Ambisome and Management of Culture-negative Neutropenic Fever Unresponsive to Antibiotics

March 9, 2011 updated by: Gilead Sciences

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

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 Overview

Status

Terminated

Conditions

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Athens, Greece, 167 77
        • Gilead Sciences

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Subjects must meet all of the following inclusion criteria to be eligible for participation in this study. Adult patients with hematologic malignancy undergoing chemotherapy for leukemia or lymphoma will be recruited into this study from 2 centers provided the following inclusion criteria are fulfilled:

    • Male or female
    • Age ≥ 18 years
    • Neutropenia (< 0.5 x 109 cells/L)
    • Received empiric antibiotic treatment for 3 days for blood culture negative infection
    • Persistent fever of ≥ 38°C
    • No known IFI at baseline during this neutropenic episode. However, patients with "missed" evidence of IFI (features absent at randomization but evidence within 48 hours [eg, positive chest computerized tomography (CT)]) will complete the randomized treatment and kinetic measurements
    • No antifungal prophylaxis or treatment in this hospital admission or for the past 30 days
    • Baseline liver function tests ≤ 10 times the upper limit of normal and baseline creatinine ≤ 2 times the upper limit of normal
    • No known hypersensitivity to amphotericin B or LAMB or any of its constituents, in particular known history of anaphylactic reaction to amphotericin B or LAMB or any of its constituents
    • Females of childbearing potential (less than 2 years post menopausal) must be surgically incapable of pregnancy, or practicing an acceptable method of birth control with a negative pregnancy test (blood or urine) at baseline
    • Ability to comply with all study requirements
    • Written informed consent

Exclusion Criteria:

  • Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

    • Evidence of proven, probably or possible invasive fungal infection
    • Chronic invasive fungal infection, defined as signs/symptoms of invasive fungal infection present for >4 weeks preceding entry into study
    • Prior systemic therapy greater or equal to 4 days with any polyene anti-fungal agent within 30 days of study enrollment
    • Prior systemic therapy with non-polyenes (i.e., azole or echinochandin derivatives) for the current ARNF. (Prior systemic anti-fungal therapy with non-polyene derivatives for prophylaxis or as empiric therapy for febrile neutropenia is permissible.)
    • Use of another investigational, unlicensed drug within 30 days of screening or concurrent participation in another clinical trial using an investigational, unlicensed drug.
    • Serum creatinine > 2x upper limit of normal (ULN)
    • Serum ALT or AST > 5x ULN
    • History of allergy or serious adverse reaction to any polyene anti-fungal agent.
    • Patients who have a positive blood culture within 5 days before day 0 with a clinically significant organism isolated from the peripheral blood, who despite appropriate antibiotics have persistent positive cultures
    • Pregnant or lactating women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: 1
AmBisome® will be given on day 0 (10 mg/kg), day 2 (5 mg/kg), and day 5 (5 mg/kg)
Other Names:
  • 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
Other Names:
  • Ambisome

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
PK Profile of the dosing regimen under study (AUC, Cmax, Cmin, and etc.)
Time Frame: throughout
throughout

Secondary Outcome Measures

Outcome Measure
Time Frame
Proportion of patients with defervescence (temperature < 38°C for ≥ 48 hours) occurring during neutropenia
Time Frame: throughout
throughout
Time to defervescence from start of study entry and from time fever first recorded
Time Frame: throughout
throughout
Proportion of patients with emergence of an IFI during AmBisome® treatment
Time Frame: throughout
throughout
Survival during hospital admission
Time Frame: throughout
throughout
Survival at 14 days after study initiation
Time Frame: Day 14
Day 14
Proportion of patients with treatment-emergent adverse events
Time Frame: throughout
throughout
Proportion of patients with treatment-emergent adverse events related to study drug
Time Frame: throughout
throughout
Proportion of patients with post-baseline toxicity grading changes in each laboratory test (those graded according to the protocol).
Time Frame: throughout
throughout

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Director: Lazaros Poughias, MD, Gilead Sciences

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2007

Primary Completion (ACTUAL)

April 1, 2008

Study Completion (ACTUAL)

May 1, 2008

Study Registration Dates

First Submitted

January 8, 2007

First Submitted That Met QC Criteria

January 10, 2007

First Posted (ESTIMATE)

January 11, 2007

Study Record Updates

Last Update Posted (ESTIMATE)

March 11, 2011

Last Update Submitted That Met QC Criteria

March 9, 2011

Last Verified

April 1, 2008

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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