micafungin klinische studien bei erwachsenen

MicafunginKlinische Studien bei Erwachsenen

Prof. Oliver A. Cornely, FIDSA

Klinik I für Innere MedizinHämatologie / Onkologie

Klinische Infektiologie / Intensivmedizin

Zentrum für Klinische StudienUniversität zu Köln

Supported by unrestricted grantsfrom Schering-Plough, Astellas Pharma and Gilead Sciences.

www.fungiscope.net

−Free species identification

−Free culture banking

−Free consult

−Moderate compensation

−Co-authorship

−Free drug level analysis

Micafungin – Klinische Studien bei Erwachsenen

1. van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versusFluconazole for Prophylaxis against Invasive Fungal Infections duringNeutropenia in Patients Undergoing Hematopoietic Stem Cell Transplantation.Clin Infect Dis 2004 Nov 15;39(10):1407-16.

2. de Wet N, Llanos-Cuentas A, Suleiman J, et al. A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazolefor the treatment of esophageal candidiasis in HIV-positive patients. ClinInfect Dis 2004 Sep 15;39(6):842-9.

3. Kuse ER, Chetchotisakd P, da Cunha CA, et al.Micafungin versus liposomal amphotericin B for candidaemia and invasivecandidosis: a phase III randomised double-blind trial. Lancet 2007 May 5;369(9572):1519-27.

4. Pappas PG, Rotstein CM, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007 Oct 1;45(7):883-93.

Clinical Infectious Diseases 2004; 39:1407–16.

Study Design

• Randomized, double-blind Phase III study• 72 centers in the US and Canada• Patient population:

– HCT candidates ≥ 6 months of age– Autologous HCT for hematologic malignancies only

Statistical Plan and Data Analysis

• Objective: Assess non-inferiority of micafungin tofluconazole over a difference of 10%

• Primary endpoint: “treatment success”– Absence of suspected, proven, or probable invasive fungal

infection through the end of prophylaxis period– Absence of a proven or probable invasive fungal infection through

the end of the 4-week post-treatment period

• Definitions– Suspected: persistent fevers (≥ 100.4°F or ≥ 38°C) during

neutropenia despite 96 hours of broad spectrum antibacterial therapy

– Proven and Probable: criteria established by BAMSG

micafungin(n=425)

253 (60%)

39 (9%)

203 (48%)

220 (52%)

127 (30%)

94 (22%)

fluconazole(n=457)

274 (60%)

45 (10%)

201 (44%)

256 (56%)

152 (33%)

104 (23%)

Male gender

Age < 16 years

Syngeneic/autologous

Allogeneic

High risk

Low risk

Demographics882 patients received at least one dose

micafungin(n=425)

178 (42%)

(n=386)104 (27%)83 (22%)46 (12%)48 (12%)

(n=39)15 (39%)

7 (18%)

fluconazole(n=457)

187 (41%)

(n=412)104 (25%)90 (22%)62 (15%)54 (13%)

(n=45)11 (24%)12 (27%)

Active underlying disease

AdultsNHLMM AMLCML

PediatricALLAML

Underlying Disease

Treatment success

Treatment difference

micafungin

340 / 425 (80%)

+6.5% (95% CI, 0.9% to 12%)

fluconazole

336 / 457 (73.5%)

P=0.03 micafungin compared to fluconazole

Results: Study Endpoints

Use of empirical antifungal therapy

micafungin

64 / 425 (15.1%)

fluconazole

98 / 457 (21.4%)

P=0.018 micafungin compared to fluconazole


Breakthrough fungal infection

Aspergillus *

Proven

Probable

Candida

Fusarium

Zygomycetes

Death

Death due to fungal infection

micafungin

7 / 425 (1.6%)

1

0

1

4

1

1

18 / 425 (4.2%)

1 (Zygomycetes)

fluconazole

11 / 457 (2.4%)

7

4

3

2

2

0

26 / 457 (5.7%)

2 (Pulmonaryaspergillosis)

* P=0.07 Micafungin compared to Fluconazole


micafungin(n=425)

80 (18.8%)

14 (3.3%)

13 (3.1%)

9 (2.1%)

3 (0.7%)

4 (0.9%)

fluconazole(n=457)

74 (16.2%)

13 (2.8%)

6 (1.3%)

3 (0.7%)

8 (1.8%)

10 (2.2%)

Serious Adverse Eventsother than death

Sepsis

Fever

Hypotension

Dyspnea

Related to Study Treatment

Serious Adverse Events

Prophylaxis Study: Treatment Conclusions• Micafungin demonstrated a greater overall

treatment difference compared with fluconazolefor antifungal prophylaxis during the neutropenicphase of HSCT– Statistically significantly overall higher treatment

success rate– Less empirical antifungal therapy– Fewer breakthrough infections with Aspergillus

• The first randomized clinical trial to demonstrate efficacy of an echinocandin for prophylaxis inneutropenic hosts

Kuse ER et al. Lancet 2007.

Micafungin100 mg QD

LiposomalAmphotericin B

3 mg/kg QD

Patient Characteristics (ITT)Candidaemia ± Invasive Candidiasis MICA 100 QD vs. L-AmB 3 QD

MicafunginN= 264

L-AmBN= 267

ICU 135 (51%) 135 (51%)Respirator 89 (34%) 99 (37%)CVC 223 (85%) 241 (80%)Dialysis 34 (13%) 23 (9%)Neutropenia 34 (13%) 28 (11%)


Overall Survival (ITT)Candidaemia ± Invasive Candidiasis MICA 100 QD vs. L-AmB 3 QD

Micafungin

L-AmB

Prop

ortio

nSu

rviv

ing

1.00

0.75

0.50

0.25

0.00

0 25 50 75 100 125 150 175Day


Overall Treatment Successby Neutropenic Status

Candidaemia ± Invasive Candidiasis MICA 100 QD vs. L-AmB 3 QD

Trea

tmen

t suc

cess

rate

(%)

*Adjusted for neutropenic statusmITT = received at least 1 dose and had confirmed candidiasis

247 247 215 22232 25

Difference in proportions: 4.5% (95% CI: –3.5 to 12.4)* MICA

L-AmB

n =

74.1

59.4

76.369.6

56.0

71.2

0

20

40

60

80

100

Overall Neutropenic Non-neutropenic


Treatment Success by Candida SpeciesCandidaemia ± Invasive Candidiasis MICA 100 QD vs. L-AmB 3 QD

Trea

tmen

t suc

cess

rate

(%)

247 247 102 110 30 19 66 62 42 38 9 10Any

Candidaspecies

C. albicans C. glabrata C. tropicalis C. parapsilosis C. krusei

mITT = received at least 1 dose and had confirmed candidiasis

74.1 76.5

63.372.7

78.6

55.6

69.6 68.263.2 67.7 71.1

60.0

0

20

40

60

80

100 MICA L-AmB

n =


Risk Factors for Failure –Multivariate Logistic Regression

Candidaemia ± Invasive Candidiasis MICA 100 QD vs. L-AmB 3 QD

Horn D et al. ECCMID 2008; Poster 1024.

Glomerular Filtration RateCandidaemia ± Invasive Candidiasis MICA 100 QD vs. L-AmB 3 QD

*p < 0.01** p < 0.001

Micafungin L-AmB

****

*


Baseline Week 1 Week 2 EoT0

20

40

60

80

100

120

140

160

180

ml/m

in*1

.73m

2

*p < 0.01**p < 0.001

** ***

Micafungin100 mg QD

Caspofungin70/50 mg QD

Micafungin150 mg QD

Pappas PG et al. Clin Infect Dis 2007.

Time to Negative Blood CultureCandidaemia ± Invasive Candidiasis MICA 100 QD vs. MICA 150 QD

vs. CAS 70/50 QD

Time on Study (Days)

Prop

ortio

n M

ycol

ogic

ally

Erad

icat

ed (%

)

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40 45 50 55 60

MICAFUNGIN 100 mgMICAFUNGIN 150 mgCASPOFUNGIN


Overall MortalityCandidaemia ± Invasive Candidiasis MICA 100 QD vs. MICA 150 QD

vs. CAS 70/50 QD

Time on Study (Days)

Prop

ortio

n Su

rviv

ing

(%)

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110

MICAFUNGIN 100 mgMICAFUNGIN 150 mgCASPOFUNGIN


Overall Treatment Success by Neutropenic StatusCandidaemia ± Invasive Candidiasis

76.481.8

75.771.4

52.9

73.172.363.6

72.9

0

20

40

60

80

100

22 169 18217 11 177Non-neutropenicNeutropenic

Trea

tmen

t suc

cess

rate

(%)

191 199 188Overall

*95% CI –9.3–7.8; †95% CI –4.4–12.3Adjusted for APACHE II score

†

*

n =

MICA 100 MICA 150 CASPO 70→50


Treatment Success by Candida Species (mITT)Candidaemia ± Invasive Candidiasis

77.2 75.0

85.7

67.7

75.9 75.069.6 71.6

88.2

60.6

71.4

62.5

73.5 71.166.7

75.0

64.3

75.0

0

10

20

30

40

50

60

70

80

90

100

Trea

tmen

t suc

cess

rate

(%)

C. albicans Any non- C. glabrata C. tropicalis C. parapsilosis C. kruseialbicans

p = NS for all comparisons.

p = 0.07

MICA 100 MICA 150 CASPO 70→50

n = 92 102 83 104102 114 28 34 33 31 33 32 29 21 42 8 8 4


Risk Factors for Failure –Multivariate Logistic Regression

Candidaemia ± Invasive Candidiasis MICA 100 QD vs. MICA 150 QD vs. CAS 70/50 QD

Horn D et al. ECCMID 2008; Poster 1024.

Safety

Hepatic function laboratory AEs suspected of being treatment-related

Treatment setting Invasive candidiasis (Pappas et al.)2

Invasive candidiasis(Kuse et al.)3

Treatment group MICA CASP MICA L-AmBDaily dose 100 mg 70/50 mg 100 mg 3 mg/kgPatients, n 200 193 316 321Adverse event (%; adults & children combined)AST increased 0.5 0.5 2.2 0.9ALT increased 0.5 1.6 1.6 0.3

Alk. phos. increased 3.5 2.6 1.9 0.9

Bilirubin increased 0 0 2.5 2.8

Alk. phos.:alkaline phosphatase; CASP: caspofungin; L-Amb: liposomal amphotericin B; MICA: micafungin; ALT: alanine aminotransferase; AST: aspartate aminotransferase

1. Astellas Pharma Europe Ltd. Data on file. February 2008; 2. Pappas PG et al. CID 2007; 45:883–933.. Kuse ER et al. Lancet 2007; 369:1519–27;

Frequency of changes in hepatic lab values: Pooled micafungin clin. database (n = 3,028)

Cornely OA et al. 47th ICAAC (2007)

ALT: alanine aminotransferase; AST: aspartate aminotransferase; EOT: end of treatment ULN: upper limit of normal; normal: ≤ ULN; high > ULNIncrease is measured as ≥ ULN at EOT

Patie

nts

(%)

50

40

30

20

10

01,654 1,654 1,102 1,753 1,753 990

Normal at baseline to > ULN at EOT

Normal at baseline to ≥ 2.5 x ULN at EOTHigh at baseline to normal at EOT

AST ALTn =

Pooled Analysis of Safety for Micafungin

Treatment duration (days to first occurrence)1–14 15–28 29–42 >42 OverallAE

n=3028 n=1341 n=348 n=168 N=3028

Nausea 78 (2.6) 5 (0.4) 0 (0.0) 1 (0.6) 84 (2.8)

Blood AP increased 68 (2.2) 9 (0.7) 4 (1.1) 0 (0.0) 81 (2.7)

Phlebitis 69 (2.3) 5 (0.4) 0 (0.0) 1 (0.6) 75 (2.5)

Vomiting 71 (2.3) 3 (0.2) 1 (0.3) 0 (0.0) 75 (2.5)

AST increased 54 (1.8) 11 (0.8) 4 (1.1) 2 (1.2) 71 (2.3)

Hypokalemia 54 (1.8) 8 (0.6) 1 (0.3) 0 (0.0) 63 (2.1)

Pyrexia 61 (2.0) 2 (0.1) 0 (0.0) 0 (0.0) 63 (2.1)

TRAE (≥2%) by Days of Exposure, n (%)

Cornely OA et al. ECCMID 2008; Poster 1023.


1–14 15–28 29–42AE

(n = 2,653) (n = 1,067) (n = 156)

Phlebitis 68 (2.6) 5 (0.5) 0 (0.0)

Nausea 65 (2.5) 5 (0.5) 0 (0.0)

Blood Alk. Phos. increased 60 (2.3) 6 (0.6) 3 (1.9)

Vomiting 63 (2.4) 3 (0.3) 0 (0.0)

AST increased 52 (2.0) 9 (0.8) 4 (2.6)

Pyrexia 57 (2.1) 2 (0.2) 0 (0.0)

Rash 53 (2.0) 3 (0.3) 0 (0.0)

Diarrhoea 52 (2.0) 2 (0.2) 1 (0.6)

Leukopenia 52 (2.0) 2 (0.2) 1 (0.6)

TRAE (≥2%) by Days of Exposure, n (%)


OverallAdults, non-

elderly(16–64 years)

Adults, elderly (≥ 65 years)

Paediatrics(< 16 years)AE

(n = 2,653) (n = 2,091) (n = 336) (n = 226)Phlebitis 73 (2.8) 64 (3.1) 6 (1.8) 3 (1.3)Nausea 70 (2.6) 62 (3.0) 7 (2.1) 1 (0.4)Blood Alk. Phos. increased 69 (2.6) 56 (2.7) 9 (2.7) 4 (1.8)

Vomiting 66 (2.5) 55 (2.6) 8 (2.4) 3 (1.3)AST increased 65 (2.5) 61 (2.9) 2 (0.6) 2 (0.9)Pyrexia 59 (2.2) 49 (2.3) 7 (2.1) 3 (1.3)Hypokalaemia 58 (2.2) 41 (2.0) 9 (2.7) 8 (3.5)Rash 56 (2.1) 50 (2.4) 2 (0.6) 4 (1.8)Diarrhoea 55 (2.1) 46 (2.2) 6 (1.8) 3 (1.3)Leukopenia 55 (2.1) 53 (2.5) 1 (0.3) 1 (0.4)ALT increased 52 (2.0) 45 (2.2) 3 (0.9) 4 (1.8)

TRAE (≥ 2%) by Age Group



Schlußfolgerungen• Micafungin ist in verschiedenen Indikationen geprüft

worden.• Es zeigte sich eine Nicht-Unterlegenheit gegenüber dem

jeweiligen Therapiestandard:Indikation Therapiestandard

Prophylaxe nach SCT Fluconazol

Candida-Ösophagitis Fluconazol

Candidämie und invasive Candidose

Caspofungin / Liposomales Amphotericin B

• Die Verträglichkeit war dem jeweiligen Standard mindestens vergleichbar.

• Die MTD liegt >=8mg/kg.

micafungin klinische studien bei erwachsenen

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