真实世界研究与随机对照试验、单病例随机对照试验在临床治疗性研究中的关系比较

真实世界研究、随机对照试验及单病例随机对照试验在设计及具体的实施环节上存在明显不同.随机对照试验属于新治疗措施实施前的研究,真实世界研究属于新治疗措施实施后的研究.两者不是对同一个问题的平行论证,而是承启关系.精心设计的随机对照试验是临床上任何干预措施效果评价的基础,其结果需要真实世界研究的进一步验证及拓展补充,综合考虑二者才是最佳的选择.单病例随机对照试验更易在短时间内获得一些特殊病例的信息,是随机对照试验结果的良好补充,也是一定条件下最经济的真实世界研究.临床工作及其研究是十分复杂的过程.不同个体虽患同种疾病,但临床表现互有差异,且临床反应的变化也不尽相同.因此,无法获得同一干预措施下不同个体的相同治疗效果;加之有的治疗措施缺乏真实性和实用价值,从而使得疗效评价成为一个难题.近些年来,普遍采用试验性的研究结果作为证据指导临床实践活动,其中以随机对照试验(RCT)最为受到重视,但由于RCT属于药物面市前研究,对研究对象的选择、治疗措施的应用等均有严格的限定.     

临床真实世界研究中的实验性研究设计

真实世界研究作为解释性随机对照试验在医疗实践中评价干预措施效果的进一步验证和补充已成为医疗卫生领域关注的焦点。但是也存在错误将真实世界研究等同于观察性研究,认为真实世界研究不能实施人为干预,更不能采取随机化。实际上,真实世界研究的基本设计既可以是观察性的,也可以是实验性的。其中真实世界研究的实验性研究设计主要是指实用性随机对照试验和基于注册登记研究的随机对照试验,也可采用非随机对照、自适应设计等其他研究设计方案。     

临床随机对照试验的外部真实性及其评价的探讨

一、临床试验及其真实性 临床随机对照试验(RCT)严格遵循随机、对照、盲法等三大设计原则,并在试验过程中有效控制了潜在的混杂与偏倚,从而保证试验结果的真实可靠.现已成为验证临床药物或某项干预措施是否安全有效的重要研究手段.     

临床随机对照试验的外部真实性及其评价的探讨

一、临床试验及其真实性 临床随机对照试验(RCT)严格遵循随机、对照、盲法等三大设计原则,并在试验过程中有效控制了潜在的混杂与偏倚,从而保证试验结果的真实可靠.现已成为验证临床药物或某项干预措施是否安全有效的重要研究手段.     

临床随机对照试验的外部真实性及其评价的探讨

一、临床试验及其真实性 临床随机对照试验(RCT)严格遵循随机、对照、盲法等三大设计原则,并在试验过程中有效控制了潜在的混杂与偏倚,从而保证试验结果的真实可靠.现已成为验证临床药物或某项干预措施是否安全有效的重要研究手段.     

临床干预措施效力-效果差距弥合的方法学研究进展（二）：增强临床试验结果的外推性

目的 随机对照试验（RCT）通常具有严格的实施标准,纳入的研究对象特征以及干预实施条件与真实临床环境具有较大差异,这会导致干预措施在实际临床应用中的风险-效益与RCT中表现出的风险-效益存在差异, 结果的外推性受到很大限制。因此需要一些方法增强RCT结果的外推性,以评估药物在真实人群和真实临床实践环境中的真实效果。方法 检索PubMed、Embase、Web of Science、万方数据知识服务平台、维普数据库、中国知网6个数据库从建库至2022年12月31日的中英文文献。采用概括性综述的方法,对纳入文献进行归纳整合和定性描述。结果 共纳入12篇文献。纳入文献中增强效力外推性的方法可以归纳为3类：①改善传统RCT设计,增强人群代表性;②将RCT数据与真实世界数据（RWD）结合分析;③根据真实世界患者特征,校准RCT结果。结论 改进RCT设计,增强人群代表性,可提高RCT结果的外推性;将RCT数据与RWD结合分析,可发挥不同来源数据的优势;根据真实世界人群特征校准RCT结果,可预估干预措施在真实世界患者群体中的效果。     

PRECIS-2:基于研究目标的试验设计

采用随机对照试验（RCT）评价的干预措施效果，涉及理论疗效和实际的临床效果两方面。PRECIS（Pragmatic-Explanatory Continuum Indicator Summary）通过评价RCT设计的解释性和实用性两方面的程度，指导研究者如何实行干预和试验设计，使RCT在内部真实性和外部真实性之间达到一个平衡。在临床试验方案设计过程中，PRECIS的作用逐渐被研究者所认同。为了确保试验的设计与结果相关联，便于患者、临床医生和政策决策者应用，国际多团队专家对PRECIS进行了修正和升级，提出了新的PRECIS-2。PRECIS-2的9个维度都是为了帮助试验设计者思考研究设计的预期效果与试验结果的一致性和特定场景的适用性。本文旨在介绍PRECIS-2的研发、基本原理、特点及应用，以期为国内临床试验设计、决策提供帮助。     

临床干预措施效力-效果差距弥合的方法学研究进展（一）：改善真实世界研究的效果估计

目的 干预措施在临床实践中的实际干预效果与随机对照试验（RCT）中表现的效力存在差异，即效力-效果差距。RCT结果与真实世界研究（RWS）结果的差异可能无法代表真实的效力-效果差距，这是因为当RWS与RCT在研究设计上有较大差异，或RWS结果估计存在偏倚时，效力-效果的估计可能是有偏的。其次，当发现干预措施存在效力-效果差距，不能对所有患者实行一刀切的临床决策，而需要进一步评估影响干预措施效果的真实世界因素，识别可能取得期望效用的患者群体。方法 检索PubMed、Embase、Web of Science、万方数据知识服务平台、维普数据库、中国知网6个数据库从建库至2022年12月31日的中英文文献，采用概括性综述的方法，对如何改进RWS设计从而弥合效力-效果差距的方法进行归纳整合和定性描述。结果 共纳入10篇文献，探讨如何以RCT研究方案为模板，制定相应的RWS方案，在正确估计效力-效果差距的基础上，进一步评估干预措施在患者亚群中的效果，选取能获得预期收益风险比的患者亚群，从而弥合效力-效果差距。结论 使用医疗大数据，模拟目标试验方案关键特征，可以提高研究结果的真实性和有效性，弥合效力-效果差距。     

基于大数据的随机对照试验

我国医疗领域目前已积累了海量数据，如何利用大数据开展随机对照试验日益得到关注。本研究结合国外利用大数据实施随机对照试验的成功经验，从数据来源、研究对象和研究结局确定、干预措施、随机化方法、知情同意的实施等方面进行梳理总结，以期为国内未来开展相关研究提供借鉴。     

再论观察与实验：大数据现实世界研究不能取代随机对照试验

传统上,流行病学多以干预划分观察和实验,干预研究等于实验研究,还认为干预研究的科学性高于观察性研究。在一般科学实验里,干预指人为施加的改变自然状况的措施。干预并不一定是有益的,也并不一定是研究者当下施加的,研究者、受试者或第三者目前或过去施加的措施都可以形成"有效的"干预。例如,由研究者、受试者和第三者通过某种方法致使视神经损伤,都可以形成有效改变视神经正常功能的干预,研究者可以由此观察到视神经和视力的关系。以此推论,由受试者自己过去施加的不良干预（如吸烟）也属于干预,那么研究吸烟和肺癌的观察性队列研究就等同于实验研究了。由此看来,干预本身并不足以有效地区分观察和实验。如果认为实验的科学性高于观察,那么在干预的基础上,只能从科学性上（即设计特征）区分观察和实验。在评估医学干预效果的临床试验中,随机分组是在传统认为的观察研究基础上引入的最重要的偏倚控制措施,应该是区分观察和实验的核心属性。如果一定要把人群研究分成观察和实验,随机对照试验才是真正的实验研究,非随机分组形成的干预研究属于试验,但不是实验。基于大数据的现实世界研究,如果没有随机分组,不能构成实验,也不能成为对干预效果的最终检验。大数据现实世界研究不能取代随机对照试验,这是本文希望传达的最重要的信息。     

耳穴贴压疗法治疗失眠症的随机对照研究

目的 探讨耳穴贴压疗法及特定穴位治疗失眠症的有效性.方法 选择符合纳入标准的失眠症患者125例,随机分为真穴治疗组63例和伪穴对照组62例.真穴组选取神门、皮质下、心、肾、肝、脾、枕等穴位,伪穴组选上述穴位旁开2～3mm处,疗程1个月.每组治疗前后均采用匹兹堡睡眠质量指数量表(PSQI)评价疗效.结果 (1)两组治疗前后PSQI各因子评分差及总分差均有统计学意义(P＜0.01);(2)两组间治疗后各因子评分及总分的比较显示,两组在睡眠质量、入睡时间、睡眠时间、睡眠效率、睡眠障碍和日间功能障碍6项的差异有统计学意义(P＜0.01);两组治疗前后其评分差值的比较也有统计学意义;(3)对两组各因子治疗前后的等级差值进行秩次分析,其差异均有统计学意义(P＜0.01).结论 耳穴贴压疗法近期内能有效改善睡眠质量,缩短入睡时间,延长睡眠时间,提高睡眠效率.     

Neighborhood effects in a behavioral randomized controlled trial

Randomized controlled trials (RCTs) of interventions intended to modify health behaviors may be influenced by neighborhood effects which can impede unbiased estimation of intervention effects. Examining a RCT designed to increase colorectal cancer (CRC) screening (N=5628), we found statistically significant neighborhood effects: average CRC test use among neighboring study participants was significantly and positively associated with individual patient’s CRC test use. This potentially important spatially-varying covariate has not previously been considered in a RCT. Our results suggest that future RCTs of health behavior interventions should assess potential social interactions between participants, which may cause intervention arm contamination and may bias effect size estimation.     

Mifepristone versus laminaria: a randomized controlled trial of cervical ripening in midtrimester termination

BACKGROUND: Mifepristone was compared with laminaria for cervical ripening in second-trimester induction of labor (IOL). STUDY DESIGN: We performed a randomized, controlled, open-label study of women undergoing second-trimester IOL for fetal demise, aneuploidy or anomalies at a single tertiary care center from January 2004 to May 2006. Main outcome measures were induction-to-delivery time and pain with cervical ripening. RESULTS: Of 50 eligible women, 37 were enrolled in the study, of whom 33 completed the study: 16 were randomized to laminaria and 17 to mifepristone. Induction-to-delivery time was significantly shorter in the mifepristone arm (mean=10 h vs. 16 h, p=.01; median=7.5 h vs. 13.4 h, p=.01). Pain with cervical ripening was also significantly less in the mifepristone group than in the laminaria group (median=1 vs. 6 on an 11-point visual analogue scale, p<.001). Maternal age, parity, gestational age, fetal demise prior to induction, need for postpartum curettage, blood loss, pain during induction, delivery and at the time of discharge were not significantly different between the two groups. CONCLUSION: Mifepristone shortens the induction-to-delivery time and decreases pain with cervical ripening when compared with laminaria for second-trimester induction.     

Efficacy of a smoking cessation intervention using the AHCPR guideline tailored for Koreans: a randomized controlled trial

This study was undertaken to evaluate a tailored smoking cessation intervention, which is applicable to Korean culture, using the Agency for Health Care Policy and Research (AHCPR) guideline. On-site counselors provided brief nurse-assisted smoking cessation counseling, including follow-up telephone support, to prevent a relapse in 200 randomly assigned smoking patients. These patients were referred by their physicians regardless of their willingness in smoking cessation in the outpatient department at a university hospital. Nicotine replacement therapy was not provided. Another 201 patients served as a control. After 5 months, current smoking cessation was self-reported on the phone and validated later by a portable carbon monoxide analyzer. After 5 months, the participants in the intervention group were no more likely to quit smoking than the control group. A subgroup analysis by age showed that the intervention among 166 younger smokers (aged 49 or less) was significantly more likely to be effective {risk ratio = 5.76 [95% confidence interval (CI) 1.34-24.74]} than it was among 235 older smokers (aged 50 or more) [risk ratio = 1.03 (95% CI 0.53-1.99)]. This study suggests a smoking cessation intervention using the AHCPR guideline tailored for Koreans, is effective for assisting outpatients aged 49 or younger to quit smoking.     

艾司西酞普兰治疗持续性躯体形式疼痛障碍的随机对照研究

目的 研究艾司西酞普兰治疗持续性躯体形式疼痛障碍的疗效和安全性.方法 采用随机对照、开放性设计,将门诊接受治疗的持续性躯体形式疼痛障碍患者随机分为两组,即治疗组(艾司西酞普兰组)40例,对照组(文拉法辛缓释剂组)40例,疗程6周,于治疗前及治疗后第1,2,4,6周末进行疗效评定,以汉密尔顿抑郁量表(HAMD)汉密尔顿焦虑量表(HAMA)减分情况评定疗效,不良反应症状量表(TESS)评定不良反应.结果 艾司西酞普兰与文拉法辛缓释剂治疗持续性躯体形式疼痛障碍均有疗效.治疗组与对照组的自觉症状缓解时间均缩短,临床疗效明显.HAMD,HAMA评分差异均无统计学意义.两组治疗6周后有效率(以减分率≥50％为标准)分别为:治疗组80％,对照组85％,P＞0.05.两组不良反应在第1周末对照组评分高于治疗组,两组差异有统计学意义(P＜0.01).结论 持续性躯体形式疼痛障碍患者多存在焦虑抑郁情绪,而使用艾司西酞普兰10 mg/d起效快,不良反应发生率低,安全性良好.     

Effects of writing down the request for help: A randomized controlled trial

Background: Studies investigating interventions, aimed at improving patient satisfaction by exploring the patient's request for help, show conflicting results.

Objectives: To investigate whether writing down the request for help on a request card, prior to the consultation improves patient satisfaction.

Methods: This study was a single-blind randomized controlled trial, in which the patients were blinded to the intervention. Patients were recruited in two rural practices (five GPs) and one urban practice (four GPs) in The Netherlands. Consecutive patients with a new request for help were asked to participate. All patients received general information about patient satisfaction. After randomization, patients in the intervention group were asked to fill in a card with their request(s) for help; the general practitioners started the consultations with these questions. We used the ‘Professional Care’ subscale of the Consultation Satisfaction Questionnaire (CSQ) to examine the effect of the intervention on patient satisfaction. Secondary outcomes were patient satisfaction measured with the patient's VAS score, the GP's VAS score on satisfaction, consultation time, the other subscales of the CSQ, and the number of consultations during follow-up.

Results: There was no difference in patient satisfaction (CSQ, VAS) between both groups. We also did not find any differences between the other subscales of the CSQ.

Conclusion: A beneficial effect of the use of a ‘request card’ by the patient on patient satisfaction of the consultation could not be demonstrated.     

Zinc supplementation fails to increase the immunogenicity of oral poliovirus vaccine: A randomized controlled trial

BackgroundPolio eradication remains a challenge in Pakistan and the causes for the failure to eradicate poliomyelitis are complex. Undernutrition and micronutrient deficiencies, especially zinc deficiency, are major public health problems in Pakistan and could potentially affect the response to enteric vaccines, including oral poliovirus vaccine (OPV).ObjectiveTo assess the impact of zinc supplementation among infants on immune response to oral poliovirus vaccine (OPV).MethodsA double-blind, randomized placebo-controlled trial was conducted in newborns (aged 0–14 days). Subjects were assigned to either receive 10 mg of zinc or placebo supplementation daily for 18 weeks. Both groups received OPV doses at birth, at 6 weeks, 10 weeks and 14 weeks. Data was collected on prior immunization status, diarrheal episodes, breastfeeding practices and anthropometric measurements at recruitment and at 6 and 18 weeks. Blood samples were similarly collected to determine the antibody response to OPV and for micronutrient analysis. Logistic regression was used to determine the relationship between seroconversion and zinc status.ResultsOverall, 404 subjects were recruited. At recruitment, seropositivity was already high for poliovirus (PV) serotype 1 (zinc: 91.1%; control: 90.5%) and PV2 (90.0%; 92.7%), with lower estimates for PV3 (70.0%; 64.8%). By week 18, the proportion of subjects with measured zinc levels in the normal range (i.e. ≥60 μg/dL) was significantly greater in the intervention group compared to the control group (71.9%; 27.4%; p < 0.001). No significant difference in seroconversion was demonstrated between the groups for PV1, PV2, or PV3.ConclusionsThere was no effect of zinc supplementation on OPV immunogenicity. These conclusions were confirmed when restricting the analysis to those with measured higher zinc levels.     

Efficacy and safety of very-low-calorie diet in Taiwanese: A multicenter randomized, controlled trial

ObjectiveVery-low-calorie diets (VLCDs) are an effective method for weight reduction in Caucasians. This study investigated the efficacy and safety of two different VLCDs (450 or 800 kcal/d) in obese Taiwanese.Methods132 participants with BMI ≥30 kg/m² were randomized to two VLCD groups for body weight reduction for 12 weeks. Each group had 66 participants. Anthropometric and metabolic parameters were measured.ResultsThe intention-to-treat analysis revealed that the percentage change in body weight over the 12-week treatment period was –9.14% in the VLCD-450 group and –8.98% in the VLCD-800 group. A total of 27 (40.9%) participants in the VLCD-450 group and 29 (43.9%) participants in the VLCD-800 group achieved 10% or more weight loss at the end of treatment. The body weight, waist circumference, hip circumference, fat mass, blood pressure, triglycerides, and blood glucose were statistically improved from baseline but not between the two groups. The improvement rate of nonalcoholic fatty liver disease (NAFLD) was 41.5% in the VLCD-450 group and 50.0% in the VLCD-800 group. The incidence of adverse events did not differ significantly between the groups and no serious adverse events were reported in either group.ConclusionBoth the VLCD-450 and 800 kcal/d can effectively and safely reduce body weight and improve NAFLD in 12 weeks in obese Taiwanese participants. However, there is no additional benefit in prescribing the more restrictive diet intervention in Taiwanese.