A randomized trial of Pegaptanib sodium for age-related macular degeneration used an innovative design to explore disease-modifying effects

ObjectiveEffectively evaluating disease-modifying effects in clinical trials has posed a problem for clinical trialists and drug development. One method that has been proposed to evaluate disease-modifying effects has been the re-randomization of active group participants to discontinue the intervention after a period sufficient to produce therapeutic effects. We aimed to determine if this design would permit inferences regarding disease modification in a trial evaluating Pegaptanib sodium, an intra-ocular injection, for the treatment of age-related macular degeneration.Study Design and SettingIn two identically designed trials, 1,186 patients were randomized to receive 54 weeks of treatment. After 54 weeks, 1,053 were re-randomized to either stay on treatment or discontinue treatment. Patients were seen at multicenter outpatient clinics.ResultsWe found that patients randomized to discontinue treatment after 54 weeks of treatment and followed for a further 48 weeks, were significantly different than the control group (sham) in loss of 15 letters of vision (Relative Risk 0.70, 95% Confidence Interval 0.57–0.88, P = 0.002), indicating that treatment is disease modifying. This effect was consistent throughout our sensitivity analyses.ConclusionThis trial is the first example of a clinical trial evaluating disease-modifying effects and this design should influence drug discovery to determine further therapeutic potential of pharmacologic interventions.