Critical Boundary Refinement in a Group Sequential Trial When the Primary Endpoint Data Accumulate Faster Than the Secondary Endpoint

2019 ◽  
pp. 205-224
Author(s):  
Jiangtao Gou ◽  
Oliver Y. Chén
Keyword(s):  
Primary Endpoint ◽  
Secondary Endpoint ◽  
Group Sequential ◽  
Sequential Trial ◽  
Critical Boundary ◽  
Endpoint Data ◽  
Boundary Refinement

Improved two-stage group sequential procedures for testing a secondary endpoint after the primary endpoint achieves significance

2018 ◽  
Vol 60 (5) ◽  
pp. 893-902
Author(s):  
Huiling Li ◽  
Jianming Wang ◽  
Xiaolong Luo ◽  
Janis Grechko ◽  
Christopher Jennison
Keyword(s):  
Primary Endpoint ◽  
Secondary Endpoint ◽  
Two Stage ◽  
Group Sequential ◽  
Sequential Procedures

scholarly journals On the sample mean after a group sequential trial

2018 ◽  
Vol 125 ◽  
pp. 104-118
Author(s):  
Ben Berckmoes ◽  
Anna Ivanova ◽  
Geert Molenberghs
Keyword(s):  
Group Sequential ◽  
Sample Mean ◽  
Sequential Trial

Abstract 15091: Significant Reductions in Both Adjudicated and Investigator-Reported Ischemic Events in REDUCE-IT

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Deepak L Bhatt ◽  
Robert Giugliano ◽  
Philippe G Steg ◽  
Michael Miller ◽  
Eliot A Brinton ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Coronary Revascularization ◽  
Hazard Ratio ◽  
Secondary Endpoint ◽  
Icosapent Ethyl ◽  
Clinical Events ◽  
High Degree ◽  
Ischemic Events ◽  
Fatal Myocardial Infarction

Introduction: REDUCE-IT was an event-driven trial that randomized 8,179 statin-treated patients with controlled LDL-C and moderately elevated triglycerides to icosapent ethyl (IPE) 4g daily or placebo, with a median of 4.9 years of follow-up. There was a significant reduction in the prespecified adjudicated rates of the primary endpoint (cardiovascular [CV] death, non-fatal myocardial infarction [MI], non-fatal stroke, coronary revascularization, and unstable angina requiring hospitalization) and of the key secondary endpoint (CV death, MI, stroke), as well as in all the primary endpoint components. We sought to determine the effect of IPE on investigator-reported events. Methods: The Clinical Endpoint Committee (CEC) blindly adjudicated investigator-reported events according to a prespecified charter. Medical records and reports were also reviewed to assess for clinical events not reported by investigators. An endpoint management team compiled and electronically provided event packets to the CEC via an adjudication database. The CEC Chair provided final adjudication if the two primary adjudicators could not reach consensus. Results: IPE significantly reduced the rate of the primary endpoint (hazard ratio 0.74, p=0.0000000002) and the key secondary endpoint (hazard ratio 0.75, p=0.000007) as reported by the site investigators, with consistent benefits in each component of the primary endpoint (Table). There was a high degree of concordance between investigator-reported and adjudicated endpoints. Conclusions: Icosapent ethyl significantly reduced multiple types of ischemic events, both by independent, blinded adjudication as well as by investigator-reported assessment. These results underscore the robustness of the benefits of icosapent ethyl seen in REDUCE-IT.

Statistical issues related to early closure of STOP-ROP, a group-sequential trial

2003 ◽  
Vol 24 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Neal L Oden ◽  
Dale L Phelps
Keyword(s):  
Group Sequential ◽  
Sequential Trial ◽  
Early Closure ◽  
Statistical Issues

P5639Risk stratification for mortality using electrocardiographic markers based on 24-hour holter recordings: the JANIES-SHD study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Kinoshita ◽  
K Hashimoto ◽  
K Yoshioka ◽  
Y Miwa ◽  
K Yodogawa ◽  
...  
Keyword(s):  
Heart Disease ◽  
Risk Stratification ◽  
Primary Endpoint ◽  
Left Ventricular ◽  
Hazard Ratio ◽  
Secondary Endpoint ◽  
Cardiac Mortality ◽  
Holter Ecg ◽  
All Cause Mortality ◽  
Holter Recordings

Abstract Background Recent guidelines have stated that reduced left ventricular ejection fraction (LVEF) is the gold standard marker for identifying patients at risk for cardiac mortality. Although reduced LVEF identifies patients at an increased risk of cardiac arrest, sudden cardiac deaths (SCDs) occur considerably more often in patients with relatively preserved LVEF. Current guidelines on SCD risk stratification do not adequately cover this general population pool. Several noninvasive electrocardiographic (ECG) risk stratifiers that reflect depolarization abnormality, repolarization abnormality, and autonomic imbalance have been evaluated so far. With current therapeutic advances using new medicines or devices, an LVEF is often preserved in patients with structural heart disease (SHD). However, the usefulness of noninvasive ECG markers for risk stratification in such a patient population has not yet been elucidated. Purpose This study aimed to assess clinical indices and ECG markers based on 24-hour Holter ECG recordings for predicting cardiac mortality in patients with SHD who have left ventricular dysfunction (LVD) but relatively preserved LVEF. Methods In total, 1,829 patients were enrolled into the Japanese Multicenter Observational Prospective Study (JANIES study). In this study, we analyzed data of 719 patients (569 men, age 64±13 years) with SHD including mainly ischemic heart disease (65.8%). As ECG markers based on 24-hour Holter recordings, nonsustained ventricular tachycardia (NSVT), ventricular late potentials, and heart rate turbulence (HRT) were assessed. The primary endpoint was all-cause mortality, and the secondary endpoint was fatal arrhythmic events. Results During a mean follow-up of 21±11 months, all-cause mortality was eventually observed in 39 patients (5.4%). Among those patients, 32 patients (82%) suffered from cardiac causes such as heart failure and arrhythmia. Multivariate Cox regression analysis showed that after adjustment for age and LVEF, documented NSVT (hazard ratio=2.82, 95% confidence interval [CI]: 1.38–5.76, P=0.005) and abnormal HRT (hazard ratio=2.31, 95% CI: 1.15–4.65, P=0.02) were significantly associated with the primary endpoint. These two ECG markers also had significant predictive values with the secondary endpoint. The combined assessment documented NSVT and abnormal HRT improved predictive accuracy. Conclusion This study demonstrated that combined assessment of documented NSVT and abnormal HRT based on 24-hour Holter ECG recordings are recommended for predicting future serious events in SHD patients who have relatively preserved LVEF. Acknowledgement/Funding Grants-in-Aid (21590909, 24591074, and 15K09103 to T.I.) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technol

Prognostic value of left ventricular remodelling index in idiopathic dilated cardiomyopathy

2020 ◽  
Author(s):  
Yuanwei Xu ◽  
Jiayi Lin ◽  
Yaodan Liang ◽  
Ke Wan ◽  
Weihao Li ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Dilated Cardiomyopathy ◽  
Primary Endpoint ◽  
Prognostic Value ◽  
Extracellular Volume ◽  
Left Ventricular ◽  
Secondary Endpoint ◽  
Idiopathic Dilated Cardiomyopathy ◽  
All Cause Mortality ◽  
Secondary Endpoints

Abstract Aims To evaluate the prognostic value of left ventricular (LV) remodelling index (RI) in idiopathic dilated cardiomyopathy (DCM) patients. Methods and results We prospectively enrolled 412 idiopathic DCM patients and 130 age- and sex-matched healthy volunteers who underwent cardiovascular magnetic resonance imaging between September 2013 and March 2018. RI was defined as the cubic root of the LV end-diastolic volume divided by the mean LV wall thickness on basal short-axis slice. The primary endpoint included all-cause mortality and heart transplantation. The secondary endpoint included the primary endpoint and heart failure (HF) readmission. During the median follow-up of 28.1 months (interquartile range: 19.3–43.0 months), 62 (15.0%) and 143 (34.7%) patients reached the primary and secondary endpoints, respectively. Stepwise multivariate Cox regression showed that RI [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.11–1.30, P < 0.001], late gadolinium enhancement (LGE) presence and log (N-terminal pro-B-type natriuretic peptide) were independent predictors of the primary endpoint, while RI (HR 1.15, 95% CI 1.08–1.23, P < 0.001) and extracellular volume were independent predictors of the secondary endpoint. The addition of RI to LV ejection fraction (EF) and LGE presence showed significantly improved global χ2 for predicting primary and secondary endpoints (both P < 0.001). Furthermore, RI derived from echocardiography also showed independent prognostic value for primary and secondary endpoints with clinical risk factors. Conclusions RI is an independent predictor of all-cause mortality, heart transplantation, and HF readmission in DCM patients and provides incremental prognostic value to LVEF and LGE presence.

scholarly journals P6419Machine learning in critical care: the role of diabetes and age in acute coronary syndromes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Cenko ◽  
M Van Der Schaar ◽  
J Yoon ◽  
Z Vasiljevic ◽  
S Kedev ◽  
...  
Keyword(s):  
Medical Treatment ◽  
Primary Endpoint ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Secondary Endpoint ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Patients With Diabetes ◽  
The Impact

Abstract Background Patients with diabetes and non-ST elevation acute coronary syndrome (NSTE-ACS) have an increased risk of mortality and adverse outcomes following percutaneous coronary intervention (PCI). Purpose We aimed to investigate the impact of early, within 24 hours PCI compared with only routine medical treatment on clinical outcomes in a large international cohort of patients with NSTE-ACS and diabetes. Methods We identified 1,250 patients with diabetes and NSTE-ACS from a registry-based population between October 2010 and April 2016. The primary endpoint was 30-day all-cause mortality. The secondary endpoint was the composite outcome of 30-day all-cause mortality and left ventricular dysfunction (ejection fraction <40%). We undertook analyses to explore the heterogeneity of treatment effects using meta-classification (MC) algorithms followed by propensity score matching and inverse-probability-of-treatment weighting (IPTW) from a landmark of 24 hours from hospitalization. Results Of 1,250 NSTE-ACS first-day survivors with diabetes (median age 67 years; 59%, men), 470 (37.6%) received early PCI and 780 routine medical treatment. The overall 30-day all-cause mortality rates were higher in the routine medical treatment than the early PCI group (6.3% vs. 2.5%). The prediction results of the MC algorithms accounted for only one interaction term that was statistically significant: age ≥65 years. After propensity-matched analysis as well as IPTW, early PCI was associated with reduced 30-day all-cause mortality in the older age (OR: 0.35; 95% CI: 0.14 to 0.92 and 0.43; 95% CI: 0.21 to 0.86, respectively), whereas younger age had no association with the primary endpoint. Similar results were also obtained for the secondary endpoint. Conclusions Among patients with diabetes hospitalized for NSTE-ACS, an early, within 24 hours, PCI strategy is associated with reduced odds of 30-day mortality only for patients aged 65 years or over. MC algorithms provide accurate identification of treatment effect modifiers.

Time to Second Objective Disease Progression (PFS2): An Emerging Clinical Trial Endpoint with Regulatory and Reimbursement Implications

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 6005-6005 ◽  
Author(s):  
Zacharie Mbanya ◽  
Shkun Chadda
Keyword(s):  
Clinical Trial ◽  
Disease Progression ◽  
Primary Endpoint ◽  
Progressive Disease ◽  
Tumour Progression ◽  
Secondary Endpoint ◽  
European Medicines Agency ◽  
Complementary Information ◽  
Stage Of Development ◽  
Cancer Trials

Abstract Introduction: Overall survival (OS) continues to be the preferred endpoint for measuring sustained clinical benefits in oncology trials. In some cases, measuring OS can be problematical due to trial design, multiple lines of treatment (Tx), long survival times, and other factors. In this context, there is growing interest in the time to second objective disease progression (PFS2) for Txs with good toxicity profiles. The European Medicines Agency (EMA) recommends the use of PFS2 to help understand the relevance of meaningful improvements in PFS when OS cannot be measured (e.g. maintenance Tx, increased number of “induction” cycles) (EMA, 2012). PFS2 is defined as “time from randomisation to objective tumour progression on next-line treatment or death from any cause. In some cases, time on next-line therapy may be used as proxy for PFS.” PFS2 is likely to become an important endpoint for regulatory and reimbursement evaluations in Europe and elsewhere as a result of the recent EMA guidance. Therefore there is a need to optimally understand the role PFS2 is likely to play in clinical trial results and their application. Methods: We undertook a search on clinicaltrials.gov for cancer trials that include PFS2 as an endpoint (search terms: cancer AND PFS; cancer AND PFS2). Through mapping of drugs vs. other endpoints, stage of development, likely or current indications, and other factors, we considered whether PFS2 would have a role in a potentially new or changed indication and therefore in regulatory and health technology assessment (HTA) submissions. Based on this, we have identified critical areas where understanding and use of PFS2 data may pose challenges in the submission processes, from the perspectives of the clinical trial sponsor and regulatory agency. Results: As of July 2014, a total of 7,957 cancer trials list PFS as an endpoint; 14 of these include PFS2. In all cases, PFS2 is listed as a secondary endpoint. PFS is the primary endpoint in 13/14, with time to failure as the primary endpoint in 1 trial. OS is not a primary endpoint in any trial that lists PFS2, but is a secondary endpoint in 13 of the 14 trials. It is being studied in the context of either maintenance (10/14 trials) or sequential Tx (3/14) and has the potential for inclusion in regulatory and HTA submissions in all cases. The types of oncology trials in which PFS2 is being assessed included multiple myeloma (n = 3), prostate cancer (n = 2), breast cancer (n = 2), head and neck cancer (n = 1), colorectal cancer (n = 4), non-small cell lung cancer (n = 1), and pancreatic cancer (n = 1). There are 6 phase 2 and 8 phase 3 trials that are listed as either not yet recruiting (n = 4), ongoing (n = 4), or recruiting (n = 6). We identified a number of issues for key groups that may arise from the inclusion of PFS2 in clinical trials. For healthcare professionals there is a need to understand the clinical relevance of a new endpoint that may provide additional and complementary information on Tx of progressive disease from both medical and patient (pt) perspectives. For trial sponsors, clear and clinically relevant communication of PFS2 results is needed and data must be included in medical and economic models. Agencies evaluating regulatory or HTA submissions must understand the benefits shown by an improved PFS2, whether or not there is an improvement in OS, and methodologies for evaluating the medical and economic value of PFS2 are required. Restricting our search to clinicaltrials.gov was associated with some limitations. For example, some trials in which PFS2 has been measured could have been missed due to ongoing updates to publically available information. Also, in some cases, post-hoc analyses may have evaluated PFS2 without a change to website details. Trials in which PFS2 has been measured and data published were not part of the search strategy. Conclusions: PFS2 is emerging as a secondary endpoint in a growing number of clinical oncology trials assessing the benefits of maintenance or sequential Tx. Although data are currently limited, the results of trials currently listed on clinicaltrials.gov will help to determine how PFS2 provides additional and complementary information about Tx of progressive disease from both medical and pt perspectives. Disclosures Mbanya: PHMR Associates: Consultancy. Chadda:PHMR Associates: Consultancy.

scholarly journals A gatekeeping procedure to test a primary and a secondary endpoint in a group sequential design with multiple interim looks

Biometrics ◽  
2017 ◽  
Vol 74 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Ajit C. Tamhane ◽  
Jiangtao Gou ◽  
Christopher Jennison ◽  
Cyrus R. Mehta ◽  
Teresa Curto
Keyword(s):  
Sequential Design ◽  
Secondary Endpoint ◽  
Group Sequential Design ◽  
Group Sequential
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