Tags

Type your tag names separated by a space and hit enter

Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.
Lancet. 2014 Aug 02; 384(9941):403-13.Lct

Abstract

BACKGROUND

Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection.

METHODS

In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782.

FINDINGS

Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration.

INTERPRETATION

Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin.

FUNDING

Janssen Infectious Diseases-Diagnostics.

Authors+Show Affiliations

Weill Cornell Medical College, New York, NY, USA. Electronic address: imj2001@med.cornell.edu.Kirby Institute, University of New South Wales, Darlinghurst, NSW, Australia.Queen Mary, University of London, London, UK.University of North Carolina at Chapel Hill, NC, USA.Institutul de Boli Infectioase, Bucharest, Romania.Smolensk Regional Clinical Hospital, Smolensk State Medical Academy, Smolensk Oblast, Russia.Vinnytsia National Medical University, Vinnytsia, Ukraine.Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy.Janssen Infectious Diseases, Beerse, Belgium.Janssen Infectious Diseases, Beerse, Belgium.Janssen Research and Development, Beerse, Belgium.Janssen Research and Development, Titusville, NJ, USA.Janssen Research and Development, Titusville, NJ, USA.Janssen Global Services, High Wycombe, UK.Janssen Infectious Diseases, Beerse, Belgium.Janssen Infectious Diseases, Beerse, Belgium.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24907225

Citation

Jacobson, Ira M., et al. "Simeprevir With Pegylated Interferon Alfa 2a Plus Ribavirin in Treatment-naive Patients With Chronic Hepatitis C Virus Genotype 1 Infection (QUEST-1): a Phase 3, Randomised, Double-blind, Placebo-controlled Trial." Lancet (London, England), vol. 384, no. 9941, 2014, pp. 403-13.
Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384(9941):403-13.
Jacobson, I. M., Dore, G. J., Foster, G. R., Fried, M. W., Radu, M., Rafalsky, V. V., Moroz, L., Craxi, A., Peeters, M., Lenz, O., Ouwerkerk-Mahadevan, S., De La Rosa, G., Kalmeijer, R., Scott, J., Sinha, R., & Beumont-Mauviel, M. (2014). Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet (London, England), 384(9941), 403-13. https://doi.org/10.1016/S0140-6736(14)60494-3
Jacobson IM, et al. Simeprevir With Pegylated Interferon Alfa 2a Plus Ribavirin in Treatment-naive Patients With Chronic Hepatitis C Virus Genotype 1 Infection (QUEST-1): a Phase 3, Randomised, Double-blind, Placebo-controlled Trial. Lancet. 2014 Aug 2;384(9941):403-13. PubMed PMID: 24907225.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. AU - Jacobson,Ira M, AU - Dore,Gregory J, AU - Foster,Graham R, AU - Fried,Michael W, AU - Radu,Monica, AU - Rafalsky,Vladimir V, AU - Moroz,Larysa, AU - Craxi,Antonio, AU - Peeters,Monika, AU - Lenz,Oliver, AU - Ouwerkerk-Mahadevan,Sivi, AU - De La Rosa,Guy, AU - Kalmeijer,Ronald, AU - Scott,Jane, AU - Sinha,Rekha, AU - Beumont-Mauviel,Maria, Y1 - 2014/06/04/ PY - 2014/6/8/entrez PY - 2014/6/8/pubmed PY - 2014/8/19/medline SP - 403 EP - 13 JF - Lancet (London, England) JO - Lancet VL - 384 IS - 9941 N2 - BACKGROUND: Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection. METHODS: In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group). Treatment duration was 24 weeks or 48 weeks in the simeprevir group according to criteria for response-guided therapy (ie, HCV RNA <25 IU/mL [undetectable or detectable] at week 4 and <25 IU/mL undetectable at week 12) and 48 weeks in the placebo group. Patients, study personnel, and the sponsor were masked to the treatment group assignment. The primary efficacy endpoint was sustained virological response 12 weeks after the planned end of treatment (SVR12) and was assessed with an intention-to-treat analysis. The results of the primary analysis (week 60) are presented for safety and SVR12. This trial is registered with ClinicalTrials.gov, number NCT01289782. FINDINGS: Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29·3% [95% CI 20·1-38·6; p<0·0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration. INTERPRETATION: Simeprevir once daily with peginterferon alfa 2a and ribavirin shortens therapy in treatment-naive patients with HCV genotype 1 infection without worsening the adverse event profiles associated with peginterferon alfa 2a plus ribavirin. FUNDING: Janssen Infectious Diseases-Diagnostics. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/24907225/Simeprevir_with_pegylated_interferon_alfa_2a_plus_ribavirin_in_treatment_naive_patients_with_chronic_hepatitis_C_virus_genotype_1_infection__QUEST_1_:_a_phase_3_randomised_double_blind_placebo_controlled_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(14)60494-3 DB - PRIME DP - Unbound Medicine ER -