Blinded analysis of double-blind randomized controlled trial for unequal integer ratio grouping

doi:10.12092/j.issn.1009-2501.2019.10.011

Abstract

Abstract:

AIM: The blinded data analysis under the conventional equal ratio grouping is easy to be realized in the double-blind randomized controlled trial.However, there is no effective blinded analysis method for the trial of unequal integer ratio grouping.To develop a blinded analysis under the unequal integer ratio grouping to avoid the bias during data analysis due to knowledge of grouping information in the double-blind randomized controlled clinical trials. METHODS: In the design phase, according to the sum of unequal integer ratios, the samples were divided into several equal split groups.The random allocation sequence was generated by means of the new split groups.The drug labeling was conducted by a third party independent of the study based on the split groups.In the statistical analysis phase, all possible combinations of the split groups were analyzed and reported.RESULTS:The implementation of blind analysis was illustrated with a clinical trial in which two groups were grouped in 2∶1 ratio. In this method, only the codes of each subgroup were known after the first level unblinding, and the corresponding real group could not be identified, so it could keep blinded to treatment allocation in the statistical analysis.The final reporting of statistical analysis could be determined after the second level unblinding.CONCLUSION: The method we proposed is simple in principle, easy to implement and in line with the regulatory requirements.In spite of increasing workload during the random allocation sequence generating, drugs labeling,and statistical analysis,it could maintain the blindness of data analysis under the unequal integer ratio grouping and effectively avoid the possible analysis bias caused by unblinding.It has unique practical value in ensuring objectivity and science of clinical trial analysis.

Key words: double-blind randomized controlled trial, integer ratio grouping, blinded analysis

CLC Number:

R969.4

LIU Yaqi, LU Mengjie, LIU Yuxiu, CHEN Yu, YUAN Yangdan, ZHOU Chongchong, LIU Man. Blinded analysis of double-blind randomized controlled trial for unequal integer ratio grouping[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(10): 1155-1160.

References

［1］Day SJ,Altman DG.Blinding in clinical trials and other studies［J］.BMJ,2000,321(7259):504.
［2］Bang H,Flaherty SP,Kolahi J,et al.Blinding assessment in clinical trials:a review of statistical methods and a proposal of blinding assessment protocol［J］.Clin Res Regul Aff,2010,27(2):42-51.
［3］Schulz KF,Chalmers I,Hayes RJ,et al.Empirical evidence of bias:dimensions of methodological quality associated with estimates of treatment effects in controlled trials［J］.JAMA,1995,273(5):408-412.
［4］Gotzsche PC.Blinding during data analysis and writing of manuscripts［J］.Control Clin Trials,1996,17(4):285-290.
［5］Kolahi J,Abrishami M.Multiple-blind:towards a new blinding protocol for future generations of clinical trials［J］.Med Hypotheses,2009,73(5):843-845.
［6］王柏松,苏炳华,何清波.盲法临床试验盲底的制作［J］.中国卫生统计,2003,20(4):228-229.
［7］Moore K,Colombo N,Scambia G,et al.Maintenance Olaparib in patients with newly diagnosed advanced ovarian cancer［J］.N Engl J Med,2018,379(26):2495-2505.
［8］Davies JC,Moskowitz SM,Brown C,et al.VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles［J］.N Engl J Med,2018,379(17):1599-1611.
［9］Maurer MS,Schwartz JH,Gundapaneni B,et al.Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy［J］.N Engl J Med,2018,379(11):1007-1016.
［10］Abou-Alfa GK,Meyer T,Cheng AL,et al.Cabozantinib in patients with advanced and progressing hepatocellular carcinoma［J］.N Engl J Med,2018,379(1):54-63.
［11］Yutaka N,Scott TM,Julie K,et al.A phase 3 trial of l-glutamine in sickle cell disease［J］.N Engl J Med,2018,379(3):226-235.
［12］Mrinal MG,Michelle RM,Brian AVT,et al.Sorafenib for advanced and refractory desmoid tumors［J］.N Engl J Med,2018,379(25):2417-2428.
［13］Molloy SF, Kanyama C, HeydermanAntifungal RS, et al.Combinations for treatment of cryptococcal meningitis in Africa［J］.N Engl J Med,2018,378(11):1004-1017.
［14］Jeffrey EO, Mark JP, Eric V, et al.Wearable cardioverter-defibrillator after myocardial infarction［J］.N Engl J Med,2018,379(13):1205-1215.
［15］Mathew SM,Jeffrey HS, Balarama G,et al.Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy［J］.N Engl J Med,2018,379(11):1007-1016.
［16］张腾跃，杨广山，马克龙,等.抗凝治疗对中晚期胃癌改善高凝状态、抗肿瘤转移的临床研究［J］.中国临床药理学与治疗学,2019,24(4): 433-439.
［17］李慧洋,李剑,吴帮卫,等.麝香保心丸对冠心病支架植入后靶血管血流改善作用的随机、双盲、对照研究［J］.中国中西医结合杂志,2018,38(3):295-299.
［18］范军铭,范小会,范伏元,等.紫贝止咳颗粒治疗急性气管-支气管炎（余邪恋肺证）的随机双盲、平行对照、多中心临床研究［J］.中药药理与临床,2017,33(2):182-186.
［19］魏连波,洪钦国,汤水福,等.中西医结合治疗难治性肾病综合征:随机、双盲、单模拟、多中心临床研究［J］.中华肾病研究电子杂志,2017,6(5):219-223.
［20］林琳,王奇,李素云,等.克咳片治疗慢性支气管炎的多中心随机对照临床研究［J］.中华中医药杂志,2015,30(7):2636-2638.

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