A Clinical Trial Study On Chronic Congestive Heart Failure With Shengmai Capsule Treatment

BackgroundAn interim analysis is any analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to formal completion of a trial. The goal of an interim analysis is to stop the trial early if the superiority of the treatment under study is clearly established, or if the demonstration of a relevant treatment difference has become unlikely, or if unacceptable adverse effects are apparent. Interim analysis design has been most widely and successfully used in large, long-term trials, and it is seen as a powerful tool in new drug development.It was acted as a platform that Shengmai capsule treatment in patients with chronic congestive heart failure in this study. It will resolve three aspects of the problems:(一)To evaluate efficacy and safety of Shengmai capsule treatment in patients with chronic congestive heart failureObjective: To evaluate efficacy and safety of Shengmai capsule treatment in patients withchronic congestive heart failure (CHF) by interim analysis.Design: Double-blind, randomized, placebo-controlled interim analysis.Selection of patients1. Setting: Second affiliated hospital, Guangzhou university of TCM and other first grade of third class hospital.2. 138 patients accord with diagnose criterion, inclusion criterion, and exclusion criterion. Sample size calculationThe efficacy variable was based on the left ventricular ejection fraction (LVEF), a total alpha of 0.05 and power of 90% and two side test, O'Brien & Fleming of the group sequential analysis and the software of PASS 2002 were chosen as interim analysis, the total of sample size were 360 patients.Intervention1. Treatment group: Patients were given an oral dose of 3 grain of Shengmai capsule, which was repeated thrice daily for 6 months.2. Control group: Patients were given an oral dose of 3 grain of placebo capsule, which was repeated thrice daily for 6 months.All patients were given the CHF' standard therapy: a diuretic, or/and an angiotensin converting enzyme inhibitor, or/and a Beta adrenoceptor antagonist, or/and a cardiac glycoside, and treatment complications also. Observation variable1. General items: Symptoms, signs, laboratory examinations, etc.2. Efficacy variable: The New York Heart Association (NYHA) classes, transthoracic Doppler echocardiography, the scores of integral symptoms of TCM, quality of life, apply of the drugs during the trial, etc.3. Mortality and serious clinical event rates.4. Safety monitoring.5. To inspect adverse events/adverse reactions, serious adverse events/serious adverse drug reactions.6. Follow-up: Patients were visit every 2 weeks, and with regular follow-up visits at before treatment, 12 weeks and 24 weeks respectively, for a planned average follow-up of 24 weeks.Interim analysis1. Method: The O'Brien & Fleming of the group sequential analysis.2. The stopping rules: The nominal alpha level and the O'Brien & Fleming decision boundary are: a1'=0.003051, Z1=2.96259; a2'=0.049002, Z2=1.96857 separately, controlling the overall type I error probability at the conventional 0.05 level of two side test.(l)p-value0. 05).6. Event rates: There were no significance differences on mortality and serious clinical event rates between 2 treatment groups (p>0. 05).7. Safety: The drug-related adverse signs and symptoms occurred in A group 4.6153%(3/65). The abnormalities of the laboratory examinations occurred no significance differences between 2 treatment groups (p>0. 05). Overall, no adverse effects were serious enough to discontinue double-blind treatment during the maintenance period. All these patients were successfully treated and discharged.Conclusions: The first interim analysis did not indicated to have differences between two groups, and can not make decisions to terminate the trial early, and to recommend to proceed with this trail.(二) The methodoIogy for performing an interim analysis in the cIinical trial of traditional Chinese medicineThe interim analysis plan1. A standard operating procedure providing for(l)The possibility of an early termination of the trial as a result of the planned interimanalysis; (2)The introduction of unscheduled interim analyses into an ongoing trial withdescriptions of authority, request for the analysis, and what actions could result; (3) Accessibility and safeguarding of patient treatment assignment codes and identifyingwhich patient data will be unblinded; (4)Documentation of all procedures followed, actions, and decisions made that couldaffect interpretation of results or conduct of the trial.2. A prospective interim analysis plan within the protocol indicating timing, methods to control type I error probability, and the decision rule describing the expected consequences of various outcomes of the interim analysis. (l)The schedule and times of interim analyses.(2)The stopping rules reflect one of the following conditions: ①There is clear evidence of harm or harmful side-effects of the treatment; ②There is no likelihood of demonstrating treatment benefit; or ③There is overwhelming evidence of the benefit of the treatment.(3)The methods of interim analyses. The structure of interim analysisThe structure of interim analysis includes blinding and unblinding parts. Four key organizations are necessary for the successful conduct of an interim analysis. These are the executive committee, the DSMB, the clinical trial investigators and the statistic analyses groups. The execution of an interim analysisThe DSMB would be responsible for the execution of the interim analysis; communication of information would follow the "need-to-know" principle. Members of the DSMB were to be selected strictly by credentials and expertise. DSMB meetings were to consist of open and closed sessions. The DSMB was required to keep detailed meeting minutes. These minutes were to be kept in a confidential file inaccessible to the sponsors. Statistical and programming processThe analysis of the data must be performed on a static version of the database, which must be archived to provide a clear audit trail as well as to allow for future analyses. Terminate trialThe sponsor should launch the news of early stop the trial without delay.(三) Efficacy endpoint selection methods and technology issues for chronic congestive heart failure with shengmai capsule treatmentMethods and selection of endpointsThe selection of the best response variables for the assessment of the efficacy of atreatment in congestive heart failure patients is: ①Mortality as an endpoint; ②Rate of (re-)hospitalization as an endpoint; ③Functional status; ④Quality of life; ⑤Worsening heart failure; ⑥Objective evaluation of functional capacity; ⑦Composite variables, etc. Evaluation technology issues1. One primary efficacy endpointThe ideal situation is one that permits characterization of the disease and patients' response by a single primary endpoint, but this is impossible in many situations,2. Multiple primary efficacy endpointsBesides the clinical desire to demonstrate therapeutic effect in several endpoints, disease complexity or lack of a clinical consensus on the most important clinical endpoint often necessitates the design of clinical trials with two or more primary endpoints.3. Composite primary efficacy endpointIn some therapeutic areas where the disease manifests itself in a multi-faceted manner, drug effectiveness is often characterized by the use of composite endpoints. Clinical and statistical expectation1. Clinical and statistical expectation under a single primary endpointFor a clinical trial with a single primary endpoint, there is a single decision-making process. Drug effectiveness is said to be demonstrated only if a clinically meaningful treatment effect size (as pre-specified in the protocol) is realized and statistical significance is shown at a prospectively specified nominal α -level with respect to the declared single primary endpoint. All therapeutic efficacy claims are limited to the efficacy evidence provided by the primary endpoint.2. Clinical and statistical expectation under multiple endpointsFor a clinical trial with two or more primary endpoints, there are at least three possible clinical decision-making scenarios regarding drug effectiveness. That is: ①statistical significance is demonstrated at the pre-specified nominal α -level for all primary endpoints, or ②statistical significance is demonstrated at the pre-specified nominal α -level for the majority (where what constitutes the majority is prospectively defined in the protocol) of the primary endpoints, or ③statistical significance is demonstrated at the pre-specified nominal α -level for one or more of the primary endpoints.3. Clinical and statistical expectations for composite endpointsThe statistical expectation of overall statistical significance is demonstrated at a pre-specified α -level for composite endpoints. Multiple endpoint adjustment strategies for controlling type I error rateIf the objective of the clinical trial is to demonstrate therapeutic effect using several independent, dissimilar, or lowly correlated (0≤p≤0.1) clinical primary endpoints and the endpoints of interest are not too many, endpoint specific conclusions can usually be made by the direct use of univariate adjustment methods. If therapeutic effect is to be...