background and study design

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Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark. 04/25/09

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Hemoglobin Decline Associated with SVR Among HCV G1-Infected

Persons: Analysis from the IDEAL Study

Sulkowski MS, Shiffman ML, Afdhal N, Reddy R, McCone J, Lee WM, Herrine SK, Harrison S, Deng W, Brass CA, Koury K, Noviello S, Albrecht

JK, McHutchison JG on behalf of the IDEAL Study Team

EASL 2009

Copenhagen, DenmarkApril 25, 2009

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Background and Study Design

Treatment-Related Anemia (30% of patients) Hemolysis (RBV) and bone marrow suppression (PegIFN) RBV dose reductions and treatment discontinuations Erythropoietin (EPO) supplementation

Maintains RBV dose levels and improves patient quality of life

Study objectives To test the hypothesis that treatment related hemoglobin decline are

associated with virologic response during treatment with peginterferon and ribavirin therapy

To assess the relationship of anemia, epoetin alfa use and virologic response during treatment with peginterferon and ribavirin

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Study Schema and Treatment Regimens

N = 1019 N = 1019 PEG-IFN alfa-2bPEG-IFN alfa-2b 1.5 1.5 μμg/kg/wk g/kg/wk

+ RBV 800-1400 mg/d + RBV 800-1400 mg/d××48 weeks48 weeks

N = 1019 N = 1019 PEG-IFN alfa-2bPEG-IFN alfa-2b 1.5 1.5 μμg/kg/wk g/kg/wk


N N = 1035= 1035PEG-IFN alfa-2a 180 PEG-IFN alfa-2a 180 μμg/wk g/wk

+ RBV 1000-1200 mg/d+ RBV 1000-1200 mg/d××48 weeks48 weeks

N N = 1035= 1035PEG-IFN alfa-2a 180 PEG-IFN alfa-2a 180 μμg/wk g/wk

+ RBV 1000-1200 mg/d+ RBV 1000-1200 mg/d××48 weeks48 weeks

N = 1016N = 1016 PEG-IFN alfa-2b 1.0 PEG-IFN alfa-2b 1.0 μμg/kg/wk g/kg/wk


N = 1016N = 1016 PEG-IFN alfa-2b 1.0 PEG-IFN alfa-2b 1.0 μμg/kg/wk g/kg/wk


ScreeningScreeningScreeningScreening

Follow-up24 weeksFollow-up24 weeks



2 4 12 24 48 4 12 24

Stratified by baseline viral load (> or ≤ 600,000 IU/mL) and race (African American)Stratified by baseline viral load (> or ≤ 600,000 IU/mL) and race (African American) Standard response stop criteria applied at weeks 12 (no EVR) and 24 (HCV RNA-positive) Standard response stop criteria applied at weeks 12 (no EVR) and 24 (HCV RNA-positive)

HCV RNAa

a LLQ <27 IU/mL (COBAS TaqMan; Roche)LLQ <27 IU/mL (COBAS TaqMan; Roche)

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Anemia and EPO Use

Anemia Protocol defined as Hb level <10 g/dL

RBV dose reductions PEG-IFN alfa-2b + RBV arms

Full dose 800-1200 mg decrease by 200 mg (first dose reduction) then by 200 mg (second dose reduction)

Full dose 1400 mg decrease by 400 mg (first dose reduction) then by 200 mg (second dose reduction)

PEG-IFN alfa-2a + RBV arm Full dose 1000-1200 mg decrease to 600 mg (product insert)

EPO use criteria Permitted in patients with Hb level <10 g/dL with simultaneous RBV

dose reduction At the discretion of investigator and patient Not provided by study

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Subject Characteristics: Hgb DeclineHb Decline ≤3 g/dL

n=771Hb Decline >3 g/dL

n=2252P

values

Male 47% 64% <.001

Race

Caucasian 63% 75% <.001

African American/Black 27% 15% <.001

Age, y, mean (SD) 45.6 (8.6) 48.2 (7.7) <.001

Weight, kg, mean (SD) 82.0 (16.9) 83.9 (16.1) .007

Baseline HCV RNA >600,000 IU/mL 79% 83% .023

Steatosis

Absence 40% 35% .011

Presence 56% 60% .038

METAVIR fibrosis score

F0/1/2 88% 83% .002

F3/4 8% 12% .004

Baseline Hb conc, g/dL, mean (SD) 14.3 (1.2) 15.2 (1.2) <.001

Baseline Cr, μmol/L, mean (SD) 70.6 (14.2) 75.4 (14.0) <.001

Baseline estimated Cr clearance,a mL/min, mean (SD) 123.3 (34.0) 118.0 (30.8) <.001

Initial RBV dose (mg/kg/d), mean (SD) 13.4 (1.6) 13.4 (1.5) .640

Hb <10 g/dL during treatment 5% 37% <.001

EPO Use 3% 20% <.001

a Using Cockcroft-Gault equation. Cr = creatinine.

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SVR and Maximum Hb DeclineP

roba

bilit

y of

SV

R

0 .0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

M aximum Drop in Hemoglobin (g/dL) From Baseline

0 1 2 3 4 5 6 7 8 9 10

M oving Average (10 % )

Fitted: P = 1/(1+exp(1.1594 - 0.1882*x))

Sustained V iro logic Respo nse: A ll T reated Patients (N = 3023)

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EOTEOTaa and SVR and SVRbb Responses by Responses by Decline in HbDecline in Hb

41.8

29.9

61.6

43.7

010203040506070

EOT SVR

≤ 3 g/dL

> 3 g/dL

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aEOT rates for >3 g/dL = 61.6% (1386/2250) and ≤3 g/dL = 41.8% (323/773); P < 0.0001. bSVR rates for >3 g/dL = 43.7% (984/2250) and ≤3 g/dL = 29.9% (231/773); P < 0.0001.

Hemoglobin Decline

Pat

ien

ts, %

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Subject Characteristics:Anemia/EPO

No Anemia (A) n = 2158

Anemia/No EPO (B)

n = 416

Anemia/EPO (C) n = 449

PA vs B

P A vs C

PB vs C

Male 67% 38% 44% <.0001 <.0001 .0667

Race

Caucasian 72% 68% 72% .0958 .8048 .2689

African American/Black 17% 21% 20% .0595 .2422 .5704

Age, y, mean (SD) 46.8 (7.9) 48.7 (8.2) 50.2 (7.6) <.0001 <.0001 .0040

Weight, kg, mean (SD) 84.7 (16.1) 79.8 (16.9) 80.5 (15.9) <.0001 <.0001 .5281

Baseline HCV RNA >600,000 IU/mL 83% 77% 84% .0048 .3971 .0053

Steatosis

Absence 36% 38% 38% .3415 .4020 .9134

Presence 60% 58% 55% .6161 .0528 .2826

METAVIR fibrosis score

F0/1/2 85% 85% 80% .6419 .0021 .0614

F3/4 10% 12% 13% .2175 .0675 .6896

Baseline Hb conc, g/dL, mean (SD) 15.2 (1.2) 14.3 (1.1) 14.3 (1.2) <.0001 <.0001 .4108

Baseline Cr, μmol/L, mean (SD) 74.5 (14.1) 72.7 (13.5) 74.1 (15.1) .0185 .6731 .1384

Baseline estimated Cr clearance,a mL/min, mean (SD)

123.3 (31.6) 110.2 (30.8) 108.9 (28.9) <.0001 <.0001 .4976

a Using Cockcroft-Gault equation. Cr = creatinine.

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Median and Mean RBV Exposure (mg/kg/d) Higher in PEG-IFN alfa-2a Arm Than in alfa-2b Arms

PEG-IFN alfa-2a+ RBV

a P < .001 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2a + RBV and for PEG-IFN alfa-2b 1.0 + RBV vs PEG-IFN alfa-2a + RBV; P = .012 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2b 1.0 + RBV. b P < .001 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2a + RBV; P = .002 for PEG-IFN alfa-2b 1.0 + RBV vs PEG-IFN alfa-2a + RBV; P = .270 PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2b 1.0 + RBV. c P < .001 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2a + RBV; P = .001 for PEG-IFN alfa-2b 1.0 + RBV vs PEG-IFN alfa-2a + RBV; P = .616 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2b 1.0 + RBV.

Treatment

No Anemiaa Anemia/No EPOb Anemia/EPOc

PEG-IFN alfa-2b 1.0 + RBV

PEG-IFN alfa-2b 1.5 + RBV

Mean (SD)

12.6 (1.3) 11.5 (1.7) 11.7 (2.0)

Mean (SD)

12.8 (1.2) 11.8 (1.7) 11.8 (1.4)

Mean (SD)

13.4 (2.0) 12.6 (2.7) 12.5 (2.3)

0

5

10

15

20

25

Med

ian

RB

V E

xpo

sure

, m

g/k

g/d

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Early Anemia Treated with EPO Resulted in Higher SVR Rate*

Onset of AnemiaAnemia/No EPO

% (n/N)

Anemia/EPO

% (n/N)P-value

≤4 weeks of treatment 23.5% (19/81) 43.0% (58/135) .004

>4-8 weeks of treatment 29.0% (18/62) 47.6% (49/103) .019

>8-12 weeks of treatment 51.6% (32/62) 47.4% (27/57) .644

>12 weeks of treatment 61.6% (130/211) 57.8% (89/154) .462

*P<0.001 for early anemia (≤8 weeks of treatment).

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Lower Discontinuation Rates in Early Anemia Treated with EPO

Onset of AnemiaAnemia/No EPO

% (n/N)

Anemia/EPO

% (n/N)P-value

≤4 weeks of treatment 6% (5/81) <1% (1/135) .019

>4-8 weeks of treatment 29% (18/62) 2% (2/103) <.001

>8-12 weeks of treatment 6% (4/62) 14% (8/57) .170

>12 weeks of treatment 22% (46/211) 27% (42/154) .227

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Odds Ratios for SVR (EPO vs No EPO)Odds Ratios for SVR (EPO vs No EPO)12

Onset of Anemia Model Odds Ratio (95% CI) P-Value

Early (<=8 weeks) Unadjusteda 2.34 (1.49, 3.68) <0.001

Model 1b 3.52 (2.05, 6.03) <0.001

Model 2c 3.13 (1.86, 5.28) <0.001

Late (> 8 weeks) Unadjusteda 0.84 (0.58, 1.20) 0.336

Model 1b 0.95 (0.62, 1.45) 0.806

Model 2c 0.92 (0.61, 1.39) 0.699

All Anemic Subjects Unadjusteda 1.08 (0.82, 1.41) 0.591

Model 1b 1.35 (0.99, 1.84) 0.059

Model 2c 1.29 (0.96, 1.75) 0.097

aNo control for potentially confounding factors.bOdds ratio adjusted for all potentially confounding factors (age, gender, race, BMI, baseline viral load, fibrosis, steatosis, fasting glucose, ALT, hemoglobin, platelet count, ribavirin (mg/kg/day) assigned, genotype (1a, 1b), and body weight).cOdds ratio adjusted for factors related to outcome (stepwise variable selection procedure based on all anemic subjects: race, baseline viral load, fibrosis, steatosis, fasting glucose, and body weight).

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SafetyNo Anemia Anemiaa/ No EPO Anemiaa/EPO

Serious adverse events 9% 12% 14%Relevant adverse events, % Fatigue 64% 67% 74%

Anaemiab 9% 87% 97% Dyspnea/exertional dyspnea 19% 29% 33%

Cardiac events

Hypertension 4% 4% 4%

Increased blood pressure 1% <1% 1% Myocardial infarction <1% <1% <1% Coronary artery disease <1% <1% 0

Congestive heart failure 0 <1% <1% Angina pectoris <1% 0 0

Thromboembolic events

Pulmonary embolism <1% 0 <1%

Deep venous thrombosis <1% 0 1% Cerebrovascular accident 0 0 <1% Cerebral hemorrhage <1% 0 0

Cancer 1% <1% 1%a Anemia based on Hb conc <10 g/dL.b Anemia based on adverse event as reported by the investigator.

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Conclusions

Higher magnitude of Hb decline is associated with higher likelihood of SVR

EPO use was associated with higher SVR rates if anemia occurred in the first 8 weeks of treatment

No benefit of EPO use in patients who became anemic after 8 weeks of treatment

Magnitude of Hb decline may be a pharmacokinetic marker for efficacy of treatment and EPO may prevent treatment discontinuation in patients with early anemia

background and study design

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