| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Invasive candidiasis, including candidemia (ICC), and esophageal candidiasis (EC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| invasive candidiasis, candidemia, esophagial candidemia which are types of fungal infections caused by a fungus called Candida |
|
| 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 | LLT |
| E.1.2 | Classification code | 10060573 |
| E.1.2 | Term | Candidemia |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064954 |
| E.1.2 | Term | Invasive candidiasis |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007161 |
| E.1.2 | Term | Candidiasis of the esophagus |
| 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 |
| To assess the safety and tolerability of voriconazole for the treatment of invasive candidiasis, including candidemia, and esophageal candidiasis in pediatric subjects 2 to <18 years of age. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of voriconazole for the treatment of invasive candidiasis, including candidemia, and esophageal candidiasis in pediatric subjects 2 to <18 years of age.
• To assess time to death and all-cause mortality during study therapy, at Day 28, and at the one month follow-up visit. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Male or female 2 to<18 yrs of age;
•A personally signed and dated informed consent document indicating that a legally authorized representative has been informed of all pertinent aspects of the study. Assent will be required for children per local regulations or/and for those who are able to comprehend;
•Willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures;
•A diagnosis of invasive candidiasis/candidemia (ICC) or esophageal candidiasis(EC);
•Therapy with voriconazole must be considered an appropriate treatment option by the investigator.
Primary ICC: the following two criteria must be met:
1. Must have at least one of the following:
•At least one positive blood culture or culture from a normally sterile site for yeast (later confirmed as Candida sp.) or for Candida sp. within the previous 7 days prior to the first dose of study medication; or
•Histopathologic/direct microscopic evidence suggestive of Candida sp. (later confirmed as Candida sp.) from at least one specimen obtained from a normally sterile site within the previous 7 days prior to the first dose of study medication; or
•At least one positive culture for yeast (later confirmed as Candida sp.) or Candida sp. from a drain placed <24 hours within the previous 7 days prior to the first dose of study medication; or
•New radiologic findings consistent with disseminated disease after a positive culture for Candida sp. within the previous 14 days prior to enrollment.
2. Must have at least one of the following:
•Fever (oral or tympanic or axillary) temperature ≥38.0°C (100.4°F)); or
•Hypothermia (temperature <36.0°C (96.8°F)); or
•SBP less than 100 mmHg,or a decrease in SBP of at least 30 mmHg from baseline; or
•Site specific signs and symptoms of Candida infection; or
•Radiologic findings consistent with Candida infection.
Salvage ICC: the following two criteria are met:
1. Must have at least one of the following:
•At least one positive blood culture or culture from a normally sterile site for yeast (later confirmed as Candida sp.) or for Candida sp. within the previous 14 days prior to the first dose of study medication; or
•Histopathologic/direct microscopic evidence suggestive of Candida sp. (later confirmed as Candida sp.) from at least one specimen obtained from a normally sterile site within the previous 14 days prior to prior to the first dose of study medication; or
•At least one positive culture for yeast (later confirmed as Candida sp.) or for Candida sp. from a drain placed <24 hours, within the previous 14 days prior to the first dose of study medication; or
•New radiologic findings consistent with disseminated disease after a positive culture for Candida sp. within the previous 14 days prior to enrollment.
2. Must have had a clinical and/or microbiologic response deemed as unsatisfactory to at least one other antifungal after at least 7 days of therapy at clinically recognized effective doses.
Primary EC: all of the following three criteria must be met:
•Must have clinical symptoms consistent with esophageal candidiasis, such as dysphagia, odynophagia and retrosternal pain, with or without concomitant oropharyngeal candidiasis withing the previous 7 days prior to enrollment.
•Must have lesions characteristic of esophageal candidiasis visualized by esophagoscopy within the previous 7 days prior to enrollment.
•Must have positive microscopy and/or mycological culture for yeast (later confirmed as Candida sp.) or Candida sp. from a brush biopsy or tissue biopsy of esophageal lesions within the previous 7 days prior to enrollment. (In subjects with neutropenia, thrombocytopenia or advanced HIV/AIDS, esophagoscopy and/or culture confirmation is not required if the risks associated with performing an esophagoscopy or obtaining a tissue specimen for culture outweigh the benefits.)
Salvage EC: all of the following two criteria are met:
•Must have clinical symptoms consistent with esophageal candidiasis, such as dysphagia, odynophagia and retrosternal pain, with or without concomitant oropharyngeal candidiasis withing the previous 14 days prior to enrollment.
•Must have lesions characteristic of esophageal candidiasis visualized by esophagoscopy within the previous 14 days prior to enrollment.
•Must have positive microscopy and/or mycological culture for yeast (later confirmed as Candida sp.) or Candida sp. from a brush biopsy or tissue biopsy of esophageal lesions within the previous 14 days prior to enrollment. (In subjects with neutropenia, thrombocytopenia or advanced HIV/AIDS, esophagoscopy and/or culture confirmation is not required if the risks associated with performing an esophagoscopy or obtaining a tissue specimen for culture outweigh the benefits.)
Must have had a clinical and/or microbiologic response deemed as unsatisfactory to at least one other antifungal after at least 7 days of therapy at clinically recognized effective doses.
|
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following exclusions will not be included in the study:
1. Known allergy, serious reaction, or hypersensitivity to voriconazole or its excipients, or any azole antifungal agent.
2. Females who are pregnant, lactating (breast feeding) or planning a pregnancy during the course of the study, or who are of childbearing potential and not using highly effective method of birth control (eg, surgically sterile, intrauterine device, oral contraceptive plus barrier contraceptive, hormone delivery system plus barrier contraceptive, or condom in combination with contraceptive cream, jelly, or foam).
Subjects are to continue contraceptive methods during the study and for at least 30 days after receiving their last treatment.
3. Subjects receiving, or are likely to receive, any Phase I investigational drug. (Note: Subjects receiving Phase II or III investigational drugs may be enrolled only with the prior approval of the Sponsor's medical monitor. Subjects receiving investigational drugs that are currently licensed for other indications may be enrolled).
4. Subjects who have received drugs that may cause QT interval prolongation within 24 hours prior to enrollment. Including, but not limited to, the following: terfenadine, astemizole, cisapride, pimozide, or quinidine.
5. Requiring continued treatment with another systemic antifungal agent.
6. Concomitantly receiving one of the following drugs: sirolimus, rifampin, rifabutin, carbamazepine, long-acting barbiturates (eg, phenobarbital, mephobarbital), ritonavir, efavirenz, or ergot alkaloids (eg, ergotamine, dihydroergotamine).
7. Concomitantly receiving drugs with clinically relevant drug interactions with voriconazole, unless closely monitored or dosage adjusted as clarified in Appendix 1.
8. Poor venous access or other considerations that would preclude intravenous drug delivery or blood sampling.
9. For Primary Therapy: Subjects who have received more than 48 hours antifungal
therapy (prior to the first dose of study drug) for the treatment of an active fungal infection. ** Please note ** Subjects receiving antifungal agents for prophylaxis (eg, for the prevention of fungal infection) prior to and up to the time of enrollment are eligible to participate in the study.
10. Liver dysfunction, at baseline, defined as total bilirubin, AST, ALT, or alkaline phosphatase >5 times the upper limit of normal. Note: If laboratory values drawn at the screening visit (prior to the first dose of study medication) exceeds the above limits for exclusion, the Sponsor's medical monitor must be contacted without delay to discuss enrollment and initiation of study treatment.
11. Subjects with moderate or severe renal impairment (creatinine clearance <50 mL/min),
•Creatinine Clearance will be calculated using the Schwartz formula.
•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. Note: Other methods of calculation creatinine clearance (eg, 24-hr urine creatinine collection) are permissible.
12. Subjects with prosthetic devices and/or vascular catheters (eg, central venous catheter, implanted port) at a suspected site of infection are to be excluded, unless the device/catheter is removed at study entry or soon after randomization (within 24 – 48 hrs). Note: In the event prosthetic devices or vascular catheters cannot be removed within this time frame, the Sponsor's medical monitor must be contacted to discuss enrollment and initiation of study treatment.
13. Subjects with a prosthetic heart valve or vascular graft suspected to be the site of the Candida infection and positive blood cultures.
14. At the discretion of the investigator, any condition including 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 the study results and would make the subject inappropriate for entry into this study. Examples include sever liver dysfunction, severe renal impairment, or known ECG abnormalities or arrhythmias.
15. Subjects with a high likelihood of death within 72 hours of enrollment due to factors unrelated to the current episode of Candida infection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability of voriconazole, as determined by the rate of adverse events (serious and non-serious), including visual-, cardiac-, and liver-related adverse effects, and treatment discontinuation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Efficacy, as determined by global response at the End of Treatment (EOT).
- Time to death and all-cause mortality during study therapy, at Day 28, and at the one
month follow-up visit.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Brazil |
| Bulgaria |
| China |
| Croatia |
| Czech Republic |
| Germany |
| Hong Kong |
| Hungary |
| Malaysia |
| Mexico |
| Philippines |
| Poland |
| Romania |
| Singapore |
| Slovakia |
| Thailand |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
