Ambisome and Management of Culture-negative Neutropenic Fever Unresponsive to Antibiotics
Administration of a single high dose (10 mg/kg) of AmBisome® no later than 72 hours after ARNF onset followed by two 5 mg/kg doses on days 2 and 5 may provide sustained tissue levels of amphotericin B that are as mycologically effective as those provided after administering the standard daily dose of 3 mg/kg/day. The new dosing regimen is anticipated to be equally clinically effective compared with the standard AmBisome® regimen when given for the duration of neutropenic fever in patients with ARNF. In addition, the degree and incidence of nephrotoxicity are predicted to be lower with the 3 sequential dose regimen compared to daily dosing with 3 mg/kg because of the lower cumulative dosage (20 mg/kg versus 42 mg/kg, respectively), which is 1 contributing factor for the development of acute renal failure. Furthermore, the lower cumulative dose may be a cost-effective strategy for the treatment of patients with ARNF.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase III Study of 3 Sequential Doses (10 mg/kg, 5 mg/kg, and 5 mg/kg) vs 3 mg/kg/Day of AmBisome® in the Management of Culture-negative Neutropenic Fever Unresponsive to Antibiotics|
- PK Profile of the dosing regimen under study (AUC, Cmax, Cmin, and etc.) [ Time Frame: throughout ] [ Designated as safety issue: No ]
- Proportion of patients with defervescence (temperature < 38°C for ≥ 48 hours) occurring during neutropenia [ Time Frame: throughout ] [ Designated as safety issue: No ]
- Time to defervescence from start of study entry and from time fever first recorded [ Time Frame: throughout ] [ Designated as safety issue: No ]
- Proportion of patients with emergence of an IFI during AmBisome® treatment [ Time Frame: throughout ] [ Designated as safety issue: No ]
- Survival during hospital admission [ Time Frame: throughout ] [ Designated as safety issue: No ]
- Survival at 14 days after study initiation [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
- Proportion of patients with treatment-emergent adverse events [ Time Frame: throughout ] [ Designated as safety issue: No ]
- Proportion of patients with treatment-emergent adverse events related to study drug [ Time Frame: throughout ] [ Designated as safety issue: No ]
- Proportion of patients with post-baseline toxicity grading changes in each laboratory test (those graded according to the protocol). [ Time Frame: throughout ] [ Designated as safety issue: No ]
|Study Start Date:||March 2007|
|Study Completion Date:||May 2008|
|Primary Completion Date:||April 2008 (Final data collection date for primary outcome measure)|
AmBisome® will be given on day 0 (10 mg/kg), day 2 (5 mg/kg), and day 5 (5 mg/kg)
|Drug: Liposomal amphotericin B (AmBisome®)|
Active Comparator: 2
AmBisome as a constant daily dose of 3 mg/kg for a maximum of 14 days or until the resolution of fever and neutropenia
Drug: Liposomal amphotericin B (AmBisome®)
Other Name: Ambisome
This is a phase III, multicenter, randomized, open-label study. One center in the United Arab Emirates and 1 center in Turkey will participate in this trial and approximately 50 patients will be recruited.
Patients will be adults with hematological malignancies undergoing chemotherapy for leukemia or lymphoma. These patients will be treated with AmBisome® until resolution of fever and neutropenia or for a maximum of 14 days.
Patients will be randomized to receive AmBisome 10 mg/kg on treatment day 0 followed by 5 mg/kg on days 2 and 5 or AmBisome 3 mg/kg/day for 14 days. Study medication will be administered during the period of ARNF until resolution of fever and neutropenia and/or a minimum of 14 days. At the end of the 14-day trial period, each patient will be classified as having responded or not responded to the treatment according to the criteria for response given below.
Patients will be examined daily for evidence of drug toxicity or intolerance and for the development of an IFI. Vital signs will be recorded every 6 hours if the patient is stable or more frequently if there is evidence of clinical deterioration. In the event of a clinical IFI (i.e., development of a halo sign or positive fungal blood cultures), the patient will be withdrawn from the study, classified as treatment failure, and receive antifungal treatment with either caspofungin or voriconazole. Daily clinical observations will ensure rapid detection of such an event in accordance with standard IDSA guidelines4. Patients who show clinical deterioration (i.e., increasing dyspnea, hypotension) but exhibit no definite evidence of an IFI may also be classified as treatment failures. Patients with evidence of biochemical and/or clinical drug toxicity will be withdrawn from the study and appropriate management will be given.
For patients who remain febrile after 14 days but who are otherwise stable and have no discernable cause for the fever, continuation of treatment with AmBisome 3 mg/kg/day or treatment with another antifungal drug treatment, antibiotic, or discontinuation of antimicrobial therapy will be undertaken at the discretion of the investigator. Patients who meet these criteria will have a thorough diagnostic evaluation to investigate the cause of their fever.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00421187
|Athens, Greece, 167 77|
|Study Director:||Lazaros Poughias, MD||Gilead Sciences|