitivity, or serious reaction to voriconazole or its excipients or to any azole antifungal.
2. Female subjects who are pregnant or lactating.
3. Sarcoidosis, Aspergilloma, or allergic bronchopulmonary aspergillosis (ABPA).
4. Chronic IA with duration of symptoms or radiological finding of more than 4 weeks prior to study entry.
5. Received within 24 hours prior to enrollment drugs that may cause QT interval
prolongation such as: terfenadine, astemizole, cisapride, pimozide, or quinidine.
6. Concomitant administration of systemic agents active against Aspergillus species.
7. Concomitantly receiving sirolimus, rifampin, rifabutin, carbamazepine, long-acting
barbiturates (eg, phenobarbital, mephobarbital), ritonavir (high dose), efavirenz, ergot alkaloids (eg, ergotamine, dihydroergotamine), or St. John’s Wort.
8. Concomitantly receiving drugs with clinically relevant interactions with voriconazole
unless closely monitored or dosage adjusted as clarified in Appendix 2.
9. Receipt of systemic antifungal treatment for the current episode of IA or rare molds such as Scedosporium or Fusarium for a duration greater than 96 hours Note: Subjects receiving prophylaxis mold-active antifungal drugs may be enrolled provided that they meet criteria for proven or probable IA at the time of enrollment.
10. Liver dysfunction (defined as total bilirubin >5x 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 (prior to first dose of study drug) exceed the above limits for exclusion, the medical monitor must be contacted without delay to discuss enrollment and initiation of study treatment.
11. Subjects with moderate or severe renal impairment (calculated creatinine clearance <50 mL/min), and creatinine clearance will be calculated using the Schwartz formula (Schwartz 1987): Creatinine Clearance (mL/min) = [k x height (cm)]/serum creatinine (mg/dL) Where k = 0.55 for either gender ≤12 years of age; k = 0.55 for females 13 to 21 years of age; and k = 0.7 for males 13 to 21 years of age.
12. Subjects on mechanical ventilation.
13. In the investigator’s judgment the subject should be excluded for safety, treatment response, or other considerations with proper documentation.
14. Participation in a study of an investigational drug or device (without any FDA and
EMEA approved indications) within four weeks of study entry. The investigational use
of licensed agents are permitted if the subject is on a stable regimen for four weeks prior to study start, and expected to remain on the stable regimen for the duration of the trial.
15. Previously enrolled in this trial.
16. Not expected to survive for at least 5 days.
17. Subjects with a high likelihood of death due to factors unrelated to Aspergillosis within 30 days following planned enrollment at the investigator's discretion (eg, due to relapsed malignancy, severe graft versus host disease, other underlying diseases, etc).
18. Any condition or finding 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.
Note: If cerebral aspergillosis is suspected; enrollment into the study must be closely
evaluated against the enrollment criteria above. This underlying condition is associated with the highest mortality of invasive aspergillosis syndromes. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is safety and tolerability throughout the study including the follow-up visit. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety and Tolerability throughout the study including follow-up visit |
|
| E.5.2 | Secondary end point(s) |
• Rate of global response at 6 weeks and EOT.
• All cause and attributable mortality at 6 weeks and EOT.
• Time to death. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Rate of global response at 6 weeks and EOT;
All cause and attributable mortality at 6 weeks and EOT; Time to death |
|
| 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 | 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA 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
|
| End of Trial in all participating countries is defined as Last Subject Last Visit (LSLV) for the entire study . |
|
| E.8.9 Initial estimate of the duration of the trial |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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