Abstract
Background: Invasive fungal diseases (IFD) are on the rise due to the increasing numbers of immunosuppressed patients including those undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation. Isavuconazole (ISA) is a novel, broad-spectrum antifungal triazole, available as a water-soluble prodrug in IV and oral formulations. IM is a life-threatening IFD with significant mortality and limited treatment options.
Methods: The VITAL study was a Phase III, multicenter, open-label, single arm, trial conducted to evaluate efficacy and safety of ISA treatment in patients with rare IFD, including IM. Eligibility criteria and evaluated outcomes are outlined in clinicaltrials.gov, NCT00634049. Patients received IV or PO ISA 200 mg TID for 2 days followed by 200 mg/day. FungiScope – Global Emerging Fungal Infection Registry maintains a global web-based database on rare IFD, including IM. Entrance criteria are outlined in clinicaltrials.gov, NCT01731353. 21 patients from the VITAL study who received ISA for the primary treatment of proven/probable IM were matched (blinded to mortality status) to up-to 3 proven/probable patients with IM who received a formulation of amphotericin B entered in FungiScope based on 3 dichotomous risk factors: severe disease (i.e. CNS/disseminated), surgical debridement, and hematologic malignancy. All-cause mortality through day 42 was summarized.
Results: 33 FungiScope matched controls were identified; 14 VITAL cases were matched to a single control each (n=14), 2 VITAL cases were matched to 2 controls each (n=4), and 5 VITAL cases were matched to 3 controls each (n=15). Demographics, treatments, matching criteria and mortality outcomes are shown in Table 1. The crude mortality rate (33.3%) through day 42 from the VITAL cases was similar to the mortality rate (39.4% crude; 41.3% weighted) from the matched controls of FungiScope.
| Parameter | Isavuconazole VITAL Cases (n=21) | FungiScopeTM Amphotericin B Matched Controls (n=33) |
|---|---|---|
| Treatment, n (%) Isavuconazole Deoxycholate amphotericin B Liposomal amphotericin B Amphotericin B Lipid Complex | 21 (100) 0 0 0 | 0 7 (21) 22 (67) 4 (12) |
| Case year, range | 2008–2013 | 2005–2013 |
| Age, median (range) | 51 (25–77) | 57 (22–81) |
| Male, n (%) | 17 (81) | 22 (67) |
| Race, n (%) White Black/African American Asian | 12 (57) 1 (5) 8 (38) | 31 (94) 0 2 (6) |
| Severe Disease,1 n (%) | 12 (57) | 13 (39) |
| Surgical Debridement,2 n (%) | 9 (43) | 13 (39) |
| Hematologic Malignancy, n (%) | 11 (52) | 18 (55) |
| Crude Mortality, n (%) | 7 (33.3) | 13 (39.4) |
| Weighted Mortality3 (%) | Not Applicable | 41.3 |
| Parameter | Isavuconazole VITAL Cases (n=21) | FungiScopeTM Amphotericin B Matched Controls (n=33) |
|---|---|---|
| Treatment, n (%) Isavuconazole Deoxycholate amphotericin B Liposomal amphotericin B Amphotericin B Lipid Complex | 21 (100) 0 0 0 | 0 7 (21) 22 (67) 4 (12) |
| Case year, range | 2008–2013 | 2005–2013 |
| Age, median (range) | 51 (25–77) | 57 (22–81) |
| Male, n (%) | 17 (81) | 22 (67) |
| Race, n (%) White Black/African American Asian | 12 (57) 1 (5) 8 (38) | 31 (94) 0 2 (6) |
| Severe Disease,1 n (%) | 12 (57) | 13 (39) |
| Surgical Debridement,2 n (%) | 9 (43) | 13 (39) |
| Hematologic Malignancy, n (%) | 11 (52) | 18 (55) |
| Crude Mortality, n (%) | 7 (33.3) | 13 (39.4) |
| Weighted Mortality3 (%) | Not Applicable | 41.3 |
1 – CNS Involvement and/or Disseminated Disease
2 – Surgery performed +/– 7 days of the initiation of isavuconazole or amphotericin.
3 – Weights were applied according to the ratio of the number of controls matched to each VITAL case.
Conclusions: Isavuconazole was as effective as amphotericin B formulations in the primary treatment of invasive mucormycosis based on this matched case comparison of mortality rates from the VITAL study and FungiScope.
Vehreschild:MJGTV has served at the speakers' bureau of Pfizer, Merck, Gilead Sciences and Astellas Pharma, received research funding from 3M and Gilead Sciences and is a consultant to Berlin Chemie.: Consultancy, Research Funding, Speakers Bureau. Vehreschild:Astellas, Gilead, Infectopharm, MSD/Merck, Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Marty:Astellas Pharma US, Merck, WHISCON: Honoraria, Research Funding. Perfect:Astellas, Pfizer, Merck, F26, Scynexis, Viarret: Consultancy, Research Funding. Ostrosky-Zeichner:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rahav:Astellas: Research Funding. Zeiher:Astellas Pharma Global Development: Employment. Lee:Astellas: Employment. Maher:Astellas: Employment. Lovell:Astellas Pharma Inc: Consultancy. Engelhardt:Basilea Pharmaceutica International Ltd: Employment. Cornely:Astellas: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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