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临床时讯 > 专家论坛


阴性结果——被冻住的希望


  在科学探索的道路上,我们并非总能得到预期结果,失望与意外时常来扰,让满心的期待戛然而止。或许失望与惊喜的并存与结果的不能预期才让我们体会到科学研究的无限乐趣,但有时P>0.05的结果确实堪忧,我们也不禁要问,这些研究中的“主角”们,还有没有春天?

提前终止,创新疗法前途渺茫

  AIM-HIGH:挑战升高HDL-C的治疗理念

  5月25日,探讨在他汀基础上加用大剂量缓释烟酸对心血管事件影响的AIM-HIGH研究被美国国立卫生研究院(NIH)提前18个月叫停。

  基于试验数据,NIH安全监督委员会认为,大剂量缓释烟酸减少心血管事件的益处并未超越他汀单药,且无证据显示该结果可能随研究的继续而改变,故建议提前终止,并建议停止后继续对受试者进行12~18个月的随访,以获得更多的安全性数据。

  近年来,低密度脂蛋白胆固醇(LDL-C)一直被作为血脂干预的主要靶点,但一些研究显示,心血管疾病及其高危患者接受他汀治疗后,仍存在较高的心血管剩余风险,而高密度脂蛋白胆固醇(HDL-C)的降低与甘油三酯(TG)的升高被认为是主要因素,很多学者相信,通过升高HDL-C水平和降低TG水平可进一步降低剩余风险。然而,从ACCORD研究中的非诺贝特并未减少糖尿病患者心血管事件,到ILLUMINATE研究中的torcetrapib反增加心血管事件,升高HDL-C降低心血管剩余风险的效果不断令人失望。AIM-HIGH试验被提前叫停,无疑是对这一理念的再次挑战,但学术界对此尚有不同观点。

  AIM-HIGH试验的共同研究者博登(Boden)教授指出,缓释烟酸对改变脂质谱产生了预期效果(升高HDL-C水平达20%,同时降低TG水平约25%),但未改变心血管事件发生率的原因可能在于:试验并未入选最高危的患者,且良好控制的LDL-C水平可能掩盖了升高HDL-C水平的额外益处,所以他认为这一结果不能外延至高危患者或在真实世界中LDL-C水平控制不佳的患者。NIH国家心肺血液病研究所(NHLBI)代理主任舒林(Shurin)教授却认为,该试验印证了既往研究结果,促使我们反思升高HDL-C水平的治疗理念,该方法或许无效,抑或HDL-C不是好的治疗靶点,寻找控制胆固醇的新方法是我们需要解决的重要问题。AIM-HIGH研究项目负责人戴维涅-尼克斯(Desvigne-Nickens)教授指出,在我们不断寻找新方法改善胆固醇控制的同时,要重视已有方法,对于胆固醇水平较高的患者,降低心血管事件风险的关键还在于降低LDL-C水平,包括使用他汀和改善生活方式等。

  升高HDL-C的治疗理念正确与否尚无定论,在这条道路上的继续探寻能否被阻止,我们期待正在进行中的HPS2-THRIVE研究能够给出答案。

  VOICE:击碎替诺福韦阴道凝胶预防HIV的梦想

  11月25日,NIH宣布,一项涉及抗逆转录药物预防人免疫缺陷病毒(HIV)感染的临床研究(VOICE)因其中一种方案无效而被部分提前终止。

  该研究共纳入5000余名未受HIV感染的女性,其中约2000名使用含1%替诺福韦的阴道凝胶预防HIV。中期评估结果显示,替诺福韦凝胶组与安慰剂组患者HIV感染率均为6%。数据安全和监测委员会建议终止该部分研究,替诺福韦口服片剂单用或与恩曲他滨联用预防HIV感染的研究继续进行。然而,由于替诺福韦-恩曲他滨片剂预防HIV感染的安慰剂对照研究已因无效于今年被提前终止,且此前其他数种预防HIV的外用药亦未在临床研究中显示出明确有效,该部分结果获得成功的前景也很渺茫。

  研究人员希利尔(Hillier)和麦高恩(McGowan)认为,目前研究将继续进行,他们都急切地想知道坚持用药、日常剂量设定、炎症或其他因素是否与有效性相关;Hillier对研究结果感到“意外和失望”,但他们须等到所有试验结束才能进行更全面的分析。

  南非艾滋病规划研究中心主任、VOICE研究区域负责人卡里姆(Karim)坦承,结果完全出人意料,因为来自实验室研究、动物试验和临床试验的诸多证据表明,替诺福韦凝胶能够预防HIV感染,但科学并非总是能够让我们得到预期的结果。

疗效不佳,试验药物前景堪忧

  STAR研究未证实奥沙利铂治疗局部晚期直肠癌有效:多项临床研究提示,在转移性结直肠癌中,基于奥沙利铂的方案优于氟尿嘧啶单药;且Ⅰ、Ⅱ期研究结果均提示,在结肠癌新辅助放化疗方案中加入奥沙利铂,可能提高手术病理完全缓解(pCR)率。然而,今年美国临床肿瘤学会(ASCO)年会公布的Ⅲ期多中心随机对照STAR研究结果却出人意料,未能证实奥沙利铂治疗局部晚期直肠癌有效。

  维生素E和二甲双胍治疗儿童脂肪肝效果不佳:《美国医学会杂志》一项多中心随机对照研究显示,与安慰剂相比,维生素E和二甲双胍均未显著降低非酒精性脂肪性肝病(NAFLD)患儿血清丙氨酸氨基转移酶(ALT)水平,也未显著改善肝脏组织学病变。

JAMA. 2011 Apr 27;305(16):1659-68.

Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.

Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; Nonalcoholic Steatohepatitis Clinical Research Network.

Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, New York, USA.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established.

OBJECTIVE: To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin.

DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks.

MAIN OUTCOME MEASURES: The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures.

RESULTS: Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features.

CONCLUSION: Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063635.

  特拉泼维作为基础治疗方案成本效益不佳:第62届美国肝病研究学会(AASLD)年会一项报告表明,对于IL-28B基因型为CC、感染基因1型丙型肝炎病毒(HCV)的患者,初始以特拉泼维作为基础治疗方案成本效益不及聚乙二醇干扰素(Peg-IFN)α联合利巴韦林(RBV)。

  N-乙酰半胱氨酸治疗酒精肝效果不显著:《新英格兰医学杂志》一项研究称,在泼尼松龙基础上加用N-乙酰半胱氨酸虽提高重度急性酒精性肝炎患者1个月生存率,但效果未能持续,并不能显著提高患者6个月生存率。

N Engl J Med. 2011 Nov 10;365(19):1781-9.

Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.

Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, Dewaele F, Ghrib S, Rudler M, Carbonell N, Tossou H, Bental A, Bernard-Chabert B, Dupas JL; AAH-NAC Study Group.

Service d'Hépato-Gastroentérologie, Amiens University Hospital, and Equipe Région INSERM 24, University of Picardy, Amiens, France.

BACKGROUND: Mortality among patients with severe acute alcoholic hepatitis is high, even among those treated with glucocorticoids. We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival.

METHODS: We randomly assigned 174 patients to receive prednisolone plus N-acetylcysteine (85 patients) or only prednisolone (89 patients). All patients received 4 weeks of prednisolone. The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 (at a dose of 150, 50, and 100 mg per kilogram of body weight in 250, 500, and 1000 ml of 5% glucose solution over a period of 30 minutes, 4 hours, and 16 hours, respectively) and on days 2 through 5 (100 mg per kilogram per day in 1000 ml of 5% glucose solution). The prednisolone-only group received an infusion in 1000 ml of 5% glucose solution per day on days 1 through 5. The primary outcome was 6-month survival. Secondary outcomes included survival at 1 and 3 months, hepatitis complications, adverse events related to N-acetylcysteine use, and changes in bilirubin levels on days 7 and 14.

RESULTS: Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (27% vs. 38%, P = 0.07). Mortality was significantly lower at 1 month (8% vs. 24%, P = 0.006) but not at 3 months (22% vs. 34%, P = 0.06). Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P<0.001), a shorter prothrombin time (P<0.001), a lower level of bilirubin at baseline (P<0.001), and a decrease in bilirubin on day 14 (P<0.001). Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group (P = 0.001); other side effects were similar in the two groups.

CONCLUSIONS: Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis, 6-month survival, the primary outcome, was not improved. (Funded by Programme Hospitalier de Recherche Clinique; AAH-NAC ClinicalTrials.gov number, NCT00863785 .).

  Atacicept治疗RA效果不佳:重组融合蛋白Atacicept可能成为改善类风湿关节炎(RA)症状的全新疗法。《关节炎与风湿病》发表的一项随机安慰剂对照Ⅱ期研究显示,与安慰剂相比,甲氨蝶呤疗效不佳且尚未应用肿瘤坏死因子拮抗剂的RA患者服用atacicept,主要终点(美国风湿病学会症状改善20%[ACR20])发生率未改变。

Arthritis Rheum. 2011 Jul;63(7):1782-92.

Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial.

van Vollenhoven RF, Kinnman N, Vincent E, Wax S, Bathon J.

Karolinska Institute, Stockholm, Sweden.

OBJECTIVE: To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist-naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.

METHODS: In this phase II study, patients with active RA (n = 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4-week loading period (twice-weekly dosing), or open-label adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C-reactive protein level (ACR20-CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety.

RESULTS: The proportion of patients meeting the primary end point (ACR20-CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20-CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50-CRP response rates were significantly higher in all active-treatment groups compared with placebo, but ACR70-CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment-free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept.

CONCLUSION: The primary end point (ACR20-CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.

  脾酪氨酸激酶抑制剂治疗活动性RA无显效:一项随机安慰剂对照Ⅱ期研究显示,与安慰剂相比,无反应活动性RA患者口服脾酪氨酸激酶抑制剂R788至3个月时,ACR20、ACR50及ACR70反应率无显著改变。

Arthritis Rheum. 2011 Feb;63(2):337-45.

An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents.

Genovese MC, Kavanaugh A, Weinblatt ME, Peterfy C, DiCarlo J, White ML, O'Brien M, Grossbard EB, Magilavy DB.

Division of Immunology and Rheumatology, Stanford University, Palo Alto, California, USA.

OBJECTIVE: To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies.

METHODS: A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, double-blind, placebo-controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score.

RESULTS: The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level.

CONCLUSION: Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level.

专家访谈:阴性研究结果的分析与判读

北京大学循证医学中心 詹思延

  任何研究均有研究假设。从统计学角度而言,一般会有一个无效假设,如设定2组之间的有效率或死亡率无差别等,通常认为统计检验显示P<0.05时,差异具有显著性,可否定无效假设,选择备择假设,我们一般所谓的阴性结果通常指统计检验显示P>0.05的结果。

  除确无差异的情况以外,还有2种与研究本身相关的情况可能导致出现阴性结果。

  一种是样本量较小或参数设定存在问题。因为研究者通常基于前人研究进行样本量估计,所以当我们看到一个阴性结果时,首先要看其是否有样本量估计依据,并由此回推样本量是否达到统计学要求,如未达到,可能只是假阴性结果,将样本量增至足够大时,可能会出现阳性结果。

  此外,还可能是研究设计或实施存在问题,如纳入人群是否合理、干预力度是否足够、患者依从性是否良好等。我们经常会看到一些研究的大组结果显示为阴性,但亚组结果却为阳性,这可能提示研究假设并非适用于所有人群,可能仅适用于其中某些病情较重或有并发症的亚组人群等。

  判断阴性结果是否具有临床价值,还要基于临床进行评价,要注意统计学意义与临床意义不同。

  此外,对于一些发表在影响因子较高杂志上的研究,也不能一概而论地认为研究本身没有问题,还要考虑研究对象是老药还是新药等问题,针对已应用几十年的传统药物进行的研究可能样本量较大,但一些针对新药甚至刚上市药物进行的研究,样本量也未必很大,所以也应客观评价发表于这些杂志的阴性结果。

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