Summary of the Main Design Features of the IVAN Trial

Feature Criteria
 
Objective
  • To estimate the relative effectiveness of two anti-VEGF drugs, i.e. Lucentis® (ranibizumab) and Avastin® (bevacizumab), on visual outcome in patients with neovascular age-related macular degeneration. Existing evidence of the benefit of anti-VEGF drugs compared to sham treatment precludes inclusion of a sham anti-VEGF arm.

  • To estimate the effectiveness of more frequent vs. less frequent anti-VEGF drug treatment in improving or maintaining visual function, with stringent criteria for restarting treatment to prevent visual acuity loss in patients receiving less frequent treatment.

  • To estimate the cost-effectiveness of the alternative treatment strategies outlined above.
 
Major Eligibility Criteria Inclusion criteria
 
  • Adults of either sex aged ≥50 years

  • Newly referred for the treatment of CNV caused by nAMD in the first or second eye

  • Corrected logMAR visual acuity (VAlogMAR) ≥25 letters read on a standard ETDRS chart

  • CNV involving the centre of the fovea
  Exclusion criteria
 
  • Corrected VAlogMAR <25 letters
  • Long standing CNV evidenced by the presence of fibrosis in excess of 50% of the total lesion

  • Presence of other active ocular disease causing concurrent vision loss, e.g. diabetic retinopathy

  • Previous treatment with photodynamic therapy (PDT) or an anti-VEGF drug in the eye being considered for inclusion

If a fellow eye develops CNV from nAMD, it will be treated with the optimum locally available treatment.
 
Method of randomisation Password-protected, internet-based system (Sealed Envelope Ltd) guaranteeing concealment of allocation until after a participant is recruited. Randomization will be stratified by centre and blocked to ensure approximately equal numbers of participants per group within a centre.

 
Randomisation Unit Patient (only one eye of each patient to be investigated)
 
Masking All participants, trial and clinical personnel responsible for assessing and managing patients will be masked to the drug allocation. Masking of allocation to more or less frequent treatment frequency (see below) will also be masked up to the three month visit. Image-grading centres will be masked both to drug and treatment frequency allocation.

 
Treatments Two treatment factors, i.e. anti-VEGF drug and treatment frequency, will be studied using a 2 x 2 factorial design.

  Lucentis Avastin
Continue treatment @ 3 months A B
Stop treatment @ 3 months C D


  1. Anti-VEGF drug:
    Participants will be randomly allocated to either (a) Lucentis® (ranibizumab) or (b) Avastin® (bevacizumab).

  2. Treatment frequency:
    Participants will be randomly allocated to either:

    (a) continuous treatment with a VEGF inhibitor monthly for 24 months

    or

    (b) treatment monthly for the first 3 months, then stopping treatment with monthly review to detect disease relapse/progression (see criteria below).

    If disease relapse/progression is detected, monthly treatment will be re-started for another cycle of 3 months, after which treatment will again be stopped. There will be no limit on the number of cycles of treatment that can be carried out.

 

Yes No Not sure
1. Is there evidence from OCT of sub-retinal fluid in the study eye?
2. Is there evidence from OCT of an increase in intra-retinal fluid in the study eye?
3. Is there fresh blood in the lesion in the study eye?
If the answer is YES to any of the above questions, start a new 3 month cycle of treatment.
4. Is there evidence from OCT of persistent intra-retinal fluid in the study eye?
5. Has the VA dropped by ≥10 letters over the last three months?

If the answer is YES to either of the above questions, start a new 3 month cycle of treatment. (NB The presence of hyporeflective spaces under the RPE on OCT are not considered an indicator of re-treatment.)

If uncertain about one or more of the above criteria, carry out fluorescein angiography.
6. Is there evidence of extension of the CNV?
7. Is there leakage from >25% of the circumference of the CNV?
If the answer is YES to either of the above questions, start a new 3 mnth cycle of treatment regardless of OCT findings.

OCT - optical coherence tomography; RPE - retinal pigment epithelium; CNV - choroidal neovascularisation.

 
 
Outcome Measures The primary outcome is corrected logMAR visual acuity, measured as the number of letters read on a standard ETDRS chart. The primary end point will be logMAR visual acuity after two years of follow-up.

Secondary outcomes:
Secondary outcomes will be analysed after one and two years of follow-up, unless otherwise stated.
  1. Frequencies of adverse effects of treatment
  2. Generic and vision-specific health-related quality of life (HRQoL)
  3. Treatment satisfaction
  4. Cumulative resource use/cost, and cost-effectiveness.
  5. Clinical measures of vision
  6. CNV morphology (from masked grading of fundus fluorescein angiography (FFA) and optical coherence tomography (OCT)).
  7. Distance logMAR visual acuity after all patients have been followed for 1 year after starting treatment.
  8. Survival free from treatment failure (i.e. satisfying one or more of the criteria for re-treatment).
 
Sample Size We propose to recruit 150 participants to each of the four cells shown in the figure above providing a sample size of 300 vs. 300 (less participants lost to follow-up) for objectives I and II.
 
Clinical Work Up
  • Retinal exam every visit (24 follow-up visits)
  • Visual acuity with refraction of both eyes at 0, 3, 6, 12, 18 and 24 months
  • Visual acuity of study eye only on every visit
  • FFA at 0, 12, and 24 (all to be submitted for grading)
  • OCT at every visit (only 3 monthly OCT images to be submitted for grading)
 
Follow-up Every month through 2 years