title: A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN).
abstract: BACKGROUND
  Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs.
  
  
  OBJECTIVE
  To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD.
  
  
  METHODS
  Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed.
  
  
  METHODS
  Twenty-three ophthalmology departments in NHS hospitals.
  
  
  METHODS
  Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required.
  
  
  METHODS
  Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated.
  
  
  METHODS
  The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes.
  
  
  RESULTS
  Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses.
  
  
  CONCLUSIONS
  Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN92166560.
  
  
  BACKGROUND
  This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.
authors.affiliation: Centre for Experimental Medicine, Institute of Clinical Science, Queen's University Belfast, Belfast, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Chakravarthy
authors.affiliation: Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Harding
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Rogers
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Downes
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lotery
authors.affiliation: Health Economic Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Dakin
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Culliford
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Scott
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Nash
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Jodi
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Centre for Experimental Medicine, Institute of Clinical Science, Queen's University Belfast, Belfast, UK.
authors.forename: Alyson
authors.initials: A
authors.lastname: Muldrew
authors.affiliation: Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Sahni
authors.affiliation: Health Economic Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wordsworth
authors.affiliation: Wessex Institute, University of Southampton, Southampton, UK.
authors.forename: James
authors.initials: J
authors.lastname: Raftery
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Tunde
authors.initials: T
authors.lastname: Peto
authors.affiliation: Clinical Trials and Evaluation Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Barnaby C
authors.initials: BC
authors.lastname: Reeves
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000191:economics / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000191:economics / Q000627:therapeutic use*; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D003362:Cost-Benefit Analysis; D005260:Female; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab / Q000191:economics / Q000627:therapeutic use*; D013222:State Medicine / Q000191:economics; D006113:United Kingdom; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D014792:Visual Acuity / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D042442:Vascular Endothelial Growth Factors; D000068258:Bevacizumab; D000069579:Ranibizumab