As097-14 eccmid 2015 renal tc.2.4.indd
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
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
Efficacy endpoints by renal status
Not 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
Day 84 al -cause mortalityb
• Triazole antifungals are central to the treatment of IA;3 however, their use
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.
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 (%)
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
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
stage renal disease (ESRD), and healthy subjects with normal renal function
Isavuconazole dosing schedule in SECURE and VITAL trials
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.
Study drug-related TEAEs, n (%)
• The large, Phase 3, randomised SECURE trial recently demonstrated
• Other endpoints included all-cause mortality through Day 84, survival
Serious TEAEs, n (%)
non-inferiority of isavuconazole compared with voriconazole for Day 42
probability through Day 84 (Kaplan–Meier method), and data-review
TEAEs leading to permanent discontinuation of the
all-cause mortality (isavuconazole 18.6% vs. voriconazole 20.2%) for the
study drug, n (%)
committee (DRC)-assessed overall response of success at EOT.
primary treatment of IA and invasive fungal disease (IFD) caused by other
TEAEs leading to death, n (%)
− Overall response was based on DRC-assessed clinical, mycological and
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
− Success was defined as complete or partial resolution of all clinical
variety of invasive mould infections, including IA.9
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.
+ 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.
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
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
− 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
Baddley, J. et al
. 2010. Clin Infect Dis
. 50:1559–1567. 2.
Vandewoude, K. et al
. 2004. J Hosp Infect
with or without renal impairment at baseline participating in the trials were
Not renally impaired (n=112)
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
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
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
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.
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
Marty, F. et al
. IDWeek 2014 annual meeting; Philadelphia, PA, USA; 8–12 October, poster 824. 10.
De Pauw, B. et al
(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.
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
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.
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
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