E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
INVASIVE CANDIDIASIS, INCLUDING CANDIDEMIA |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064954 |
E.1.2 | Term | Invasive candidiasis |
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 |
• To assess the safety and tolerability of anidulafungin when used to treat children with invasive candidiasis, including candidemia. |
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E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of anidulafungin, as measured by global response, at the following time points: EOIVT, end of treatment (EOT), 2-week follow-up (FU) visit and 6-week FU visit;
• To explore pharmacokinetic parameters of anidulafungin in children aged 1 month to <2 years following IV infusion of anidulafungin (AUC24 and Cmax);
• To explore the exposure-response (safety and efficacy endpoints) relationship of anidulafungin using a nonlinear mixed effects approach as appropriate, including exploring the association between PK-PD index (eg, AUC/MIC) and efficacy endpoints;
• To assess rates of relapse at the Week 2 and Week 6 FU visits;
• To assess rates of new infection at the Week 2 and Week 6 FU visits;
• To assess all-cause mortality during study therapy and Follow-Up visits. |
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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 |
A sub-study to explore the pharmacokinetic parameters in children aged 1 month to <2 years will be performed on a limited number of subjects prior to complete enrollment of this age group in this study.First 6 subjects enrolled in this age category will have PK-PD samples drawn. Samples will be analyzed in real time and results reviewed prior to enrolling additional subjects in this age cohort. This is all part of the A8851008 study. |
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E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriate qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Definitive diagnosis of invasive candidiasis/candidemia (ICC) is based on the growth of Candida sp. from a blood and/or tissue culture obtained from a normally sterile site.
For the purpose of study entry, a subject must have at least one microbiologic AND at least one clinical criteria listed below.
Microbiologic Criteria:
Subject must have at least one of the criteria listed below either at the time of study entry or within 96 hours prior to study entry.
Candidemia: At least one blood culture positive for Candida sp. (in the absence of other demonstrated foci of infection) or;
Other forms of invasive candidiasis:
Positive culture for Candida sp. from a specimen from a normally sterile site (other than blood), with or without a positive blood culture;
Positive culture for Candida sp. from a percutaneous drain (eg, chest tube, intra-abdominal) placed <24 hours in a normally sterile site;
Positive blood culture for Candida sp. plus ophthalmic examination consistent with Candida endophthalmitis;
Candida endocarditis: At least one positive blood culture for Candida sp. and evidence of endocarditis on echocardiogram;
Candida osteomyelitis: At least one positive culture for Candida sp. from a bone biopsy or aspirate and evidence of osteomyelitis on a magnetic resonance imaging (MRI) study;
Clinical Criteria:
Subject must have at least one of the criteria listed below either at the time of study entry or within 96 hours prior to study entry.
Fever, defined as an oral/tympanic temperature ≥100.4°F (38.0oC), rectal temperature ≥101.4oF (38.6oC) or an axillary temperature ≥99.4oF (37.4oC);
Hypothermia, defined as a temperature less than 96.8°F (36.0oC);
Hypotension, defined as a systolic blood pressure of less than 100% for age and gender norms (per National High Blood Pressure Education Program (NHBPEP) Working Group on Children and Adolescents guidelines);7
Other signs or symptoms of candidemia/invasive candidiasis, which may include the following: feeding intolerance, bloody stools, abdominal distension, thrombocytopenia, lethargy, color change, hyperglycemia, glycosuria, unexplained metabolic acidosis.
** Important Notes **
Subjects may be enrolled in the study on the basis of mycologic evidence highly suggestive of Candida sp. (eg, the growth of yeast in culture and/or the direct microscopic visualization of yeast, hyphae, or pseudohyphae) from a sample obtained from a normally sterile site (eg, blood and/or tissue). However, in these subjects, culture confirmation of Candida sp. must be obtained within 96 hours post treatment
initiation. If culture confirmation is not obtained within this time period, subjects will be discontinued from study treatment but will remain in the study for continued safety monitoring. These subject will be required to return for the 2-week and 6-week follow-up visits.
Positive cultures for Candida sp. from urine (in the absence of clinical signs and symptoms of pyelonephritis), sputum, bronchoalveolar lavage (BAL), endotracheal aspiration, gastric drainage or gastric aspiration do not qualify as a positive culture for study entry.
2. Male or female between the ages of 1 month and <18 years. Females of childbearing potential must have adequate contraception as determined by the Investigator for the duration of the trial.
3. For each subject, parent or legal guardian must be willing and able to provide signed and dated written informed consent documentation. Assent from the child or adolescent will be obtained as appropriate. This is to be obtained prior to enrollment.
4. Will be available for the duration of the study and be able to abide by the study restrictions. |
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E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Premature neonates born at gestation of less than 36 weeks (unless the sum of gestational age plus chronological age is at least 44 weeks).
Note: Rounding to the closest week is round up one week if birth occurred on days 4 to 6 of the week and round down one week if birth occurred on Days 1 to 3 of the week.
2. Known history of intolerance, allergy, hypersensitivity or serious reaction to anidulafungin or any of its excipients (including fructose), or to other echinocandin antifungals.
3. Female subjects who are pregnant or lactating, or planning a pregnancy during the course of the study.
4. Subjects who have received more than 48 hours of systemic antifungal therapy for the Candida infection for which their enrollment is being considered.
** Important Note ** Prior antifungal prophylaxis (ie, the use of an antifungal agent for the prevention of fungal infection) is allowed.
5. Subjects who have failed antifungal therapy with any systemic antifungal for this episode of candidiasis/candidemia. Recurrence within 2 weeks is considered failure of previous therapy.
6. Subjects with any of the following abnormal laboratory values: Total bilirubin, AST or ALT >5 times the upper limit of normal (ULN).
7. Subjects who require continued treatment with another systemic antifungal agent [oral nonabsorbable azoles (eg, clotrimazole troches) will be permitted]. Exception: the first 6 subjects enrolled who are between 1 month to <2 years of age may receive a second systemic antifungal agent at the investigator’s discretion.
8. Subjects with poor venous access that would preclude IV drug delivery or multiple blood draws.
9. Subjects who have participated 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.
10. Life expectancy <72 hours.
11. Subjects with suspected Candida meningitis.
12. Subjects with a prosthetic device and/or vascular catheter (including central venous catheter or an implantable port) at a suspected site of infection are to be excluded, unless the device is removed at study entry or soon after randomization (within 24 – 48 hours).
** Important Note ** If it is anticipated that a prosthetic device or vascular catheter cannot be removed within this time frame, the medical monitor should be contacted to discuss enrolment.
13. Subjects with a vascular graft suspected to be the site of the Candida infection and positive blood cultures.
14. Subjects with prosthetic or native valve Candida endocarditis who have not and/or cannot undergo valvular replacement surgery prior to or soon after study entry.
15. Subjects with Candida osteomyelitis associated with a prosthetic device in whom the prosthetic device has not been and/or cannot be removed surgically prior to or soon after study entry.
16. Other severe acute or chronic medical or psychiatric condition, electrocardiogram (ECG) abnormalities, or laboratory abnormality 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,
would make the subject inappropriate for entry into this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• The primary endpoint will be an assessment of the safety and tolerability of anidulafungin. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of Intravenous Therapy. |
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E.5.2 | Secondary end point(s) |
Global response (based on the clinical and microbiological responses) at the EOIVT
and subsequent time points;
Pharmacokinetic parameters of anidulafungin in children aged 1 month to <2 years
following IV infusion of anidulafungin: AUC24 and Cmax;
Exposure-response (efficacy and safety endpoints) relationships of anidulafungin
using a nonlinear mixed effects approach as appropriate;
Rates of relapse (recurrence) at the Week 2 and Week 6 FU visits;
Rates of new infection at the Week 2 and Week 6 FU visits;
All-cause mortality during study therapy and Follow-Up visits. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of Therapy if switch to oral treatment. |
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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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | 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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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
| Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
Brazil |
France |
Germany |
Greece |
Italy |
Korea, Republic of |
Portugal |
Russian Federation |
Spain |
Taiwan |
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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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |