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


METHODS
In 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.


RESULTS
We 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.


CONCLUSIONS
This 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.
Mills
Edward
E
Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. millsej@mcmaster.ca
Heels-Ansdell
Diane
D
Kelly
Steven
S
Guyatt
Gordon
G
D052157:Aptamers, Nucleotide / Q000008:administration & dosage*; D020256:Choroidal Neovascularization; D004334:Drug Administration Schedule; D006801:Humans; D007267:Injections; D008268:Macular Degeneration / Q000188:drug therapy* / Q000503:physiopathology; D008875:Middle Aged; D011446:Prospective Studies; D012107:Research Design; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014792:Visual Acuity / Q000502:physiology; D014822:Vitreous Body
D052157:Aptamers, Nucleotide; D042461:Vascular Endothelial Growth Factor A; C495058:pegaptanib