Mills Edward, Heels-Ansdell Diane, Kelly Steven, Guyatt Gordon
Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
J Clin Epidemiol. 2007 May;60(5):456-60. doi: 10.1016/j.jclinepi.2006.09.001. Epub 2006 Dec 11.
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.
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.
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.
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.
在临床试验中有效评估疾病修饰效应一直是临床试验人员和药物研发面临的一个问题。一种被提议用于评估疾病修饰效应的方法是，在足以产生治疗效果的一段时间后，将活性组参与者重新随机分组以停止干预。我们旨在确定这种设计是否能在一项评估用于治疗年龄相关性黄斑变性的眼内注射药物培加他尼钠的试验中，对疾病修饰作用进行推断。
在两项设计相同的试验中，1186名患者被随机分组接受54周的治疗。54周后，1053名患者被重新随机分组，要么继续治疗，要么停止治疗。患者在多中心门诊接受检查。
我们发现，在接受54周治疗后被随机分组停止治疗并再随访48周的患者，在视力下降15个字母方面与对照组（假治疗组）有显著差异（相对风险0.70，95%置信区间0.57 - 0.88，P = 0.002），表明该治疗具有疾病修饰作用。在我们所有的敏感性分析中，这种效应都是一致的。
这项试验是评估疾病修饰效应的临床试验的首个实例，这种设计应会影响药物研发，以确定药物干预的进一步治疗潜力。
