Immunogenicity and safety of an egg culture-based quadrivalent inactivated non-adjuvanted subunit influenza vaccine in subjects ≥3 years: A randomized,multicenter, double-blind,active-controlled phase III,non-inferiority trial

Subunit influenza vaccine only formulated with surface antigen proteins has better safety profiles relative to split-virion influenza vaccine. Compared to the traditional quadrivalent split-virion influenza vaccine, a novel quadrivalent subunit influenza vaccine is urgently needed in China. We completed a phase 3, randomized, double-blind, active-controlled, non-inferiority clinical study at two sites in Henan Province, China. Eligible volunteers were split into four age cohorts (3–8 years, 9–17 years, 18–64 years, and ≥ 65 years, based on their dates of birth) and randomly assigned (1:1) to the subunit and the split-virion ecNAIIV4 groups. All volunteers were intramuscularly administered a single vaccine dose at baseline, and children aged 3–8 years received a boosting dose at day 28. And the immune response was evaluated by measuring hemagglutinin-inhibition antibody titers against the four vaccine strains in blood samples. Safety profiles had nonsignificant differences between the study groups in ≥ 3 years cohort. Most adverse reactions post-vaccination, both local and systemic, were mild to moderate and resolved within 3 days. And no serious adverse events occurred. The immunogenicity of the trial vaccine was non-inferior to the comparator. Further, a two-dose vaccine series can provide better seroprotection than that of a one-dose series in children aged 3–8 years, with clinically acceptable safety profiles.Clinical Trials Registration. ChiCTR2100049934.     

Power and sample size for cost-effectiveness analysis: fFN neonatal screening

Randomised controlled trials (RCTs) which involve cost-effectiveness evaluations rarely use health economic input when undertaking sample size calculations for the trial design; however, in studies undertaken with cost-effectiveness as the primary outcome, sample size calculations should be directly related to the cost-effectiveness result rather than to the effectiveness outcome alone. This paper reports on a case in which a clinical trial design sample size and power calculations were determined with regard to cost-effectiveness using the net monetary benefit (NMB) approach to demonstrate the feasibility of sample size calculation for cost-effectiveness in a real life setting.The proposed RCT of fetal fibronectin screening (fFN) for women with threatened pre-term labour is discussed, followed by the design of a preliminary model to inform the trial design calculation. The predictions from this pre-trial indicate potential cost-savings, but with a marginal detrimental impact on the effectiveness endpoint, neonatal morbidity. The NMB approach for cost-effectiveness is discussed and used to calculate the required sample sizes for different powers. The sample size calculations are then recalculated using a non-inferiority margin, to ensure that the NMB sample size for the trial was also sufficient to demonstrate non-inferiority for the effectiveness endpoint. Finally, a probabilistic analysis explored uncertainty in the model parameters and the impact on sample size.Considerations of economic assessments alongside clinical trials can and should be used to guide conventional trial design. This paper demonstrates the feasibility of such calculations, whilst simultaneously highlighting limitations and demonstrating the role for economic considerations to guide non-inferiority margins.     

Inequality in access to CABG and PCI

Abstract

Non-inferiority trials are questionable when death and serious complications are included among outcomes. The term itself “non-inferiority” is misleading, since such a study would not demonstrate that a new treatment is non-inferior to a control treatment, but simply that the inferiority would not reach a pre-specified level, deemed as acceptable by the designers of the trial. Group cross-over, assay-sensitivity and the need of a placebo arm are major issues for the reliability of non-inferiority trials.

The SYNTAX trial for severe coronary artery disease was designed on a non-inferiority margin of 6.6%. In this paper we show that the SYNTAX designers were ready to accept up to 30% higher rate of death and major adverse events to claim the non-inferiority of percutaneous coronary intervention versus coronary artery bypass grafting. Eventually the SYNTAX study failed because percutaneous patients sustained an even higher rate of adverse events. We propose major caution in performing non-inferiority randomized trials.     

Non-inferiority tests for binary endpoints with variable margins

ABSTRACT

Non-inferiority comparison between binary response rates of test and reference treatments is often performed in clinical studies. The most common approach to assess non-inferiority is to compare the difference between the estimated response rates with some margin. Previous methods use a variety of margins, including fixed margin, step-wise constant margin, and piece-wise smooth margin, where the latter two are functions of the reference response rate. The fixed margin approach assumes that the margin can be determined from historical trials with the consistent difference between the reference treatment and placebo, which may not be available. The step-wise constant margin approach suffers discontinuity in the power function which can cause trouble in sample size determination. Furthermore, many methods ignore the variability in margins dependent on the estimated reference response rate, leading to poor type I error control and power function approximation. In this study, we propose a variable margin approach to overcome the difficulties in fixed and step-wise constant margin approaches. We discuss several test statistics and evaluate their performance through simulation studies.     

非劣效性临床试验中两组率差值的协变量调整方法

目的 解决新药非劣效性临床试验评价中两组率差值的协变量调整问题.方法 利用ROC曲线与两组率差值的对应关系,通过ROC分析间接得到调整协变量之后两组率之差的估计值及标准误.结果 给出了一种新的非参数分层分析方法,如果协变量对有效率有影响,可以通过调整分析得到更准确的检验结果.结论 本文提供的方法能够更直观、有效地对新药临床试验的数据进行非劣效性评价.     

红花黄色素冻干粉针剂与红花黄色素滴注液治疗冠心病心绞痛(心血瘀阻证)的临床非劣性试验

目的　评价红花黄色素冻干粉针剂与红花黄色素滴注液治疗冠心病心绞痛(心血瘀阻证)的有效性和安全性,并与阳性对照药丹参注射液作非劣性分析。方法　选择每周心绞痛发作2次以上的Ⅰ、Ⅱ、Ⅲ级稳定型劳累性心绞痛者784例进行分层分段随机、盲法、同一阳性药对照、五组平行、多中心的非劣性临床试验,其中试验组1纳入224例,采用红花黄色素冻干粉剂80mg+ 0 9%NS250ml静滴,每日1次;试验组2纳入112例,采用红花黄色素冻干粉针剂160mg+ 0 9% NS250ml静滴,每日1次;试验组3纳入112例,采用红花黄色素滴注液200ml(160mg)静滴,每日1次;试验组4纳入224例,采用红花黄色素滴注液100ml(80mg)静滴,每日1次。对照组纳入112例,给予丹参注射液20ml+ 0 .9% NS250ml静滴,每日1次。治疗14天后,评价各试验组及其对照组的临床有效性和安全性。结果　治疗心绞痛疗效(PP数据):试验组1~4与对照组相比,其显效率为分别为53 .27%、69 .44%、70. 09%、55. 09%和26. 00%,总有效率分别为88 .79%、92 .59%、93. 46%、89 .81%和73. 00%。试验组1与试验组2比较、试验组3与试验组4比较、试验组1~4分别与对照组比较,其差异均有统计意义(P<0 .05),试验组2的疗效优于试验组1,试验组3的疗效优于试验组4, 4个试验组的疗效均优于对照组,非劣性检验合格     

Randomized controlled trial of two dosing schedules for human papillomavirus vaccination among college age males

Background

Quadrivalent human papillomavirus (HPV) vaccine, for protection against sexually transmitted HPV infection, is licensed for females and males 9–26 years on a 3-dose schedule (0, 2, and 6 months; Standard schedule). Vaccine uptake has been low and catch-up vaccination of older adolescents using an alternate dosing schedule may increase coverage. This study tested the non-inferiority of the immunogenicity of an alternate dosing schedule (0, 2, 12 months) among college age males.

Methods

220 18–25 year old males were randomly assigned to Standard or Alternate schedules. Blood samples were drawn immediately before Dose 1 and 2–6 weeks after Dose 3 and analyzed for antibody titers using a Luminex immunoassay. A value <1.5 for the upper 95% confidence interval (CI) bound of the Standard to Alternate schedule geometric mean titer (GMT) ratio was deemed non-inferior.

Results

Participants averaged 21.3 years old; 19.1% were non-white; completion rate was 93%. The anti-HPV titers for the Alternate schedule group were non-inferior to those of Standard schedule group for all four HPV vaccine virus types. Our results also demonstrated superiority of the Alternate schedule group for all four HPV vaccine virus types.

Conclusion

A delayed third dose at 12 months is immunologically non-inferior and superior for four HPV virus types. Using an alternate dosing schedule offers more flexibility to receive the 3-dose HPV vaccine and may result in higher vaccination rates among college-age males.     

Immunogenicity and safety of two novel human papillomavirus 4- and 9-valent vaccines in Chinese women aged 20–45 years: A randomized,blinded, controlled with Gardasil (type 6/11/16/18), phase III non-inferiority clinical trial

BackgroundHuman papillomavirus (HPV) infections were the main cause of anogenital cancers and warts. HPV 6/11/16/18 vaccines provide protection against the high-risk types of HPV responsible for 70% of cervical cancers and 90% of genital warts. This randomized, blinded, non-inferiority phase III trial was to determine whether immunogenicity and tolerability would be non-inferior among women after receiving two novel 4- and 9-valent HPV vaccines (4vHPV, HPV 6/11/16/18; 9vHPV, HPV 6/11/16/18/31/33/45/52/58) compared with those receiving Gardasil 4 (4-valent).Methods1680 females between 20 and 45 years were randomized in a 2:1:1 ratio to 20–26, 27–35, or 36–45 y groups. Subjects then equally assigned to receive 4vHPV, 9vHPV or Gardasil 4 (control) vaccine at months 0, 2, and 6. End points included non-inferiority of HPV-6/11/16/18 antibodies for 4vHPV versus control, and 9vHPV versus control and safety. The immunogenicity non-inferiority was pre-defined as the lower bound of 95% confidence interval (CI) of seroconversion rate (SCR) difference > ?10% and the lower bound of 95% CI of geometric mean antibody titer (GMT) ratio > 0.5.ResultsAmong the three vaccine groups, more than 99% of the participants seroconverted to all 4 HPV types. The pre-specified statistical non-inferiority criterion for the immunogenicity hypothesis was met: all the lower bounds of 95% CIs on SCR differences exceeded ?10% for each vaccine HPV type and the corresponding lower bounds of 95% CIs for GMT ratios > 0.5. Across vaccination groups, the most common vaccination reaction were injection-site adverse events (AEs), including pain, swelling, and redness. General and serious AEs were similar in the three groups. There were no deaths.ConclusionsThis study demonstrated that the novel 4- and 9-valent HPV vaccination was highly immunogenic and generally well tolerated, both of which were non-inferior to Gardasil 4 in immunogenicity and safety.     

Centchroman Regresses Mastalgia: A Randomized Comparison with Danazol

We conducted a randomized trial to evaluate effectiveness of Centchroman in control of mastalgia and compared it with Danazol. Research Question- Is proportion of pain relief achieved by Centchroman similar to or inferior to that achieved by Danazol? In a randomized controlled trial of Centchroman vs. Danazol in mastalgia, 81 patients with mastalgia were studied. Thirty-nine patients were randomized to Danazol arm and 42 in Centchroman arm. The treatment was given for 12 weeks, followed by observation for 12 weeks. The pain was measured by visual analogue scale (VAS) of 0–10. At 12 weeks 89.7% women achieved reduction in pain score to ≤3 in Centchroman group (pvalue 0.001). In Danazol group 69.44% women achieved reduction in pain score to ≤ 3 (p = 0.001). Three months after stopping therapy, Centchroman was more effective in pain score reduction at 24 weeks as compared to Danazol (p = 0.019). Centchroman is an effective, safe and inexpensive alternative to Danazol for treatment of mastalgia.

Electronic supplementary material

The online version of this article (doi:10.1007/s12262-010-0216-z) contains supplementary material, which is available to authorized users.