title: Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomised, double-blind, non-inferiority phase 3 trial.
abstract: BACKGROUND
  We did a phase 3 study in previous non-responders with chronic hepatitis C virus (HCV) genotype 1 infection and compensated liver disease that related to the standard of care for these patients at the time this study was initiated. We investigated whether simeprevir is non-inferior in terms of efficacy to telaprevir, each in combination with peginterferon alfa-2a and ribavirin.
  
  
  METHODS
  We did this randomised, double-blind, phase 3 trial at 169 investigational sites in 24 countries. We enrolled adults (≥18 years) with chronic HCV genotype 1 infection, compensated liver disease, and plasma HCV RNA higher than 10 000 IU/mL who were null or partial responders during at least one previous course of peginterferon alfa-2a and ribavirin treatment. We randomly assigned (1:1) patients (stratified by HCV genotype 1 subtype [1a plus other/1b] and previous treatment response [partial or null]) to receive simeprevir (150 mg once a day) plus telaprevir placebo (three times a day 7-9 h apart) or telaprevir (750 mg three times a day) plus simeprevir placebo (once a day) in combination with peginterferon alfa-2a and ribavirin for 12 weeks followed by 36 weeks of peginterferon alfa-2a and ribavirin alone. The primary efficacy endpoint was sustained virological response 12 weeks after end of treatment (SVR12) in the intention-to-treat and the per-protocol population. We compared groups with the Cochran-Mantel-Haenszel test. We established a non-inferiority margin of 12%. Adverse events were reported descriptively. This trial is registered with ClinicalTrials.gov, number NCT01485991.
  
  
  RESULTS
  Patient screening began on Jan 19, 2012, and the last visit was on April 7, 2014. We included 763 patients (472 previous null responders [62%]). Simeprevir and peginterferon alfa-2a and ribavirin was non-inferior to telaprevir and peginterferon alfa-2a and ribavirin for SVR12 (54% [203/379] vs 55% [210/384]; difference -1·1%, 95% CI -7·8 to 5·5; p=0·0007). SVR12 was achieved in 70% (101/145) versus 68% (100/146) of previous partial responders and 44% (102/234) versus 46% (110/238) of previous null responders with simeprevir and peginterferon alfa-2a and ribavirin and telaprevir and peginterferon alfa-2a and ribavirin treatment, respectively. We recorded differences between treatment groups in simeprevir or telaprevir-related adverse events (69% [261/379] in the simeprevir group vs 86% [330/384] in the telaprevir group), serious adverse events (2% [8/379] vs 9% [33/384]), and adverse events leading to simeprevir or telaprevir discontinuation (2% [7/379] vs 8% [32/384]).
  
  
  CONCLUSIONS
  Simeprevir once a day with peginterferon alfa-2a and ribavirin was well tolerated in HCV genotype 1-infected previous non-responders and was non-inferior to telaprevir, thus providing an alternative treatment in areas of the world where all-oral HCV regimens are not available or accessible.
  
  
  BACKGROUND
  Janssen.
authors.affiliation: Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: rajender.reddy@uphs.upenn.edu.
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: Department of Medicine, JW Goethe University Hospital, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Hospices Civils de Lyon, INSERM U1052, Lyon 1 University, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Weiland
authors.affiliation: Warsaw Medical University and Hospital of Infectious Diseases, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Horban
authors.affiliation: Gastromedica Clinic, University Hospital St Spiridon, Iasi, Romania.
authors.forename: Carol
authors.initials: C
authors.lastname: Stanciu
authors.affiliation: CIPREC, Buenos Aires, Argentina.
authors.forename: Federico Guillermo
authors.initials: FG
authors.lastname: Villamil
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, University of Bologna and AOU Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Andreone
authors.affiliation: Storr Liver Unit, Westmead Hospital and Westmead Millennium Institute, Westmead, NSW, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dammers
authors.affiliation: Janssen Research and Development, Spring House, PA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Fu
authors.affiliation: Janssen Research and Development, Titusville, NJ, USA.
authors.forename: Darryl
authors.initials: D
authors.lastname: Kurland
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Sivi
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Verbinnen
authors.affiliation: Janssen Global Services, High Wycombe, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Scott
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jessner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D010919:Placebos / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D000069616:Simeprevir; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D016898:Interferon-alpha; D009842:Oligopeptides; D010919:Placebos; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; D000069616:Simeprevir; C100416:peginterferon alfa-2a