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Safety and Outcomes in Invasive Aspergillosis Patients with Renal vs. No Renal Impairment
Johan Maertens, MD, PhD
Treated with Isavuconazole: Experience from the SECURE (Randomised) and VITAL Trials
UZ Leuven,
Telephone: +32 16 347682
Kathleen M. Mullane1, Mickael Aoun2, Billy Franks3, Nkechi Azie3, Salim Mujais3, Achim Kaufhold4, Johan Maertens5 1University of Chicago Medicine, Chicago, IL, USA; 2Institut Jules Bordet, Brussels, Belgium; 3Astellas Pharma Global Development, Northbrook, IL, USA; 4Basilea Pharmaceutica International Ltd, Basel, Switzerland; 5UZ Leuven, Leuven, Belgium INTRODUCTION AND PURPOSE
Table 1. Patient characteristics
Table 2. Efficacy endpoints by renal status
Renally impaired
Not renally impaired
Renally impaired
Not renally impaired
• Patients with renal impairment and invasive aspergillosis (IA) represent a Efficacy outcome n (%)
special patient group as up to 40% of patients with IA can have underlying IV or PO 200 mg QD Age [years], median (range) Day 42 al -cause mortalitya renal impairment.1,2 Day 84 al -cause mortalityb • Triazole antifungals are central to the treatment of IA;3 however, their use Study day
eGFR-MDRD [mL/min/1.73 m2], mean ± SD DRC-assessed overall success rate at EOT may be restricted in patients with renal impairment.
Renal impairmenta, n (%) aA patient with unknown survival status at Day 42 was counted as a death.
b Follow up 28 days A patient with unknown survival status before Day 84 was counted as a death.
− Caution is recommended for use of itraconazole in this patient cOne of the 112 patients in this pool was actively participating in the study at time of the data cut-off and was not included in the EOT analysis at this time point. − Voriconazole and posaconazole are restricted in patients with moderate- Risk factors for development of infectionb, n (%) Study day
to-severe renal impairment due to inclusion of cyclodextrin in their Al ogeneic HSCT, n (%) Haematological malignancy status, n (%) • In total, 31 (100%) patients with renal impairment and 107 (96%) patients intravenous (IV) formulations.5,6 IV 4 mg/kg or PO 200 mg BID Neutropaeniac, n (%) without renal impairment at baseline reported at least one TEAE (Table 3).
• Isavuconazole is a novel, broad-spectrum, triazole antifungal agent, which is Corticosteroid use, n (%) − The most common serious TEAEs observed in renally impaired and administered as the water-soluble prodrug, isavuconazonium sulfate. T-cel immunosuppressant use non-renally impaired patients were infections and infestations (10 [32%] • The oral (PO) and cyclodextrin-free IV formulations of the prodrug were recently Uncontrolled malignancyd, n (%) and 25 [22%], respectively) and respiratory, thoracic and mediastinal approved for the primary treatment of adults with IA and mucormycosis by the New diagnosis/active disease disorders (5 [16%] and 21 [19%], respectively).
US Food and Drug Administration.7 IV or PO 200 mg TID IV or PO 200 mg QD • Doubling of serum creatinine values was observed for 1/30 (3%) patients • Dosing information is expressed as the isavuconazole equivalent of the prodrug: with renal impairment and in 14/109 (13%) patients without renal impairment − Oral capsules each contain isavuconazonium sulfate 186 mg, Follow up 28 days Underlying disease, n (%) during the course of this study.
equivalent to isavuconazole 100 mg; vials for IV infusion each contain Acute myeloid leukaemia − Serum creatinine data was only available for 109/112 patients without isavuconazonium sulfate 372 mg, equivalent to isavuconazole 200 mg.7 Study day 1 2 3
Chronic lymphocytic leukaemia baseline renal impairment.
• A Phase 1 study showed no clinically meaningful differences in BID, twice daily; QD, Once daily; TID, Three times daily Acute lymphocytic leukaemia isavuconazole exposure between subjects with renal impairment and end- Red dots represent isavuconazole and blue dots represent voriconazole Non-Hodgkin's lymphoma stage renal disease (ESRD), and healthy subjects with normal renal function Figure 1. Isavuconazole dosing schedule in SECURE and VITAL trials
Table 3. Safety data summary
Diabetes mel itus (data on file).
Renally impaired Not renally impaired
− Therefore, isavuconazole dose adjustment is not warranted in patients Pathogen causing IFD, n (%) with renal impairment or ESRD.
• The key endpoint was all-cause mortality through Day 42.
Aspergillus spp. only Study drug-related TEAEs, n (%) • The large, Phase 3, randomised SECURE trial recently demonstrated • Other endpoints included all-cause mortality through Day 84, survival Aspergillus NOS Serious TEAEs, n (%) non-inferiority of isavuconazole compared with voriconazole for Day 42 probability through Day 84 (Kaplan–Meier method), and data-review Aspergillus fumigatus TEAEs leading to permanent discontinuation of the all-cause mortality (isavuconazole 18.6% vs. voriconazole 20.2%) for the Aspergillus flavus study drug, n (%) committee (DRC)-assessed overall response of success at EOT.
primary treatment of IA and invasive fungal disease (IFD) caused by other Aspergillus terreus TEAEs leading to death, n (%) − Overall response was based on DRC-assessed clinical, mycological and filamentous fungi.8 Aspergillus niger Study drug-related TEAEs leading to permanent discontinuation of the study drug, n (%) • The Phase 3 VITAL trial has shown that isavuconazole is effective against a Aspergillus versicolor − Success was defined as complete or partial resolution of all clinical variety of invasive mould infections, including IA.9 Aspergillus sydowi symptoms and physical findings, presumed or documented eradication All reported deaths after first dose of study drug are reported, regardless of the number of days after the last dose of the study drug.
• We report outcomes in a pooled population of patients with IA and baseline and complete resolution or improvement of radiological abnormalities. Aspergillus + other mould spp.
renal impairment enrolled in the SECURE and VITAL trials, who received No pathogen identified Stage 3 renal impairment defined as eGFR-MDRD between 30–<60 mL/min/1.73 m2 and stage 4 renal impairment defined as GFR-MDRD between 15–<30 mL/min/1.73 m2.
bPatients could have >1 risk factor. • The incidence, nature and severity of treatment-emergent adverse events cPresence of neutropaenia was based on an absolute neutrophil count <0.5 x 109/L at baseline; persistence of neutropaenia was defined as 2 consecutive absolute neutrophil counts <0.5 x 109/L on 2 separate days.
d Patients with malignancy diagnosis and new/active disease or relapse.
(TEAEs) were monitored and assessed in all patients who received at least HSCT, haematopoietic stem cel transplant.
• Renal impairment is common in patients with IA; however, the one dose of isavuconazole.
use of some triazole antifungals is restricted in patients with Study design
renal impairment, while others require dose adjustment or • SECURE (ClinicalTrials.gov identifier: NCT00412893) was a global, Phase caution when administered in this patient group.
3, multi-centre, double-blind, parallel-group, non-inferiority trial, which evaluated isavuconazole vs. voriconazole for the primary treatment of IA • Isavuconazole was safe and efficacious in patients with renal and IFD caused by other filamentous fungi.
impairment enrolled in the SECURE and VITAL trials.
• Of the 527 patients randomised in SECURE and 149 patients enrolled • VITAL (ClinicalTrials.gov identifier: NCT00634049) was a global, Phase 3, • These findings support previous trial data that dose in VITAL, 143 patients with proven/probable IA were treated with multi-centre, open-label trial, which evaluated isavuconazole therapy in adjustments are not required for isavuconazole in patients with patients with IA and renal impairment, and in patients with IFD caused by renal impairment.
− Of these, 31 (22%) had renal impairment and 112 (78%) did not have emerging moulds, yeasts and dimorphic fungi.
renal impairment (Table 1).
• Patients, ≥18 years of age, with proven/probable IA (EORTC/MSG criteria10) Renally impaired (n=31) − The mean ± standard deviation (SD) eGFR-MDRD at baseline for patients REFERENCES 1. Baddley, J. et al. 2010. Clin Infect Dis. 50:1559–1567. 2. Vandewoude, K. et al. 2004. J Hosp Infect. 56:269–276.
with or without renal impairment at baseline participating in the trials were Not renally impaired (n=112) 3. Walsh, T. et al. 2008. Clin Infect Dis. 46:327–360 4. Janssen Pharmaceutica N.V. 2011. Sporanox® (itraconazole) prescribing
with and without renal impairment was 41 ± 12 mL/min/1.73 m2 and 125 ± information (Accessed 12 February, 2015, at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020657s027lbl.pdf). included in this analysis.
56 mL/min/1.73 m2, respectively (Table 1).
5. Pfizer Inc. 2014. VFEND® (voriconazole) prescribing information (Accessed 12 February, 2015, at http://www.accessdata.
− Baseline renal-impairment was defined according to the guidelines of the fda.gov/drugsatfda_docs/label/2014/021266s037,021267s044,021630s027lbl.pdf). 6. Merck & Co, Inc. 2014. Noxafil®
(posaconazole) prescribing information (Accessed 12 February, 2015, at http://www.accessdata.fda.gov/drugsatfda_docs/ National Kidney Foundation Kidney Disease Outcomes Quality Initiative as Study day
label/2014/205596s000lbl.pdf). 7. Astel as Pharma US Inc. 2015. CRESEMBA® (isavuconazonium sulfate) prescribing information
No. of patients at risk
(Accessed 10 March, 2015 at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf). 8. Maertens,
an estimated glomerular filtration rate (eGFR-Modification of Diet in Renal • All-cause mortality through Day 42 was comparable between patients with J. et al. European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Barcelona, Spain; 10–13 May, 2014; O230a. Disease [MDRD]) of <60 mL/min/1.73 m2.11 9. Marty, F. et al. IDWeek 2014 annual meeting; Philadelphia, PA, USA; 8–12 October, poster 824. 10. De Pauw, B. et al. 2008.
(13%) and without renal impairment (19%) at baseline (Table 2).
Clin. Infect. Dis. 46:1813–1821. 11. National Kidney Foundation KDOQI Clinical Practice Guidelines for Chronic Kidney Disease:
Not renally 112 110 104 100 • In both studies, isavuconazole 200 mg IV loading dose was administered • Survival probability through Day 84 (Kaplan–Meier method) was similar Evaluation, Classification and Stratification. 2002. (Accessed 19 February, 2015, at https://www.kidney.org/sites/default/files/docs/ 3 times daily on Days 1 and 2, followed by either IV or PO isavuconazole between patients with and without renal impairment at baseline (Figure 2).
Patients were censored on their last assessment day (open circles).
Although there were patients that survived through Day 84, this figure only displays the probability of survival up to Day 84.
DISCLOSURES K. Mullane has received grant support from Astellas Pharma Global Development, Anson, Chimerix, Merck,
200 mg once daily from Day 3 to end of treatment (EOT) (Figure 1).
• DRC-assessed overall successful response at EOT was comparable Rebiotix, ViroPharma and Pfizer and research support and consulting fees from Cubist/Optimer. J. Maertens has received personal Figure 2. Survival up to 84 days in patients treated with isavuconazole with and
fees from Astel as Pharma Global Development and grant support and personal fees from Gilead Sciences, MSD and Pfizer. − Isavuconazole was administered up to 84 and 180 days in the SECURE between patients with and without renal impairment (32% vs. 36%, A. Kaufhold is an employee of Basilea Pharmaceutica International Ltd. B. Franks, N. Azie and S. Mujais are employees of without renal impairment at baseline and VITAL studies, respectively.
respectively; Table 2).
Astellas Pharma Global Development.
ACKNOWLEDGEMENTS Isavuconazonium sulfate has been co-developed by Astellas Pharma Global Development and Basilea Pharmaceutica International Ltd. Poster development support was provided by Barrie J. Anthony, PhD, a medical writer at Envision Scientific Solutions, funded by Astellas Pharma Global Development.
To obtain a PDF of this poster, click on this QR code or go to the website below. Presented at the 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Copenhagen, Denmark; 25-28 April, 2015; EV0932

Source: https://docs.astellas.us/QR/Medical_Publications/ECCMID%202015%20Renal_15April15_IP.pdf