Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: A combined analysis of 3 phase 2/3 clinical trials

Michael P. Manns, Jonathan Mccone, Mitchell N. Davis, Lorenzo Rossaro, Eugene R Schiff, Mitchel L. Shiffman, Bruce Bacon, Marc Bourliere, Mark S. Sulkowski, Savino Bruno, Luis Balart, Jean Pierre Bronowicki, Paul Kwo, Fred Poordad, Franco Felizarta, K. Rajender Reddy, Frans A. Helmond, Heather L. Sings, Lisa D. Pedicone, Margaret BurroughsClifford A. Brass, Janice K. Albrecht, John M. Vierling

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background & Aims: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. Methods: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. Results: Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. Conclusions: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.

Original languageEnglish
Pages (from-to)707-719
Number of pages13
JournalLiver International
Volume34
Issue number5
DOIs
StatePublished - Jan 1 2014

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Phase III Clinical Trials
Ribavirin
Chronic Hepatitis C
Genotype
Safety
Dysgeusia
Therapeutics
Neutropenia
Anemia
peginterferon alfa-2b
N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
Standard of Care
Protease Inhibitors
Treatment Failure
Pharmaceutical Preparations
Nausea
Fatigue
Diarrhea
Hemoglobins
Neutrophils

Keywords

  • Antiviral therapy
  • Victrelis

ASJC Scopus subject areas

  • Hepatology

Cite this

Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1 : A combined analysis of 3 phase 2/3 clinical trials. / Manns, Michael P.; Mccone, Jonathan; Davis, Mitchell N.; Rossaro, Lorenzo; Schiff, Eugene R; Shiffman, Mitchel L.; Bacon, Bruce; Bourliere, Marc; Sulkowski, Mark S.; Bruno, Savino; Balart, Luis; Bronowicki, Jean Pierre; Kwo, Paul; Poordad, Fred; Felizarta, Franco; Reddy, K. Rajender; Helmond, Frans A.; Sings, Heather L.; Pedicone, Lisa D.; Burroughs, Margaret; Brass, Clifford A.; Albrecht, Janice K.; Vierling, John M.

In: Liver International, Vol. 34, No. 5, 01.01.2014, p. 707-719.

Research output: Contribution to journalArticle

Manns, MP, Mccone, J, Davis, MN, Rossaro, L, Schiff, ER, Shiffman, ML, Bacon, B, Bourliere, M, Sulkowski, MS, Bruno, S, Balart, L, Bronowicki, JP, Kwo, P, Poordad, F, Felizarta, F, Reddy, KR, Helmond, FA, Sings, HL, Pedicone, LD, Burroughs, M, Brass, CA, Albrecht, JK & Vierling, JM 2014, 'Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: A combined analysis of 3 phase 2/3 clinical trials', Liver International, vol. 34, no. 5, pp. 707-719. https://doi.org/10.1111/liv.12300
Manns, Michael P. ; Mccone, Jonathan ; Davis, Mitchell N. ; Rossaro, Lorenzo ; Schiff, Eugene R ; Shiffman, Mitchel L. ; Bacon, Bruce ; Bourliere, Marc ; Sulkowski, Mark S. ; Bruno, Savino ; Balart, Luis ; Bronowicki, Jean Pierre ; Kwo, Paul ; Poordad, Fred ; Felizarta, Franco ; Reddy, K. Rajender ; Helmond, Frans A. ; Sings, Heather L. ; Pedicone, Lisa D. ; Burroughs, Margaret ; Brass, Clifford A. ; Albrecht, Janice K. ; Vierling, John M. / Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1 : A combined analysis of 3 phase 2/3 clinical trials. In: Liver International. 2014 ; Vol. 34, No. 5. pp. 707-719.
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abstract = "Background & Aims: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. Methods: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. Results: Only two adverse events, anaemia and dysgeusia, occurred 20{\%} more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5{\%} greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. Conclusions: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.",
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AU - Manns, Michael P.

AU - Mccone, Jonathan

AU - Davis, Mitchell N.

AU - Rossaro, Lorenzo

AU - Schiff, Eugene R

AU - Shiffman, Mitchel L.

AU - Bacon, Bruce

AU - Bourliere, Marc

AU - Sulkowski, Mark S.

AU - Bruno, Savino

AU - Balart, Luis

AU - Bronowicki, Jean Pierre

AU - Kwo, Paul

AU - Poordad, Fred

AU - Felizarta, Franco

AU - Reddy, K. Rajender

AU - Helmond, Frans A.

AU - Sings, Heather L.

AU - Pedicone, Lisa D.

AU - Burroughs, Margaret

AU - Brass, Clifford A.

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AU - Vierling, John M.

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AB - Background & Aims: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies. Methods: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial. Results: Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts. Conclusions: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs.

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KW - Victrelis

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