| 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 |
| Invasive Fungal Infection |
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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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064954 |
| E.1.2 | Term | Invasive candidiasis |
| E.1.2 | System Organ Class | 100000004862 |
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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 |
Objective: To compare caspofungin to amphotericin B deoxycholate with respect to the efficacy endpoint of fungal-free survival at the 2-week post-therapy follow-up visit (i.e., the proportion of patients who survived through the 2-week post-therapy follow-up period and had documented microbiological eradication of Candida sp. from follow-up cultures collected after the initiation of study therapy).
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| E.2.2 | Secondary objectives of the trial |
Efficacy:
To assess in neonates and infants who are treated with caspofungin or amphotericin B deoxycholate for documented invasive candidiasis, fungal-free survival at the end of study therapy (i.e., the proportion of patients who survived through the end of study therapy visit period and had documented microbiological eradication of Candida sp. from follow-up cultures collected after the initiation of study therapy).
Safety:
To assess the safety in neonates and infants who are treated with caspofungin or amphotericin B deoxycholate for documented invasive candidiasis.
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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 (buccal swab) 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. Patient is <3 months (90 days) of age on day of informed consent.
2. Patient (either symptomatic or at-risk) has a documented (culture-confirmed), invasive Candida infection, as defined by the presence of (a) a positive culture for Candida spp. collected from a normally sterile body fluid within 96 hours of study entry or (b) a positive culture for Candida spp. collected within 96 hours of study entry from a newly-placed drain inserted into a normally sterile body site. "At-risk" is defined by the presence of one or more of the risk factors included in the protocol.
3. Parent (or guardian) understands the study procedures, alternative treatments available, and risks involved with the study and voluntarily agree to the patient’s participation by giving written informed consent.
4. Parent (or guardian) provides written informed consent for the trial. The parent (or guardian) may also provide consent for Future Biomedical Research. However, the patient may participate in the main trial without participating in Future Biomedical Research.
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| E.4 | Principal exclusion criteria |
1. Patient is ≥3 months (≥90 days) of age at the time of informed consent.
2. Patient has Candida disease limited to the oropharynx, esophagus, or other mucosal or superficial skin surfaces (e.g., vagina or other genitalia, colonic tract, skin folds, nail beds, etc.).
3. Patient has evidence of infection limited to a positive culture for Candida spp. From the sputum, broncho-alveolar lavage (BAL), catheter tip, or previously placed indwelling non-vascular catheters/drains.
4. Patient has a prosthetic device (e.g., prosthetic heart valve) at a suspected site of Candida infection.
5. Patient is actively co-infected with a non-Candida fungal organism.
6. Patient has received more than 48 hours of systemic (IV or oral) antifungal treatment since the time the positive Candida index culture was collected as therapy for this episode of invasive candidiasis.
7. Patient has failed prior systemic (IV or oral) antifungal therapy for this episode of invasive candidiasis.
8. Patient has exclusionary laboratory values (obtained within 48 hours of study therapy initiation) as listed below:
•ď€ Aspartate aminotransferase (AST, also referred to as SGOT) >3 times the upper limit of normal, for age.
•ď€ Alanine aminotransferase (ALT, also referred to as SGPT) >3 times the upper limit of normal, for age.
9. Patient is not expected to survive at least 5 days.
10. Patient has a diagnosis of acute hepatitis or cirrhosis due to any cause.
11. Patient is currently participating or has participated in a study with an investigational compound or device.
12. Patient has previously participated in this study.
13. Patient is scheduled or anticipated to receive rifampin or other systemic (IV or oral) antifungal therapy (i.e., an intravenous or oral formulation of the member of the polyene, triazole, or echinocandin class) while on study therapy.
14. Patient has known renal insufficiency, which, in the investigator's assessment, has the potential to worsen as a result of subsequent study therapy with amphotericin B deoxycholate.
15. Patient or the patient’s mother has a history of allergy, hypersensitivity, or any serious reaction to caspofungin or another member of the echinocandin class (e.g., micafungin, anidulafungin, or aminocandin).
16. Patient or the patient’s mother has a history of allergy, hypersensitivity, or any serious reaction to amphotericin B deoxycholate or other members of the polyene class (e.g., amphotericin B lipid complex, liposomal amphotericin B, or amphotericin B colloidal dispersion).
17. Patient has a severe congenital disorder known to lower immune response.
18. Patient has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might confound the results of the study, or interfere with the patient’s participation for the full duration of the study, such that it is not in the best interest of the patient to participate.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic (PK) profile (Cmax [peak], C24 hr [trough]) of the administered dose of caspofungin will be determined for neonates and infants less than three months of age on or around Days 4 and 7 of study therapy. Pharmacokinetic profiling will be the responsibility of the Drug Metabolism department of the SPONSOR (or its designee).
The primary efficacy endpoint of interest will be fungal-free survival at two weeks posttherapy. Fungal-free survival is defined as those patients who survived at the time point of interest and had documented microbiological eradication of Candida sp. from follow-up cultures collected after the initiation of study therapy. Microbiological eradication denotes negative follow-up cultures for Candida sp. from the site of infection at the time of evaluation. If a culture is not obtained on the day of assessment, the last culture after study entry may be used to assist in the assessment of microbiological eradication. If the last culture is negative for Candida sp., then microbiological eradication would be considered achieved. Fungal-free survival also assumes no additional antifungal therapy is required for the treatment of the underlying Candida infection once study therapy has ended; however, once study therapy has ended, prophylaxis with an antifungal agent (e.g., fluconazole) may be administered, if this is deemed appropriate by the investigator.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 2 weeks following the completion of study therapy |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint will be fungal-free survival at the end of study therapy. In addition, there will be two exploratory efficacy endpoints:
•Fungal-free survival at 2 weeks posttherapy in the subset of patients with Candida meningoencephalitis at study entry
•Development of complicated candidiasis while on study therapy or during the 8-week posttherapy follow-up period. Complicated candidiasis is defined as the development of any one of the following on or after Day 5 of study therapy: (a) valvular vegetation or mural thrombus on echocardiogram, (b) meningitis documented by the presence of Candida in CSF culture or a CSF WBC count >25 cells/mm3 with no other organism identified, (c) evidence of abdominal abscess, or (d) documented endophthalmitis.
Safety: To address the secondary safety objective, the following safety endpoints will be evaluated: (1) the development of adverse experience(s) during the study therapy period or during the 2-week posttherapy follow-up period; (2) the development of drug-related adverse experience(s) during the study therapy period or during the 2-week posttherapy follow-up period; (3) the development of serious adverse experience(s) during study therapy period or during the 2-week posttherapy follow-up period; (4) the development of drug-related, serious adverse experience(s) during study therapy period or during the 2 week posttherapy follow-up period; (5) the development of adverse experiences that necessitate discontinuation of study therapy; and (6) the development of drug-related adverse experiences that necessitate discontinuation of study therapy.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| amphotericin B deoxycholate |
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| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Bulgaria |
| Colombia |
| Mexico |
| Romania |
| South Africa |
| Turkey |
| Ukraine |
| 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 | 2 |
| 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 | 5 |
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