Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection

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http://www.nejm.org/doi/full/10.1056/NEJMoa1014463?query=TOC &

Original Article

Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection

E. Sherman, M.D., Ph.D., L. Flamm, M.D., Nezam H. Afdhal, M.D.,

R. , M.D., Mark S. Sulkowski, M.D., T. Everson, M.D.,

W. Fried, M.D., Adler, M.D., Ph.D., Hendrik W. Reesink, M.D.,

Ph.D., Marie , Ph.D., Abdul J. Sankoh, Ph.D., Nathalie Adda, M.D.,

S. Kauffman, M.D., Ph.D., , M.D., I. , M.D.,

Ph.D., and Fred Poordad, M.D. for the ILLUMINATE Study Team

N Engl J Med 2011; 365:1014-1024September 15, 2011

Background

Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often

need 48 weeks of peginterferon–ribavirin treatment for a sustained virologic

response. We designed a noninferiority trial (noninferiority margin, −10.5%)

to compare rates of sustained virologic response among patients receiving two

treatment durations.

Methods

We enrolled patients with chronic infection with HCV genotype 1 who had not

previously received treatment. All patients received telaprevir at a dose of 750

mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and

ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed

by peginterferon–ribavirin. Patients who had an extended rapid virologic

response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned

after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more

weeks (T12PR48). Patients without an extended rapid virologic response were

assigned to T12PR48.

Results

Of the 540 patients, a total of 352 (65%) had an extended rapid virologic

response. The overall rate of sustained virologic response was 72%. Among the

322 patients with an extended rapid virologic response who were randomly

assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the

T12PR48 group had a sustained virologic response (absolute difference, 4

percentage points; 95% confidence interval, −2 to 11), establishing

noninferiority. Adverse events included rash (in 37% of patients, severe in 5%)

and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was

based on adverse events in 18% of patients overall, as well as in 1% of patients

(all of whom were randomly assigned) in the T12PR24 group and 12% of the

patients randomly assigned to the T12PR48 group (P<0.001).

Conclusions

In this study, among patients with chronic HCV infection who had not received

treatment previously, a regimen of peginterferon–ribavirin for 24 weeks, with

telaprevir for the first 12 weeks, was noninferior to the same regimen for 48

weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended

rapid virologic response achieved in nearly two thirds of patients. (Funded by

Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number,

NCT00758043.)

Supported by Vertex Pharmaceuticals and Tibotec.

Disclosure forms provided by the authors are available with the full text of

this article at NEJM.org.

We thank the study coordinators, nurses, and patients involved in the study; the

contract research organizations ICON and I3 for coordinating and implementing

various aspects of the study; Alam, M.D. (a former employee of Vertex

Pharmaceuticals), for his contribution to the study design; and various Vertex

Pharmaceuticals employees: Kleber for clinical project management; Tara

L. Kieffer, Ph.D., and Doug J. Bartels, Ph.D., for virology analyses;

Abensohn and Pamela Ryley for statistical programming; Concetta Marfella, Ph.D.,

for checking data accuracy and creating figures; and Mrudula Donepudi, Ph.D.,

for medical writing, editorial assistance, and coordination.

Source Information

From the Division of Digestive Diseases, University of Cincinnati College of

Medicine, Cincinnati (K.E.S.); the Division of Hepatology, Northwestern

University Medical School, Chicago (S.L.F.); the Division of Gastroenterology

and Hepatology, Beth Israel Deaconess Medical Center, Boston (N.H.A.); the

Section of Hepatology, University of Florida, Gainesville (D.R.N.); the Viral

Hepatitis Center, s Hopkins University School of Medicine, Baltimore

(M.S.S.); the Section of Hepatology, Division of Gastroenterology and

Hepatology, University of Colorado School of Medicine Denver, Aurora (G.T.E.);

the UNC Liver Center, University of North Carolina, Chapel Hill (M.W.F.); the

Department of Gastroenterology and Hepatopancreatology, Erasme Hospital

Brussels, Brussels (M.A.); the Department of Hepatology, Academic Medical Center

of the University of Amsterdam, Amsterdam (H.W.R.); Vertex Pharmaceuticals,

Cambridge, MA (M.M., A.J.S., N.A., R.S.K., S.G., C.I.W.); and the Department of

Medicine, Cedars–Sinai Medical Center, Los Angeles (F.P.).

Address reprint requests to Dr. Sherman at the Division of Digestive Diseases,

University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati,

OH 45267-0595, or at shermake@....

The ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir)

study investigators are listed in the Supplementary Appendix, available at

NEJM.org

[Guest guest]

http://www.nejm.org/doi/full/10.1056/NEJMoa1014463?query=TOC &

Original Article

Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection

E. Sherman, M.D., Ph.D., L. Flamm, M.D., Nezam H. Afdhal, M.D.,

R. , M.D., Mark S. Sulkowski, M.D., T. Everson, M.D.,

W. Fried, M.D., Adler, M.D., Ph.D., Hendrik W. Reesink, M.D.,

Ph.D., Marie , Ph.D., Abdul J. Sankoh, Ph.D., Nathalie Adda, M.D.,

S. Kauffman, M.D., Ph.D., , M.D., I. , M.D.,

Ph.D., and Fred Poordad, M.D. for the ILLUMINATE Study Team

N Engl J Med 2011; 365:1014-1024September 15, 2011

Background

Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often

need 48 weeks of peginterferon–ribavirin treatment for a sustained virologic

response. We designed a noninferiority trial (noninferiority margin, −10.5%)

to compare rates of sustained virologic response among patients receiving two

treatment durations.

Methods

We enrolled patients with chronic infection with HCV genotype 1 who had not

previously received treatment. All patients received telaprevir at a dose of 750

mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and

ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed

by peginterferon–ribavirin. Patients who had an extended rapid virologic

response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned

after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more

weeks (T12PR48). Patients without an extended rapid virologic response were

assigned to T12PR48.

Results

Of the 540 patients, a total of 352 (65%) had an extended rapid virologic

response. The overall rate of sustained virologic response was 72%. Among the

322 patients with an extended rapid virologic response who were randomly

assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the

T12PR48 group had a sustained virologic response (absolute difference, 4

percentage points; 95% confidence interval, −2 to 11), establishing

noninferiority. Adverse events included rash (in 37% of patients, severe in 5%)

and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was

based on adverse events in 18% of patients overall, as well as in 1% of patients

(all of whom were randomly assigned) in the T12PR24 group and 12% of the

patients randomly assigned to the T12PR48 group (P<0.001).

Conclusions

In this study, among patients with chronic HCV infection who had not received

treatment previously, a regimen of peginterferon–ribavirin for 24 weeks, with

telaprevir for the first 12 weeks, was noninferior to the same regimen for 48

weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended

rapid virologic response achieved in nearly two thirds of patients. (Funded by

Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number,

NCT00758043.)

Supported by Vertex Pharmaceuticals and Tibotec.

Disclosure forms provided by the authors are available with the full text of

this article at NEJM.org.

We thank the study coordinators, nurses, and patients involved in the study; the

contract research organizations ICON and I3 for coordinating and implementing

various aspects of the study; Alam, M.D. (a former employee of Vertex

Pharmaceuticals), for his contribution to the study design; and various Vertex

Pharmaceuticals employees: Kleber for clinical project management; Tara

L. Kieffer, Ph.D., and Doug J. Bartels, Ph.D., for virology analyses;

Abensohn and Pamela Ryley for statistical programming; Concetta Marfella, Ph.D.,

for checking data accuracy and creating figures; and Mrudula Donepudi, Ph.D.,

for medical writing, editorial assistance, and coordination.

Source Information

From the Division of Digestive Diseases, University of Cincinnati College of

Medicine, Cincinnati (K.E.S.); the Division of Hepatology, Northwestern

University Medical School, Chicago (S.L.F.); the Division of Gastroenterology

and Hepatology, Beth Israel Deaconess Medical Center, Boston (N.H.A.); the

Section of Hepatology, University of Florida, Gainesville (D.R.N.); the Viral

Hepatitis Center, s Hopkins University School of Medicine, Baltimore

(M.S.S.); the Section of Hepatology, Division of Gastroenterology and

Hepatology, University of Colorado School of Medicine Denver, Aurora (G.T.E.);

the UNC Liver Center, University of North Carolina, Chapel Hill (M.W.F.); the

Department of Gastroenterology and Hepatopancreatology, Erasme Hospital

Brussels, Brussels (M.A.); the Department of Hepatology, Academic Medical Center

of the University of Amsterdam, Amsterdam (H.W.R.); Vertex Pharmaceuticals,

Cambridge, MA (M.M., A.J.S., N.A., R.S.K., S.G., C.I.W.); and the Department of

Medicine, Cedars–Sinai Medical Center, Los Angeles (F.P.).

Address reprint requests to Dr. Sherman at the Division of Digestive Diseases,

University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati,

OH 45267-0595, or at shermake@....

The ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir)

study investigators are listed in the Supplementary Appendix, available at

NEJM.org