Systematic review and network meta-analysis of clinical outcomes associated with isavuconazole versus relevant comparators for patients with invasive aspergillosis

Figures & data

Table 1. Parameters and criteria for the systematic review.

Parameter	Criteria
Population	Adult patients with proven, probable or possible invasive fungal disease caused by Aspergillus species
Intervention	Isavuconazole
Comparators	Voriconazole, liposomal amphotericin B, amphotericin B deoxycholate
Outcomes	Mortality (n, %) Overall response (success; n, %) Rate of hospitalization (including intensive care unit) and length of stay Discontinuation due to adverse event (treatment emergent and drug related) Discontinuation due to any reason Adverse events (treatment emergent and drug related) Serious adverse events (treatment emergent and drug related)
Study types	Randomized controlled trials
Language	English language only
Years	Last 20 years
Exclusions	Combination treatment studies Reviews, discussion papers, non-research letters and editorials Qualitative studies Case studies, case series Animal studies Conference abstracts

Figure 1. Flow diagram of studies included and excluded at each step. ^aTwo articles published after the performance of the systematic search were also included: Herbrecht et al. 2015²⁵ and Maertens et al. 2016⁴.

Figure 2. Comparisons in studies identified in the systematic review included in the network analysis. Abbreviations. AmB-D, amphotericin B deoxycholate; ISAV, isavuconazole; L-AmB, liposomal amphotericin B; VRC, voriconazole. ^aMaertens et al. 2016⁴. ^bHerbrecht et al. 2015²⁵. ^cLeenders et al. 1998²⁰. ^dCornely et al. 2011²².

Table 2. Studies identified for the analysis.

Study	Study drugs (patient numbers)	Primary end point (populations, time points)	Selected secondary end points	Time points
Study 1: Leenders et al. 1998^20	AmB-D 1 mg/kg (n = 34) L-AmB 5 mg/kg (n = 32)	Therapeutic response (CE, 2 weeks)	Clinical success and improvement Mortality rate	Completion of therapy During therapy and 4 weeks after completion of therapy
Study 2: Cornely et al. 2011 (AmBiLoad)^22	L-AmB 3 mg/kg (n = 45) L-AmB 10 mg/kg (n = 38)	Overall response (ITT, mITT; 12 weeks)	Survival	12 weeks
Study 3: Herbrecht et al. 2015^25	Voriconazole 4 mg/kg IV or 200 mg oral BID^a (n = 124) AmB-D 1.0–1.5 mg/kg^a (n = 113)	Successful outcome (ITT, mITT; 12 weeks)	Successful response (favorable response) Survival	End of initial therapy End of therapy 12 weeks
Study 4: Maertens et al. 2016 (SECURE)^4	Isavuconazole 200 mg QD^a (n = 143) Voriconazole 4 mg/kg or 200 mg oral BID^a (n = 129)	All-cause mortality (ITT, mITT; 42 days)	All-cause mortality Efficacy	84 days, EOT 42 days, 84 days, EOT

Abbreviations. AmB-D, amphotericin B deoxycholate; BID, twice daily; CE, clinical evaluable population; EOT, end of treatment; ITT, intent-to-treat population; IV, intravenous; L-AmB, liposomal amphotericin B; mITT, modified intent-to-treat population; QD, once daily.

^a Maintenance dose.

Table 3. Infection sites and underlying diseases in patients with proven or probable invasive fungal diseases^a.

Study	Treatment arm	Site of infection	Primary underlying disease	Baseline neutropenia
Study 1: Leenders et al. 1998^20	L-AmB	Pulmonary, 56% Not reported, 44%	Acute non-lymphocytic leukemia/myelodysplastic syndromes, 56%; ALL, 19%; chronic leukemia, 6%; other, 19%	94%^b
	AmB-D	Pulmonary, 65% Not reported, 35%	Acute non-lymphocytic leukemia/myelodysplastic syndromes, 59%; ALL, 6%; chronic leukemia, 9%; other, 26%	88%^b
Study 2: Cornely et al. 2011^22	L-AmB 3 mg/kg	Pulmonary only, 80%	Hematologic malignancies, 89%; HSCT, 20%	62%^b
	L-AmB 10 mg/kg	Pulmonary only, 79%	Hematologic malignancies, 92%; HSCT, 16%	63%^b
Study 3: Herbrecht et al. 2015^25	VRC	Pulmonary only, 85% Sinus, 6% Cerebral, 3% Disseminated, 3% Other, 3%^c	AML, 36%; HSCT, 29%; ALL, 8%; other hematologic malignancies, 12%; solid organ cancer, 1%; SOT, 6%; other non-malignant disease, 8%^d	50%^b,^d
	AmB-D	Pulmonary only, 88% Sinus, 5% Cerebral, 4% Disseminated, 1% Other, 2%^c	AML, 38%; HSCT, 26%; ALL, 7%; other hematologic malignancies, 15%; SOT, 4%; other non-malignant disease, 10%^d	49.4%^b,^d
Study 4: Maertens et al. 2016^4	ISAV	Pulmonary only, 81% Pulmonary and other organ, 8% Non-pulmonary only, 10%	AML, 38%; ALL, 12%; lymphoma, 13%; myelodysplastic syndrome, 9%; CLL, 4%; aplastic anemia, 3%; CML, 2%; multiple myeloma, 2%; COPD, 2%; Hodgkin’s disease, 1%; diabetes mellitus, 2%	63.2%^b
	VRC	Pulmonary only, 83% Pulmonary and other organ, 12% Non-pulmonary only, 5%	AML, 49%; ALL, 9%; lymphoma, 9%; myelodysplastic syndrome, 5%; CLL, 5%; aplastic anemia, 3%; CML, 3%; multiple myeloma, 3%; COPD, 1%; Hodgkin’s disease, 1%	67.8%^b

Abbreviations. ALL, acute lymphoblastic leukemia; AmB-D, amphotericin B deoxycholate; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; COPD, chronic obstructive pulmonary disease; HSCT, hematopoietic stem cell transplantation (includes both allogeneic and autologous); IA, invasive aspergillosis; ISAV, isavuconazole; L-AmB, liposomal amphotericin B; SOT, solid organ transplantation; VRC, voriconazole.

^a For Study 1, certainty of diagnosis was categorized as “documented” and “highly suspected”²⁰; Study 3 was an analysis of patients with proven or probable IA.

^b Defined as absolute neutrophil count < 0.5 × 10⁹/L.

^c Percentage of patients with definite or probable IA in the parent study²³.

^d Percentage of patients with proven, probable or possible IA in the re-analysis.

Figure 3. All-cause mortality in individual studies (A) and odds ratios^a for comparisons with isavuconazole in the network meta-analysis (B). Odds ratio shown as natural log. ^aCalculated using exact logistic regression factoring in malignancy status. Abbreviations. AmB-D, amphotericin B deoxycholate; CrI, credible interval; ISAV, isavuconazole; L-AmB, liposomal amphotericin B; NR, not reported; NS, not significant; VRC, voriconazole.

Table 4. Clinical/pharmacologic aspects of isavuconazole, voriconazole, amphotericin B deoxycholate and liposomal amphotericin B in the treatment of invasive mold disease^a.

Characteristic	Isavuconazole	Voriconazole	Amphotericin B deoxycholate	Liposomal amphotericin B
Indication for IMD	IA, mucormycosis^b	IA, serious IMD due to Scedosporium apiospermum, Fusarium spp.	IA, mucormycosis	IA, mucormycosis
Guideline recommendations for treatment of IA
ECIL-6^6	Grade A I^c: as effective as voriconazole and better tolerated	Grade A I^c	Grade A I^c against use as first-line treatment: less effective and more toxic	Grade B I^d
IDSA^5	Alternative to voriconazole	Primary recommendation	Should be reserved for use in resource-limited settings in which no alternative agents are available	Alternative to voriconazole; use should be considered in settings in which azoles are contraindicated or not tolerated
ESCMID/ECMM/ERS^7	Grade A I^c (pulmonary IA)	Grade A I^c (pulmonary IA); Grade A II^e (extrapulmonary IA)	Grade D I^f	Grade B II^g (pulmonary IA); Grade A II^e (extrapulmonary IA)
Available formulations (guideline recommendations for dosing in IA)	IV or oral (200 mg daily)^h	IV (4 mg/kg twice daily) or oral (200 mg twice daily)^i	IV (1–1.5 mg/kg)^j	IV (3–5 mg/kg)^k
Clinical guideline recommendations for TDM
ECIL-6	No recommendation	Indicated	Not applicable	Not applicable
IDSA	Further studies needed to know whether it is helpful or necessary	Moderate amount of evidence to support value for enhancing efficacy	Not applicable	Not applicable
ESCMID/ECMM/ERS	Potentially useful	Indicated	Not applicable	Not applicable
Drug–drug interactions	•Moderate inhibitor of CYP3A4•Mild inhibitor of P-gp, OCT2•Substrate for CYP3A4/5•Co-administration of strong inhibitors or inducers of CYP3A4 contraindicated	•Strong inhibitor of CYP3A4•Substrate for CYP2C19, CYP2C9, CYP3A4•Co-administration of strong inhibitors or inducers of CYP3A4 contraindicated•Monitoring and potential dose adjustments required with inhibitors of CYP2C19, CYP2C9	•Potential for interactions with antineoplastic agents, corticosteroids and corticotropin, digitalis glycosides, flucytosine, imidazoles, other nephrotoxic medications, skeletal muscle relaxants, leukocyte transfusions	•Potential for interactions with antineoplastic agents, corticosteroids and corticotropin, digitalis glycosides, flucytosine, azoles, other nephrotoxic medications, skeletal muscle relaxants, leukocyte transfusions

Abbreviations. CYP, cytochrome P450; ECIL-6, 6th European Conference on Infections in Leukemia; ECMM, European Confederation of Medical Mycology; ERS, European Respiratory Society; ESCMID, European Society for Clinical Microbiology and Infectious Diseases; IA, invasive aspergillosis; IDSA, Infectious Diseases Society of America; IMD, invasive mold disease; IV, intravenous; OCT2, organic cation transporter 2; P-gp, P-glycoprotein; TDM, therapeutic drug monitoring.

^a From ECIL-6, ESCMID/ECMM/ERS, and IDSA clinical guidelines and prescribing information.

^b Approval of isavuconazole for mucormycosis by the European Medicines Agency stipulates its use in patients for whom amphotericin B is not appropriate.

^c Good evidence to support a recommendation for use; evidence from ≥1 properly randomized, controlled trial.

^d Moderate evidence to support a recommendation for use; evidence from ≥1 properly randomized, controlled trial.

^e Good evidence to support a recommendation for use; evidence from ≥1 well designed non-randomized trial, case–control study, multiple time series or dramatic results of uncontrolled experiments.

^f Good evidence to support a recommendation against use; evidence from ≥1 properly randomized, controlled trial.

^g Moderate evidence to support a recommendation for use; evidence from ≥1 well designed non-randomized trial, case–control study, multiple time series or dramatic results of uncontrolled experiments.

^hMaintenance dose, following loading dose of 200 mg every 8 h for 48 h.

ⁱ Maintenance dose, following loading dose of 6 mg/kg IV every 12 h for 24 h.

^j Dose recommendation not provided in ECIL-6 guidelines.

^k IDSA recommendation, 3–5 mg/kg; ECIL-6, ESCMID/ECMM/ERS recommendation, 3 mg/kg.

Figure 4. Overall response in individual studies (A) and odds ratios for comparisons with isavuconazole in the network meta-analysis (B). Odds ratio shown as natural log. Abbreviations. AmB-D, amphotericin B deoxycholate; CrI, credible interval; ISAV, isavuconazole; L-AmB, liposomal amphotericin B; NR, not reported; NS, not significant; VRC, voriconazole.

Herbrecht R, Patterson TF, Slavin MA, et al. Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group. Clin Infect Dis 2015;60:713-20

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