E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Invasive fungal infections (IFI) in subjects with Acute Lymphoblastic Leukemia (ALL) undergoing remission induction chemotherapy |
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E.1.1.1 | Medical condition in easily understood language |
Serious infections caused by fungi in patients receiving early, high dose chemotherapy for the treatment of acute lymphoblastic leukaemia.
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
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 | 10017533 |
E.1.2 | Term | Fungal infection |
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 determine the prophylactic efficacy of AmBisome compared to placebo in preventing IFIs in subjects with ALL undergoing remission induction chemotherapy. |
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E.2.2 | Secondary objectives of the trial |
• To determine the safety and tolerability of prophylactic AmBisome in subjects with ALL undergoing remission induction chemotherapy.
• To determine the impact of IFI prevention on the efficacy of remission induction chemotherapy in subjects with ALL.
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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 |
Randomized subjects from a subset of sites will be given the option to consent to a 40 subject PK sub-study to determine the minimum levels of AmBisome during the twice weekly dosing. The PK monitoring will consist of drawing an additional blood sample to assess AmBisome levels just prior to each infusion of study drug for four weeks (8 study drug infusions), starting just prior to the second infusion. With the 2:1 randomization schedule this is expected to provide minimum concentration levels of AmBisome obtained with twice weekly dosing, for approximately 26 subjects. |
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E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
• Newly diagnosed ALL receiving an ALL chemotherapy regimen that typically induces at least 10 days of neutropenia, defined as an absolute neutrophil count (ANC) 500 cells/mm3 or 0,5x109 cells/L
Note: Subjects with lymphoblastic lymphoma or any malignancy other than ALL are NOT eligible for this study.
• Age ≥ 18 years
• Able to have all screening tests performed quickly to ensure results can be obtained and evaluated before randomization so that the first dose of randomized study drug for IFI prophylaxis can be administered no later than 5 days after the start of remission-induction chemotherapy
Note: With respect to this timing, pre-remission induction treatment (i.e. pre-phase) with a minimally or non-myelosuppressive regimen for up to one week is not considered to constitute the biginning of remission induction chemotherapy.
• Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures.
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
• Known hypersensitivity to amphotericin B or AmBisome, the metabolites or formulation excipients, in particular known history of anaphylactic reaction to amphotericin B or AmBisome or any of its metabolites or formulation excipients.
• Known hypersensitivity to the excipients of the placebo formulation
• Current fever (≥38°C) unless fungal causes have clearly been excluded, e.g. negative lung and sinus imaging, documented drug-fever, or response to anti-bacterial antibiotic treatment.
• Subjects with proven, probable or possible IFI (according to EORTC/MSG criteria) at screening or in subject history
• Pulmonary infiltrates
• Concomitant or previous treatment with an antifungal drug within the previous 30 days unless the plasma level is below the limit of detection or at least 5 half-lives of the antifungal has elapsed since the treatment was given.
• Serum creatinine > 2 x the upper limit of the normal range (ULN)
• Grade 3 Liver function test results (prior to starting remission induction chemotherapy): alanine aminotransferase or aspartate aminotransferase > 5 x ULN; total bilirubin > 2.5 x ULN
• Any severe co morbidity other than underlying hematological disease (ALL), which in the investigator’s judgment may interfere with study evaluations or affect the subject’s safety.
• Subjects who have taken any investigational drug in the last 30 days prior to screening, with the exception of ALL chemotherapy investigational products being used as part of the subject’s current ALL treatment protocol.
• Pregnant or nursing females
• Subjects with a prior history of a malignancy that was treated with a myeloablative chemotherapy regimen are NOT eligible for this study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this study is to assess antifungal prophylaxis efficacy of AmBisome 5 mg/kg compared to placebo.
The primary efficacy endpoint in support of this objective is the proportion of subjects with proven or probable IFIs during remission induction chemotherapy for ALL. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis for efficacy when 50% of subjects have completed the study.
Final analysis when all subjects have completed the protocol defined last patient last visit. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints to be assessed during remission induction chemotherapy for ALL are as follows:
• The proportion of subjects with pulmonary infiltrates
• The proportion of subjects diagnosed with proven or probable IFIs according to the EORTC/MSG criteria, as assessed by the investigator.
• Time to diagnosis of proven or probable IFIs according to the EORTC/MSG criteria, as assessed by the IDRB
• The proportion of subjects diagnosed with proven invasive fungal infections, according to the EORTC/MSG criteria as assessed by the IDRB.
• The proportion of subjects diagnosed with probable invasive fungal infections, according to the EORTC/MSG criteria as assessed by the IDRB.
• The proportion of subjects requiring antifungal treatment according to the protocol guidelines prior to starting consolidation chemotherapy.
• The proportion of subjects who die due to fungal infection; causality as assessed by the IDRB.
• The proportion of subjects who die due to fungal infection; causality as assessed by the investigator.
Secondary endpoints to evaluate the potential impact of IFI prevention on the efficacy of remission induction chemotherapy for ALL are as follows:
• The median duration of remission induction chemotherapy (i.e., the time from beginning of remission induction chemotherapy until the beginning of consolidation therapy)
• The proportion of subjects with complete remission at the end of remission induction
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final analysis when all subjects have completed the protocol defined last patient last visit. |
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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 | Yes |
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 | 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 | 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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 63 |
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 |
Austria |
Belgium |
Brazil |
France |
Germany |
Greece |
Israel |
Italy |
Portugal |
Spain |
Switzerland |
Turkey |
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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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Last patient, last visit. |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |