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

Common threads between sample size recalculation and group sequential procedures

2003 ◽  
Vol 2 (4) ◽  
pp. 263-271 ◽  
Author(s):  
Todd A. Schwartz ◽  
Jonathan S. Denne
Keyword(s):  
Sample Size ◽  
Group Sequential ◽  
Sequential Procedures

Group sequential designs with robust semiparametric recurrent event models

2018 ◽  
Vol 28 (8) ◽  
pp. 2385-2403 ◽  
Author(s):  
Tobias Mütze ◽  
Ekkehard Glimm ◽  
Heinz Schmidli ◽  
Tim Friede
Keyword(s):  
Error Rate ◽  
Joint Distribution ◽  
Recurrent Events ◽  
Type I Error ◽  
Type I ◽  
Sequential Designs ◽  
Group Sequential ◽  
Type I Error Rate ◽  
Sequential Procedures ◽  
Group Sequential Designs

Robust semiparametric models for recurrent events have received increasing attention in the analysis of clinical trials in a variety of diseases including chronic heart failure. In comparison to parametric recurrent event models, robust semiparametric models are more flexible in that neither the baseline event rate nor the process inducing between-patient heterogeneity needs to be specified in terms of a specific parametric statistical model. However, implementing group sequential designs in the robust semiparametric model is complicated by the fact that the sequence of Wald statistics does not follow asymptotically the canonical joint distribution. In this manuscript, we propose two types of group sequential procedures for a robust semiparametric analysis of recurrent events. The first group sequential procedure is based on the asymptotic covariance of the sequence of Wald statistics and it guarantees asymptotic control of the type I error rate. The second procedure is based on the canonical joint distribution and does not guarantee asymptotic type I error rate control but is easy to implement and corresponds to the well-known standard approach for group sequential designs. Moreover, we describe how to determine the maximum information when planning a clinical trial with a group sequential design and a robust semiparametric analysis of recurrent events. We contrast the operating characteristics of the proposed group sequential procedures in a simulation study motivated by the ongoing phase 3 PARAGON-HF trial (ClinicalTrials.gov identifier: NCT01920711) in more than 4600 patients with chronic heart failure and a preserved ejection fraction. We found that both group sequential procedures have similar operating characteristics and that for some practically relevant scenarios, the group sequential procedure based on the canonical joint distribution has advantages with respect to the control of the type I error rate. The proposed method for calculating the maximum information results in appropriately powered trials for both procedures.

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.

Some group sequential procedures for comparing several treatments with a control

1996 ◽  
Vol 23 (4) ◽  
pp. 371-383 ◽  
Author(s):  
W. Liu
Keyword(s):  
Group Sequential ◽  
Sequential Procedures

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

scholarly journals TRLS-03. PHASE II TRIAL OF GDC-0084 IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i9-i9
Author(s):  
Jose Pablo Leone ◽  
Lorenzo Trippa ◽  
Lindsey Milisits ◽  
Chelsea Andrews ◽  
Jennifer Ligibel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Cns Metastases ◽  
Her2 Positive ◽  
Two Stage ◽  
Her2 Positive Breast Cancer ◽  
Cns Metastasis ◽  
Positive Breast Cancer

Abstract BACKGROUND: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha < 10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983.

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.

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