Designing clinical trials with (restricted) mean survival time endpoint: Practical considerations

2020 ◽  
Vol 17 (3) ◽  
pp. 285-294
Author(s):  
Anne Eaton ◽  
Terry Therneau ◽  
Jennifer Le-Rademacher
Keyword(s):  
Survival Time ◽  
Primary Endpoint ◽  
R Package ◽  
Rank Test ◽  
Mean Survival Time ◽  
Log Rank Test ◽  
Restricted Mean Survival Time ◽  
Time Test ◽  
The Mean ◽  
The Difference

Background/aims: The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators’ lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint. Methods: A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs. Results: Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied. Conclusion: The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint.

scholarly journals Assessing Clinical Equivalence in Oncology Biosimilar Trials With Time-to-Event Outcomes

2019 ◽  
Vol 3 (4) ◽  
Author(s):  
Hajime Uno ◽  
Deborah Schrag ◽  
Dae Hyun Kim ◽  
Dejun Tang ◽  
Lu Tian ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Time ◽  
Primary Endpoint ◽  
Reference Product ◽  
Survival Curve ◽  
Treatment Decision ◽  
Hazard Ratio ◽  
Treatment Decision Making ◽  
Mean Survival Time ◽  
Restricted Mean Survival Time

Abstract A typical biosimilar study in oncology uses the overall response evaluated at a specific time point as the primary endpoint, which is generally acceptable regulatorily, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, progression-free or overall survival would be a secondary endpoint in a biosimilar trial. With a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study. In this article, we show that an alternative procedure based on the restricted mean survival time, which has been discussed extensively for design and analysis of a general equivalence study, is readily applicable to a biosimilar trial. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence. Using the restricted mean survival time as a summary measure of the survival curve will enhance better treatment decision making in adopting a biosimilar product over the reference product.

scholarly journals Design of non-inferiority randomized trials using the difference in restricted mean survival times

2018 ◽  
Vol 15 (5) ◽  
pp. 499-508 ◽  
Author(s):  
Isabelle R Weir ◽  
Ludovic Trinquart
Keyword(s):  
Sample Size ◽  
Survival Time ◽  
Trial Design ◽  
Time Horizon ◽  
Hazard Ratio ◽  
Sample Sizes ◽  
Time To Event ◽  
Mean Survival Time ◽  
Restricted Mean Survival Time ◽  
The Difference

Background/aims Non-inferiority trials with time-to-event outcomes are becoming increasingly common. Designing non-inferiority trials is challenging, in particular, they require very large sample sizes. We hypothesized that the difference in restricted mean survival time, an alternative to the hazard ratio, could lead to smaller required sample sizes. Methods We show how to convert a margin for the hazard ratio into a margin for the difference in restricted mean survival time and how to calculate the required sample size under a Weibull survival distribution. We systematically selected non-inferiority trials published between 2013 and 2016 in seven major journals. Based on the protocol and article of each trial, we determined the clinically relevant time horizon of interest. We reconstructed individual patient data for the primary outcome and fit a Weibull distribution to the comparator arm. We converted the margin for the hazard ratio into the margin for the difference in restricted mean survival time. We tested for non-inferiority using the difference in restricted mean survival time and hazard ratio. We determined the required sample size based on both measures, using the type I error risk and power from the original trial design. Results We included 35 trials. We found evidence of non-proportional hazards in five (14%) trials. The hazard ratio and the difference in restricted mean survival time were consistent regarding non-inferiority testing, except in one trial where the difference in restricted mean survival time led to evidence of non-inferiority while the hazard ratio did not. The median hazard ratio margin was 1.43 (Q1–Q3, 1.29–1.75). The median of the corresponding margins for the difference in restricted mean survival time was −21 days (Q1–Q3, −36 to −8) for a median time horizon of 2.0 years (Q1–Q3, 1–3 years). The required sample size according to the difference in restricted mean survival time was smaller in 71% of trials, with a median relative decrease of 8.5% (Q1–Q3, 0.4%–38.0%). Across all 35 trials, about 25,000 participants would have been spared from enrollment using the difference in restricted mean survival time compared to hazard ratio for trial design. Conclusion The margins for the hazard ratio may seem large but translate to relatively small differences in restricted mean survival time. The difference in restricted mean survival time offers meaningful interpretation and can result in considerable reductions in sample size. Restricted mean survival time-based measures should be considered more widely in the design and analysis of non-inferiority trials with time-to-event outcomes.

Effect of Aggressive Haemoperfiusion on the Clinical Course of Patients with Paraquat Poisonin

1993 ◽  
Vol 12 (4) ◽  
pp. 323-327 ◽  
Author(s):  
Kouichiro Suzuki ◽  
Nobukatsu Takasu ◽  
Toru Okabe ◽  
Shinichi Ishimatsu ◽  
Akinori Ueda ◽  
...  
Keyword(s):  
Survival Time ◽  
Clinical Course ◽  
Survival Rates ◽  
Urine Volume ◽  
Rank Test ◽  
Log Rank Test ◽  
Paraquat Poisoning ◽  
Initial Plasma ◽  
Number Of Patients ◽  
The Difference

The effect of aggressive haemoperfusion; i.e. haemoperfusion of 10 h or more during the first 24 h after ingestion, on the clinical course of paraquat poisoning was studied. Among 40 patients admitted within 15 h after ingestion of paraquat with an SIPP of less than 100 (h x μg ml-1), 21 received aggressive haemoperfusion and 19 received conventional haemoperfusion; i.e. haemoperfusion of less than 10 h during the same period. Survival rates of patients with severity between an SIPP of 100 and Proudfoof's curve in the two groups were compared by the log-rank test. Aggressive haemoperfusion did not improve the outcome but did improve the survival rates; that is, the number of patients surviving at particulalr points in time (P<0,05). The length of haemoperfusion for the aggressive haemoperfusion group was longer than that for the conventional group on the first day (P<0.001 ), but the difference was insignificant during the following two days. Neither the time from ingestion to haemoperfusion, urine volume from the first to third day, nor initial plasma-paraquat concentrations and SIPP were significant between groups. These findings imply that aggressive haemoperfusion reduces the severity of paraquat poisoning and elongates survival time. We, therefore, propose that the efficacy of more aggressive haemoperfusion, such as the 'continuous haemoperfusion' proposed by Okonek et al., should be further studied.

scholarly journals Sobrevida em crianças e adolescentes infectados via vertical pelo hiv e fatores associados ao óbito

2017 ◽  
Vol 11 (12) ◽  
pp. 5328
Author(s):  
Jucielma De Jesus Dias ◽  
Maria Conceição Oliveira Costa ◽  
Carlos Alberto Lima Da Silva ◽  
Gabrielly Carneiro Dias
Keyword(s):  
Survival Time ◽  
Opportunistic Infections ◽  
Clinical Laboratory ◽  
Rank Test ◽  
Protection Factor ◽  
Log Rank Test ◽  
Factores De Riesgo ◽  
The Mean ◽  
Transmisión Vertical ◽  
Clinical Records

RESUMOObjetivo: analisar o tempo de sobrevida e fatores associados ao óbito em crianças e jovens infectados via vertical pelo HIV. Método: estudo quantitativo, observacional, longitudinal, utilizando registros do Centro de Referência DST/HIV/SIDA. Foram revisados 63 prontuários clínicos de indivíduos entre 0 e 24 anos e utilizada análise de sobrevivência com teste log-rank e regressão de riscos proporcionais de Cox para estimativa ajustada dos fatores de risco para óbito. Resultados: análises multivariadas mostraram significância para idade cronológica como fator de proteção (HR: 0,88; IC 95%: 0,78-0,98) e infecção oportunista não oral como fator de risco (HR:4,3; IC 95%: 1,51-12,1). O tempo médio da sobrevida foi 8,8 anos, sendo 10,6 anos, após uso de antirretroviral, e 6 anos, sem uso. Conclusão: houve aumento da sobrevida, com uso de TARV pela maioria, controle clínico-laboratorial e infecções oportunistas, possivelmente influenciando este resultado e predomínio de óbitos relacionados à AIDS. Descritores: HIV; Sobrevida; Fatores Associados; Transmissão Vertical.ABSTRACTObjective: to analyze survival time and factors associated with death in HIV-infected children and adolescents. Method: this is a quantitative, observational, longitudinal study using records from the STD/HIV/AIDS Reference Center. Sixty-three clinical records of individuals between 0 and 24 years old were reviewed and a survival analysis with a log-rank test and Cox proportional risk regression were used to estimate the risk factors for death. Results: multivariate analyses showed significance for chronological age, as protection factor (RR: 0.88; 95% CI: 0.78-0.98); non-oral opportunistic infection as a risk factor (RR: 4.3; 95% CI: 1.51-12.1). The mean survival time was 8.8 years; being 10.6 years, after antiretroviral use and 6 years, without using it. Conclusion: there was an increase in survival, with the use of ART by the majority, clinical-laboratory control, and opportunistic infections, possibly influencing this result and the predominance of AIDS-related deaths. Descriptors: HIV; Survival; Associated factors; Vertical Transmission.RESUMENObjetivo: analizar tiempo de sobrevivencia y factores asociados al óbito en niños y jovenes infectados via vertical por el VIH. Método: estudio cuantitativo, observacional, longitudinal, utilizando registros del Centro de Referencia DST/HIV/SIDA. Fueron revisados 63 prontuarios clínicos de individuos entre 0 a 24 años y fue utilizado el análisis de sobrevivencia con teste log-rank y regresión de riesgos proporcionales de Cox, para estimativa ajustada de los factores de riesgo para óbito. Resultados: análisis multivariados mostraron significancia para edad cronológica, como factor de protección (HR: 0,88; IC 95%: 0,78-0,98); infección oportunista no oral, como factor de riesgo (HR:4,3; IC 95%: 1,51-12,1). El tiempo medio de sobrevivência fue 8,8 años; siendo 10,6 años, después con uso de antirretroviral y 6 años sin uso. Conclusión: hubo aumento de la sobrevivencia, con uso de TARV por la mayoría, control clínico-laboratorial e infecciones oportunistas, posiblemente influyendo este resultado y predominio de óbitos relacionados al Sida. Descriptores: VIH; Supervivencia; Factores Asociados; Transmisión Vertical.

Meld Score: A Reliable Predictor of Mortality and Post Operative Complications in Patients with Chronic Liver Disease Undergoing Non-Transplant Surgeries

2021 ◽  
Vol 28 (03) ◽  
pp. 355-360
Author(s):  
Talha Kareem ◽  
Muhammad Farrukh Aftab ◽  
Junaid Hashmi ◽  
Muzzafar Aziz ◽  
Abdul Hanan Javaid ◽  
...  
Keyword(s):  
Liver Disease ◽  
Survival Time ◽  
Operative Mortality ◽  
Scoring Systems ◽  
Meld Score ◽  
Rank Test ◽  
P Value ◽  
Log Rank Test ◽  
The Mean ◽  
End Stage

Context: Patients with liver disease are always at high risk of post-operative complications. The prediction of postoperative outcome is very crucial in the management of these patients. Various prediction models are in use to serve this purpose. Childs-Turcotte-Pugh (CTP) and Model of End-Stage Liver Disease (MELD) scoring systems are globally used to predict post-operative mortality in end stage liver disease patients. Aims: To compare the results of CTP and MELD scoring systems for predicting outcome in patients of chronic liver disease and to conclude which model is better for risk stratification, so as to enable us in better management of these patients. Settings and Design: Observational study Methods and Material: This is an Observational study that was carried out at General Surgery Department of Nishtar Medical University and Hospital from October 2019 to March 2020. We collected data from 30 patients. All the surgeries were done by the same team of consultant surgeons. All the investigations were done by the same institution. Scores of both CTP and MELD models were calculated preoperatively and post-operative outcome was compared with them to find out which model was a better predictor of mortality. Statistical analysis used: All the continuous variables were reported as mean ± standard deviation. Kaplan Meyer Survival Analysis was conducted to compare post-op survival time among patients divided on the basis of MELD score and CTP Grade. Pooled log rank test was conducted to determine if there were differences in the survival distributions for the different categories in each group. Significant results were followed-up by pair-wise log rank test, at Bonferroni adjusted α level of p <0.0167. Results: In our study the mean survival time of 71.20, 54.93, 8.40 for MELD scores of 11-20, 21-30 and >30 has a P value of <0.001. The mean survival time of 56, 54.85, 42.40 for CTP grades of A, B, and C respectively has a P value of 0.582. It shows that according to our study the MELD score has performed better in predicting the post-operative outcome of patients with liver diseases than CTP score. Conclusions: Although CTP and MELD both are widely used to predict the post-operative mortality but in our study MELD score has predicted the outcome more effectively than CTP scoring system.

scholarly journals Clinicopathological study of gastrointestinal Lymphomas and their survival in the patients referred to Yazd hospitals during 2011 to 2016

2020 ◽  
Author(s):  
Shokouh Taghipour Zahir ◽  
Mohammad Shafiee ◽  
Mohammad Hossein MirArabshahi2
Keyword(s):  
Survival Rate ◽  
Survival Time ◽  
B Cell Lymphoma ◽  
Common Type ◽  
Rank Test ◽  
Gastrointestinal Lymphoma ◽  
Mean Survival Time ◽  
Gastrointestinal Lymphomas ◽  
The Mean ◽  
Hodgkin's Lymphomas

Introdution: Malignant lymphoma is divided into two subgroups of Hodgkin's and non-Hodgkin's, and 40% of them occur in areas other than the lymph node, the most common being the digestive tract. According to studies, in recent years the prevalence of non-Hodgkin's lymphomas has increased over the past. Therefore, in this study, we investigated the gastrointestinal lymphoma and the survival rate of the patients with this disease based on clinicopathologic characteristics. Methods: This study was an analytic-cross sectional study. The study population included 97 patients with various types of gastrointestinal lymphoma referring to 3 hospitals in Yazd during 2011-2011. Sampling was done by census. Referring to pathology department of hospitals, all cases related to gastrointestinal tract lymphoma extracted and the information (age, sex, year of diagnosis, type of lymphoma, location of lymphoma, treatment method and survival rate) using the checklist was recorded. The data were analyzed by SPSS18 software and patients' survival was assessed using Kaplan-Meier curves and Log-Rank test. Results: The results of the study showed that out of 97 patients, 69 patients (71.1%) were male and 28 (28.9%) were female. The mean age of the patients was 49.28±21.5. The most common site of lymphoma was stomach (45.4%), the most common type of treatment, surgical+ chemotherapy (53.6%), and the most common type of lymphoma, B cell lymphoma (50%). The mean survival time was 48 months and there was a significant relationship between mean survival time according to type of treatment. Conclusion: According to the results, it can be concluded that the appropriate treatment for patients with gastrointestinal lymphomas is surgical+chemotherapy combination therapy.

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