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| Name | Class |
|---|---|
| Astellas Pharma US, Inc. | INDUSTRY |
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Invasive fungal infections are an important cause of morbidity and mortality in patients with neutropenia who are receiving chemotherapy for cancer. Early diagnosis of these infections is difficult and fever may be the only sign. A delay in treatment while a diagnosis is pursued may lead to increased morbidity and mortality. There are now several echinocandins available with similar in vitro spectrum of activity. Caspofungin is the only echinocandin Food and Drug Administration (FDA) approved for empiric antifungal therapy in febrile neutropenia. Although all echinocandin antifungal agents have similar spectrum of activity, there are limited data on the use of micafungin in patients with persistent fever and neutropenia (FN). In November 2006 the Pharmacy and Therapeutics Committee at Brigham & Women's Hospital / Dana Farber Cancer Institute (BWH/DFCI) switched from caspofungin to micafungin as our formulary echinocandin. Given the limited clinical data on the use of micafungin as empiric antifungal therapy in patients with FN, we sought to evaluate the safety and effectiveness of micafungin, compared with caspofungin, for this indication using a sequential cohort analysis of patients treated before and after the formulary change at Brigham and Women's Hospital.
Objectives
This retrospective cohort analysis of converting from caspofungin to micafungin as empiric antifungal therapy for cancer patients who are persistently febrile and neutropenic after receiving broad spectrum antibiotics at Brigham & Women's Hospital / Dana Farber Cancer Institute (BWH/DFCI) is designed to evaluate the following objectives:
Study Design
Retrospective cohort analysis - limited to medical records
Data to be collected include the following:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Caspofungin arm | All patients admitted to BWH/DFCI who received at least 2 doses of caspofungin with an Absolute Neutrophil Count (ANC) < 500, for persistent febrile neutropenia from 11/1/2005 - 10/31/2006, as there first antifungal agent. | ||
| Micafungin arm | All patients admitted to BWH/DFCI who received at least 2 doses of micafungin with an Absolute Neutrophil Count (ANC) < 500 for persistent febrile neutropenia from 11/1/2006 - 10/31/2007 as there first antifungal agent |
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| Measure | Description | Time Frame |
|---|---|---|
| Composite Primary Endpoint: Number of Participants With an Overall Favorable Response to Echinocandin Therapy for Empiric Antifungal Therapy for Persistent Febrile Neutropenia (FN) | Overall favorable response was defined as achievement of successful treatment of baseline fungal infections, survival to hospital discharge, absence of breakthrough Ivasive fungal disese (IFD), and lack of advserse events (AE) attributable to treatment that led to discontinuation of echinocandin therapy. | 11/1/2005 - 10/31/2007 |
| Successful Treatment of Any Baseline Invasive Fungal Disease (IFD) | Possible or proven baseline invasive fungal disease were defined as were diagnosed within the 2 days of initiating echinocandin therapy for persistent febrile neutropenia | 11/1/2005 - 10/31/2007 |
| Mortality at Hospital Discharge | We assessed all patients in the study cohort who dischaged from the hospital alive | 11/1/2005 - 10/31/2007 |
| Absence of Any Breakthrough Invasive Fungal Disease (IFD) | a breakthrough invasive fungal disesase was defined as any fungal infection that was diagnosed > 3 days on or during therapy or within 7 days after completion of therapy with an echinocandin | 11/1/2005 - 10/31/2007 |
| Lack of an Adverse Drug Event (ADE) Attributable to Echinocandin (EC) Therapy That Led to Discontinuation of Therapy | Defined as any advsere event directly attributable to echinocandin treatment that led to discontinuation of therapy or switch to alternative therapy | 11/1/2005 - 10/31/2007 |
| Measure | Description | Time Frame |
|---|---|---|
| Duration of Echinocadin Therapy for Persistent Febrile Neutropenia (FN) | median duration of therapy with an echinocandin (caspofungin or micafungin) for persistent febrile neutropenia (FN) | 11/1/2005 - 10/31/2007 |
| Liver Function Tests (LFTs) Elevated During or After Echinocandin Therapy |
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Inclusion Criteria:
Exclusion Criteria:
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Cancer patients who are persistently febrile and neutropenic after receiving broad spectrum antibiotics and receive empiric antifungal therapy with either caspofungin or micafungin
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| Name | Affiliation | Role |
|---|---|---|
| David W Kubiak, PharmD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17396041 | Background | Schuler U, Bammer S, Aulitzky WE, Binder C, Bohme A, Egerer G, Sandherr M, Schwerdtfeger R, Silling G, Wandt H, Glasmacher A, Ehninger G. Safety and efficacy of itraconazole compared to amphotericin B as empirical antifungal therapy for neutropenic fever in patients with haematological malignancy. Onkologie. 2007 Apr;30(4):185-91. doi: 10.1159/000100055. Epub 2007 Mar 23. | |
| 17202726 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Caspofungin Arm | All patients admitted to BWH/DFCI who received at least 2 doses of caspofungin with an ANC < 500, for persistent febrile neutropenia from 11/1/2005 - 10/31/2006, as there first antifungal agent. |
| FG001 | Micafungin Arm | All patients admitted to BWH/DFCI who received at least 2 doses of micafungin with an ANC < 500 for persistent febrile neutropenia from 11/1/2006 - 10/31/2007 as there first antifungal agent |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Caspofungin Arm | All patients admitted to BWH/DFCI who received at least 2 doses of caspofungin with an ANC < 500, for persistent febrile neutropenia from 11/1/2005 - 10/31/2006, as there first antifungal agent. |
| BG001 | Micafungin Arm |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Composite Primary Endpoint: Number of Participants With an Overall Favorable Response to Echinocandin Therapy for Empiric Antifungal Therapy for Persistent Febrile Neutropenia (FN) | Overall favorable response was defined as achievement of successful treatment of baseline fungal infections, survival to hospital discharge, absence of breakthrough Ivasive fungal disese (IFD), and lack of advserse events (AE) attributable to treatment that led to discontinuation of echinocandin therapy. | Posted | Number | participants | 11/1/2005 - 10/31/2007 |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Caspofungin Arm | All patients admitted to BWH/DFCI who received at least 2 doses of caspofungin with an ANC < 500, for persistent febrile neutropenia from 11/1/2005 - 10/31/2006, as there first antifungal agent. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| AST > 5x ULN | Hepatobiliary disorders | Non-systematic Assessment |
Retrospective, observational, sequential cohort study conducted at a single center. Only adult patients were treated at our institution, so these results cannot be extrapolated to a pediatric population.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David Kubiak, Principle Investigator | Brigham and Women's Hospital | 617-525-8417 | dwkubiak@partners.org |
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| ID | Term |
|---|---|
| D064147 | Febrile Neutropenia |
| ID | Term |
|---|---|
| D009503 | Neutropenia |
| D000380 | Agranulocytosis |
| D007970 | Leukopenia |
| D000095542 | Cytopenia |
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aspartate aminotransferase (AST) or alanine aminotransferase (ALT)> 5x the upper limit of normal (ULN) or total bilirubin > 3x the upper limit of normal (ULN) |
| 11/1/2005 - 10/31/2007 |
| Specific Type of Adverse Event That Resulted in Echinocandin (EC) Therapy Discontinuation | The description of the adverse event that resulted in discontinuation of echinocandin (EC) therapy | 11/1/2005 - 10/31/2007 |
| Duration of Hospitization | Median number of days patients were hospitalized during the study period | 11/1/2005 - 10/31/2007 |
| Duration of Neutropenia | Median number of days patients were neutropenic during the study period | 11/1/2005 - 10/31/2007 |
| Background |
| Toubai T, Tanaka J, Ota S, Shigematsu A, Shono Y, Ibata M, Hashino S, Kondo T, Kakinoki Y, Masauzi N, Kasai M, Iwasaki H, Kurosawa M, Asaka M, Imamura M. Efficacy and safety of micafungin in febrile neutropenic patients treated for hematological malignancies. Intern Med. 2007;46(1):3-9. doi: 10.2169/internalmedicine.46.6021. Epub 2007 Jan 1. |
| 16048942 | Background | Seibel NL, Schwartz C, Arrieta A, Flynn P, Shad A, Albano E, Keirns J, Lau WM, Facklam DP, Buell DN, Walsh TJ. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother. 2005 Aug;49(8):3317-24. doi: 10.1128/AAC.49.8.3317-3324.2005. |
| 15459300 | Background | Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, Cornely OA, Bourque MR, Lupinacci RJ, Sable CA, dePauw BE. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004 Sep 30;351(14):1391-402. doi: 10.1056/NEJMoa040446. |
| 11807146 | Background | Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, Yanovich S, Stiff P, Greenberg R, Donowitz G, Schuster M, Reboli A, Wingard J, Arndt C, Reinhardt J, Hadley S, Finberg R, Laverdiere M, Perfect J, Garber G, Fioritoni G, Anaissie E, Lee J; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002 Jan 24;346(4):225-34. doi: 10.1056/NEJM200201243460403. |
| 11073745 | Background | Wingard JR, White MH, Anaissie E, Raffalli J, Goodman J, Arrieta A; L Amph/ABLC Collaborative Study Group. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis. 2000 Nov;31(5):1155-63. doi: 10.1086/317451. Epub 2000 Nov 7. |
| 11014720 | Background | Winston DJ, Hathorn JW, Schuster MG, Schiller GJ, Territo MC. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med. 2000 Mar;108(4):282-9. doi: 10.1016/s0002-9343(99)00457-x. |
| 10072411 | Background | Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999 Mar 11;340(10):764-71. doi: 10.1056/NEJM199903113401004. |
| 11731939 | Background | Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ; Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002 Jan 1;34(1):7-14. doi: 10.1086/323335. Epub 2001 Nov 26. |
| 11850858 | Background | Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, Feld R, Pizzo PA, Rolston KV, Shenep JL, Young LS. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002 Mar 15;34(6):730-51. doi: 10.1086/339215. Epub 2002 Feb 13. No abstract available. |
| 8274615 | Background | Vartivarian SE, Anaissie EJ, Bodey GP. Emerging fungal pathogens in immunocompromised patients: classification, diagnosis, and management. Clin Infect Dis. 1993 Nov;17 Suppl 2:S487-91. doi: 10.1093/clinids/17.supplement_2.s487. |
| 15546119 | Background | Perfect JR, Dodds Ashley E, Drew R. Design of aerosolized amphotericin b formulations for prophylaxis trials among lung transplant recipients. Clin Infect Dis. 2004 Oct 15;39 Suppl 4:S207-10. doi: 10.1086/421958. |
| 18032613 | Background | Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Diekema DJ. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol. 2008 Jan;46(1):150-6. doi: 10.1128/JCM.01901-07. Epub 2007 Nov 21. |
| 17482982 | Background | Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, Sekhon JS, Freire A, Ramasubramanian V, Demeyer I, Nucci M, Leelarasamee A, Jacobs F, Decruyenaere J, Pittet D, Ullmann AJ, Ostrosky-Zeichner L, Lortholary O, Koblinger S, Diekmann-Berndt H, Cornely OA; Micafungin Invasive Candidiasis Working Group. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet. 2007 May 5;369(9572):1519-1527. doi: 10.1016/S0140-6736(07)60605-9. |
| 16595990 | Background | Yanada M, Kiyoi H, Murata M, Suzuki M, Iwai M, Yokozawa T, Baba H, Emi N, Naoe T. Micafungin, a novel antifungal agent, as empirical therapy in acute leukemia patients with febrile neutropenia. Intern Med. 2006;45(5):259-64. doi: 10.2169/internalmedicine.45.1498. Epub 2006 Apr 3. |
| 17806055 | Background | Pappas PG, Rotstein CM, Betts RF, Nucci M, Talwar D, De Waele JJ, Vazquez JA, Dupont BF, Horn DL, Ostrosky-Zeichner L, Reboli AC, Suh B, Digumarti R, Wu C, Kovanda LL, Arnold LJ, Buell DN. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007 Oct 1;45(7):883-93. doi: 10.1086/520980. Epub 2007 Aug 29. |
| 19724014 | Background | Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of antifungals. Ann Pharmacother. 2009 Oct;43(10):1647-57. doi: 10.1345/aph.1M237. Epub 2009 Sep 1. |
| 20435233 | Result | Kubiak DW, Bryar JM, McDonnell AM, Delgado-Flores JO, Mui E, Baden LR, Marty FM. Evaluation of caspofungin or micafungin as empiric antifungal therapy in adult patients with persistent febrile neutropenia: a retrospective, observational, sequential cohort analysis. Clin Ther. 2010 Apr;32(4):637-48. doi: 10.1016/j.clinthera.2010.04.005. |
All patients admitted to BWH/DFCI who received at least 2 doses of micafungin with an ANC < 500 for persistent febrile neutropenia from 11/1/2006 - 10/31/2007 as there first antifungal agent |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Primary Underlying Disease | primary oncological diagnosis | Number | participants |
|
| hematopoietic stem cell transplantation status | Number | participants |
|
| Patient Weight, kg | Median | Inter-Quartile Range | kilograms |
|
All patients admitted to BWH/DFCI who received at least 2 doses of micafungin with an ANC < 500 for persistent febrile neutropenia from 11/1/2006 - 10/31/2007 as there first antifungal agent |
|
|
|
| Primary | Successful Treatment of Any Baseline Invasive Fungal Disease (IFD) | Possible or proven baseline invasive fungal disease were defined as were diagnosed within the 2 days of initiating echinocandin therapy for persistent febrile neutropenia | Posted | Number | participants | 11/1/2005 - 10/31/2007 |
|
|
|
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| Primary | Mortality at Hospital Discharge | We assessed all patients in the study cohort who dischaged from the hospital alive | Posted | Number | participants | 11/1/2005 - 10/31/2007 |
|
|
|
|
| Primary | Absence of Any Breakthrough Invasive Fungal Disease (IFD) | a breakthrough invasive fungal disesase was defined as any fungal infection that was diagnosed > 3 days on or during therapy or within 7 days after completion of therapy with an echinocandin | Posted | Number | participants | 11/1/2005 - 10/31/2007 |
|
|
|
|
| Primary | Lack of an Adverse Drug Event (ADE) Attributable to Echinocandin (EC) Therapy That Led to Discontinuation of Therapy | Defined as any advsere event directly attributable to echinocandin treatment that led to discontinuation of therapy or switch to alternative therapy | Posted | Number | participants | 11/1/2005 - 10/31/2007 |
|
|
|
|
| Secondary | Duration of Echinocadin Therapy for Persistent Febrile Neutropenia (FN) | median duration of therapy with an echinocandin (caspofungin or micafungin) for persistent febrile neutropenia (FN) | Posted | Median | Inter-Quartile Range | days | 11/1/2005 - 10/31/2007 |
|
|
|
|
| Secondary | Liver Function Tests (LFTs) Elevated During or After Echinocandin Therapy | aspartate aminotransferase (AST) or alanine aminotransferase (ALT)> 5x the upper limit of normal (ULN) or total bilirubin > 3x the upper limit of normal (ULN) | Posted | Number | participants | 11/1/2005 - 10/31/2007 |
|
|
|
| Secondary | Specific Type of Adverse Event That Resulted in Echinocandin (EC) Therapy Discontinuation | The description of the adverse event that resulted in discontinuation of echinocandin (EC) therapy | Posted | Number | participants | 11/1/2005 - 10/31/2007 |
|
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| Secondary | Duration of Hospitization | Median number of days patients were hospitalized during the study period | Posted | Median | Inter-Quartile Range | days | 11/1/2005 - 10/31/2007 |
|
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|
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| Secondary | Duration of Neutropenia | Median number of days patients were neutropenic during the study period | Posted | Median | Inter-Quartile Range | days | 11/1/2005 - 10/31/2007 |
|
|
|
|
| 3 |
| 149 |
| 15 |
| 149 |
| EG001 | Micafungin Arm | All patients admitted to BWH/DFCI who received at least 2 doses of micafungin with an ANC < 500 for persistent febrile neutropenia from 11/1/2006 - 10/31/2007 as there first antifungal agent | 2 | 174 | 18 | 174 |
| Liver function test elevation | Hepatobiliary disorders | Non-systematic Assessment |
|
| Anaphylaxis | Immune system disorders | Systematic Assessment |
|
| ALT > 5x ULN | Hepatobiliary disorders | Non-systematic Assessment |
|
| Total Bilirubin > 3x ULN | Hepatobiliary disorders | Non-systematic Assessment |
|
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| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007960 | Leukocyte Disorders |
| Unsuccessfully treated baseline IFD |
|
| ALT > 5x upper limit of normal |
|
| Total Bilirubin >3x upper limit of normal |
|
| Liver function Test (LFT) increase |
|
| Anaphylaxis |
|