臨床試驗文獻評價

1、,第四節(jié) 臨床文獻評價 真實性 重要性 實用性,臨床科研設計書的主要內容1.研究題目：主要研究問題和次要研究問題，說明課題的科 學性與可行性。2.樣本含量估計：計算方法和本研究采用樣本量的依據(jù)。3.研究對象的診斷、納入、排除標準。4.設計方案、隨機方法和研究地點。5.效應指標和測量方法。6.控制偏倚的措施。7.統(tǒng)計分析。8.醫(yī)德問題。,一、真實性評價1.研究證據(jù)是否來源于真正的隨機對照試驗

2、？2.研究對象是否明確限定？3.防治措施的具體內容是否明確？4.是否觀察、報告了全部臨床結果？5.報道的結果是否包括了全部納入的病例？6.統(tǒng)計方法的使用是否合適？是否注意了統(tǒng)計 學意義與臨床意義？,（一）研究證據(jù)是否來源于真正的隨機對照試驗？ 隨機分組的方法是否交代、是否恰當、是否采用 了隱匿？ 試驗組和對照組例數(shù)是否相等或接近？ 兩組的基線資料和其它非試驗因素是否可比？ 分層隨機的分層因素

3、是否合適？分層各組的樣本 量要仔細計算。,（二）研究對象是否明確限定？ 診斷標準 納入標準 排除標準,（三）防治措施的具體內容是否明確？ 1.藥物：劑量、劑型、給藥方法與途徑、療程、 相應的配套治療。 2.保證防治措施的正確實施。 3.沾染和干擾的預防。 4.依從性的檢查。,（四）是否觀察、報告了全部臨床結果？ 效益和危害---治療作用與毒副反應 效應指

4、標及其觀察時間、空間和測量方式是否合適 是否合適的采用盲法,（五）報道的結果是否包括了全部納入的病例？ 確保失訪（lost follow)率?10%。 如失訪率? 20%，沒有多大的臨床價值。 失訪率在10%--20%之間：采用意愿治療 分析(intention-to-treat analysis) 試驗組失訪人數(shù)按無效計算 對照組失訪人數(shù)按有效計算,（六）統(tǒng)計方法的使用是

5、否合適？是否注意了統(tǒng)計學意義與臨床意義？ 統(tǒng)計學意義只表明試驗組與對照組之間的差異來自防治措施的本身，只能評價這種差異的真實程度，但并不表明療效差異大小的臨床意義。CER ARR NNT的應用。,二、重要性評價真正的陰性結果真正的尚有爭議的結果真實有效的結果,（一）效果究竟有多大？明確試驗組與對照組事件發(fā)生率（如治愈率、死亡率、不良反應等）各有多大，以及組間的差值，對這些差值的臨床意義做出評價。,（二

6、）試驗效果的準確度如何？常用95%的可信區(qū)間表示（95%CI confidence interval)可信區(qū)間越小，可信度越靠近真值，反之可信度就要差一些。,三、實用性評價患者的情況是否與我們的相一致？可行性如何？干預措施的“利”與“弊”,（一）試驗的證據(jù)是否與我們經治的患者情況一致？根據(jù)患者的病情、病理損害程度、社會人口特點（人種、性別、年齡等）、亞組的分析特點“對號入座”。,（二）試驗結果的可行性如何？技術的可行

7、性病人接受的可行性經濟的可行性,（三）試驗結果的“利”與“弊”對試驗結果施加給病人后可能獲得多大程度的效果和引起不良反應的風險度要權衡比較，只有在確定“利”肯定大于“弊”時才能接受、實踐這種試驗結果。Likelihood of being helped versus harmed LHH,,A Multicenter Study of Grepafloxacin (格雷沙星）and Clarithromycin in the

8、Treatment of Patients With Community-Acquired Pneumonia* S. Moola, MBChB; Lars Hagberg, MD, PhD; Gavin A. Churchyard, MBBCh; Joe S. Dylewski, MDCM; Sangeeta Sedani, BSc and Heather Staley, BSc Chest. 1999;11

9、6:974-983.,Study objectives: To compare the efficacies of 10-day regimens of grepafloxacin (GFX) (Raxar or Vaxar; Glaxo Wellcome; Greenford, UK), 600 qd, and clarithromycin (CLA) (Klacid, Biaxin, or Klaracid; Abbott Lab

10、oratories; Chicago, IL), 500 mg bid, in patients with community-acquired pneumonia (CAP), on the basis of clinical response, including radiographic evidence, and bacteriologic efficacy.,Patient Population and Study Desig

11、nThis was a phase IIIb, double-blind, randomized, prospective, parallel-group, comparative study (protocol GFXB3003) conducted at 58 centers in 11 countries (Australia, Canada, Czech Republic, Germany, Italy, Israel, Ne

12、w Zealand, Poland, South Africa, Spain, and Sweden). Regulatory approval was obtained where appropriate, and the study was approved by local ethics committees. Written, informed consent was obtained for each participant

13、in accordance with national guidelines and the Declaration of Helsinki (Hong Kong amendment, 1989).,Patients with chest radiographs taken within 2 days of the start of study medication confirming pulmonary infiltration o

14、r consolidation （實變）likely to be caused by pneumonia, and patients presenting with one or more of the clinical signs and symptoms consistent with CAP—pleuritic chest pain, cough, fever ( 38°C), and auscultatory fin

15、dings such as rales and/or evidence of consolidation—were included in the study.,Sputum production was not a requirement for study entry; however, when patients were producing sputum, a sample was collected for culture.

16、Patients could be treated in the community or could be admitted to the hospital, depending on the standard medical practice in different countries.,Patients were excluded if they had nosocomial （院內）pneumonia; required im

17、mediate IV antibiotic therapy; had received antibiotic therapy within 3 days before study entry; or had bronchial carcinoma, empyema（膿胸）, lung abscess, uncontrolled asthma, pulmonary tuberculosis, or cystic fibrosis.,As

18、well as other standard exclusion criteria for clinical trials, patients with an immunocompromised status, malabsorption （吸收障礙）syndromes, hepatic or renal impairment, and history of seizure（癲癇） disorders were excluded, as

19、 were those with known sensitivity to any quinolone or macrolide antibiotic.,Patients were randomized to receive either oral GFX, 600 mg qd for 10 days (251 patients) or oral CLA, 500 mg bid for 10 days (253 patients). I

20、n addition to the active medication, patients received concurrent placebo for study-blinding purposes. Administration of additional antimicrobials was not permitted for the duration of the study, and a record was kept of

21、 any medication taken concomitantly.,AssessmentsAfter entry into the study and pretreatment assessment, patients were reassessed during treatment (4 to 6 days after treatment initiation), after treatment (1 to 3 days a

22、fter completion), and at follow-up (28 to 35 days after treatment completion). At each assessment, patients were evaluated for resolution of signs and symptoms of pneumonia. Before treatment and at follow-up (or withdraw

23、al), chest radiography and physical examinations were performed.,At each assessment, sputum samples were collected (if available) for Gram's stain, culture, and susceptibility testing (only samples meeting the recogn

24、ized criteria of 25 neutrophils and 10 epithelial cells per low-power field were cultured). Blood was collected for culture at the pretreatment assessment, and if the results were positive or if the subject remained

25、febrile, blood was collected for culture at the posttreatment and follow-up assessments.,Primary identification of isolated pathogens was performed using routine laboratory culture methods. Bacterial isolates were tested

26、 by disk diffusion for susceptibility to GFX and CLA; in addition, the minimal inhibitory concentration was determined. Production of ß-lactamase was determined by the nitrocefin method where appropriate. For S pneu

27、moniae isolates, susceptibility testing to penicillin was performed.,In addition, serology was performed by a central laboratory on pretreatment and follow-up blood or urine samples for detection of the atypical respirat

28、ory pathogens Mycoplasma pneumoniae, Chlamydia pneumoniae（衣原體）, and L pneumophila. The presence of Chlamydia and Mycoplasma spp was established using indirect fluorescent antibody assay kits for both IgG and IgM (MRL Dia

29、gnostics; Cypress, CA and Zeus Scientific; Raritan, NJ). Tests were interpreted from comparisons of pretreatment and follow-up samples according to the instructions of the manufacturer.,At least a fourfold rise in recipr

30、ocal (互補）value titer for IgG or IgM from pretreatment to follow-up was required to indicate a positive test result. For M pneumoniae, an IgG titer of 1:128 was required unless a fourfold increase in IgM was also presen

31、t, when a titer of 1:64 was acceptable. Legionella spp were detected using radioimmune assays (Bimax; Portland, ME) of urine samples.,C-reactive protein (CRP) determinations were made on blood samples taken before and

32、after treatment to evaluate this test as an additional surrogate（替代） marker to indicate the presence of bacterial infection. The number of patients with a CRP value > 50 mg/L at the pretreatment and posttreatment asse

33、ssments was determined and was also analyzed in conjunction with clinical outcome.,Details of adverse events and any other problems elicited by nonspecific questioning were recorded at each visit.,Efficacy MeasuresThe p

34、rimary measure of efficacy was the clinical and radiographic response at follow-up; this was assessed for all patients and for patients with documented infection with either typical or atypical pathogens.,Table 1. Defini

35、tions of Clinical Responses Clinical ResponsesDefinitionsCure Improvement or resolution of clinical signs and symptoms

36、 after treatment and absence, including radiographic evidence, at follow-upImprovement Improvement but incomplete resolution of clinical signs and symptoms, i

37、ncluding radiographic evidence, at followFailure No improvement during or after treatment or discontinuation of therapy because of a drug-related adverse eventRec

38、urrence Resolution or improvement after treatment with recurrence of clinical symptoms, including radiographic evidence, at follow-upUnable to be Significant devi

39、ations from protocol evaluated,,,,To grade the clinical outcome, the radiographic response was classified at follow-up as resolved (areas of infiltration or consolidation completely clear), improved (areas of infiltrati

40、on or consolidation still exist but show evidence of clearing), or unchanged or worse (areas of infiltration or consolidation unchanged or show evidence of spread or increased density).,Table 2. Definitions of Bacteriolo

41、gic Responses Bacteriologic Responses DefinitionsCure Initial pathogen eradicatedPresumed cure Clinical cure or

42、improvement in the absence of sputum or blood cultureCure with superinfection Eradication of initial pathogen with isolation of new organism(s)

43、 associated with clinical symptoms of infectionCure with colonization Eradication of initial pathogen with isolation of new nonpathogenic

44、 organism(s) not associated with clinical symptoms of infectionRecurrence Initial bacteriologic cure with reisolation of original pathogen at

45、 follow-upFailure Initial pathogen not eradicated during treatmentPresumed failure Clinical failure in the absence of sputum or blood cultureFailure

46、with superinfection Initial pathogen not eradicated plus isolation of new pathogen(s)Failure with resistance Initial pathogen(s) developing resistance during therapyUnable to be evaluated Inability

47、 to identify or culture pretreatment pathogens, and any other deviation from protocol,,,,Statistical AnalysisA satisfactory response rate (clinical cure or improvement)

48、 of 80 to 89% at follow-up with a broad-spectrum antibiotic was assumed. Assuming an inability to evaluate rate of 25%, at least 450 patients were required to establish equivalence in both the intent-to-treat (ITT, pat

49、ients who were randomly assigned and received at least one dose of the study medication) and clinically evaluated populations (eg, patients who were able to be clinically evaluated (CE) in accordance with the study proto

50、col criteria),,using a 95% confidence interval (CI) calculated for a two-tailed test of significance at the 15% level with 90% power.9 Equivalence was demonstrated if the lower limit of the 95% CI of the difference in re

51、sponse rate among patients receiving GFX minus the response rate to CLA was > -15%.,Primary efficacy data were analyzed for the ITT and CE populations. Analyses were also performed on the microbiologic intent-to-treat

52、 (MITT; patients in the ITT population who had a pathogen isolated on study entry) and the microbiologically and clinically evaluated (MCE; patients in the MITT population who were able to be clinically evaluated) study

53、populations.,Results:1. Patient Demographics and Disposition2. Primary Assessment of Clinical Response at the Follow-Up Visit3. Posttreatment Assessment of Clinical Response4. Assessment of Clinical Response in

54、 Patients With Confirmed Infection5. Bacteriologic Response6. Pathogens Isolated and Antibiotic Susceptibility7. Safety,Results Patient Demographics and DispositionPatients were recruited at 58 centers in 11 co

55、untries; 43% of the patients were treated in the community setting (general practice or outpatient clinic), and 57% of patients were hospitalized in accordance with the standard medical management of such patients in dif

56、ferent countries.,Patient demographics were similar with respect to age, sex, and ethnic origin between the two study groups (Table 3 ). The majority of patients, 73%, were > 35 years old, with 23% being > 65 years

57、 old. Sixty-two percent of patients had a preexisting medical condition on entry into the study, with cardiovascular (23%) and respiratory (17%) conditions being the most common. The most commonly reported pretreatment s

58、ymptoms were cough and adventitial sounds, recorded for 95% and 85% of the patients, respectively.,Table 3. Summary of Demographic and Baseline Characteristics*Patient Characteristics GFX, n = 251 CLA, n

59、= 253 Total, n = 504SexFemale 106 (42.2) 98 (38.7) 204 (40.5)Male 145 (57.8) 155 (61.3)

60、 300 (59.5)Age, yr 47.7 ± 17.9 49.2 ± 18.0 48.5 ± 18.0Ethnic origin Asian 4 (1.6)

61、 7 (2.8) 11 (2.2)Black 40 (15.9) 41 (16.2) 81 (16.1)White 198 (78.9)

62、202 (79.8) 400 (79.4)Other 9 (3.6) 2 (1.2) 12 (2.4)Height, cm 169.8 ± 9.4 170.3 &#

63、177; 9.6 170.1 ± 9.5 Weight, kg 72.89 ± 16.36 73.45 ± 16.54 73.17 ± 16.43,,,,A total of 504 patients were recruited to the study (ITT population), of who

64、m 251 patients were randomized to receive GFX and 253 to receive CLA. There were 106 withdrawals (21%) from the study (51 GFX, 55 CLA; p = 0.78) because of lack of efficacy (4%), adverse events (7%), failure to return fo

65、r assessment (4%), or other reasons (6%; Fig 1 ). Compliance was good, with > 99% of urine test results being positive for the presence of antibiotic and 84% of patients taking their medication in accordance with the

66、protocol.,,,[HELP with high resolution image viewing] [Return to Article]                        

67、0;                                    &#

68、160;      Figure 1. Patient flow through trial. *Two patients in the GFX group and four in the CLA group had both typical and atypical pathogens present before treatment. [Return to Article

69、],,Radiographic findings and the nature and severity of signs and symptoms were comparable in the two treatment groups. At the pretreatment assessment, 78%, 43%, 48%, and 48% of patients reported moderate or severe cough

70、, dyspnea, pleuritic chest pain, and chills, respectively, compared with 3%, 3%, 1%, and 1% of patients at follow-up. No differences were demonstrated between the two treatment groups. Likewise, adventitial sounds, dulln