scholarly journals Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure

Circulation ◽  
2018 ◽  
Vol 138 (10) ◽  
pp. 1039-1053 ◽  
Author(s):  
Stephen J. Greene ◽  
Robert J. Mentz ◽  
Mona Fiuzat ◽  
Javed Butler ◽  
Scott D. Solomon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Drug Development ◽  
Phase Ii ◽  
Temporal Trends ◽  
Lessons Learned ◽  
Phase Iii ◽  
End Points ◽  
Surrogate Outcomes ◽  
Past Experiences

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.

scholarly journals Problems with the outcome measures in randomized controlled trials of traditional Chinese medicine in treating chronic heart failure caused by coronary heart disease: a systematic review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiayuan Hu ◽  
Ruijin Qiu ◽  
Chengyu Li ◽  
Min Li ◽  
Qianqian Dai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Outcome Measures ◽  
Safety Evaluation ◽  
Reporting Quality ◽  
Risk Of Bias ◽  
Efficacy And Safety ◽  
End Points ◽  
Randomized Controlled ◽  
Surrogate Outcomes

Abstract Background Traditional Chinese medicine (TCM) has gained widespread application in treating chronic heart failure (CHF) secondary to coronary heart disease (CHD). However, the sound clinical evidence is still lacking. Corresponding clinical trials vary considerably in the outcome measures assessing the efficacy of TCM, some that showed the improvement of clinical symptoms are not universally acknowledged. Rational outcome measures are the key to evaluate efficacy and safety of each treatment and significant elements of a convincing clinical trial. We aimed to summarize and analyze outcome measures in randomized controlled trials (RCTs) of TCM in treating CHF caused by CHD, subsequently identify the present problems and try to put forward solutions. Methods We systematically searched databases including Embase, PubMed, Cochrane Library, CBM, CNKI, VIP and Wanfang from inception to October 8, 2018, to identify eligible RCTs using TCM interventions for treating CHF patients caused by CHD. Cochrane Database of Systematic Reviews (CDSR) was searched to include Cochrane systematic reviews (CSRs) of CHF. Two authors independently assessed the risk of bias of the included RCTs according to the Cochrane Handbook. Outcome measures of each trial were extracted and analyzed those compared with the CSRs. We also evaluated the reporting quality of the outcome measures. Results A total of 31 RCTs were included and the methodology quality of the studies was generally low. Outcome measures in these RCTs were mortality, rehospitalization, efficacy of cardiac function, left ventricular ejection fraction (LVEF), 6 min’ walk distance (6MWD) and Brain natriuretic peptide (BNP), of which mortality and rehospitalization are clinical end points while the others are surrogate outcomes. The reporting rate of mortality and rehospitalization was 12.90% (4/31), the other included studies reported surrogate outcomes. As safety measure, 54.84% of the studies reported adverse drug reactions. Two trials were evaluated as high in reporting quality of outcomes and that of the other 29 studies was poor due to lack of necessary information for reporting. Conclusions The present RCTs of TCM in treating CHF secondary to CHD did not concentrate on the clinical end points of heart failure, which were generally small in size and short in duration. Moreover, these trials lacked adequate safety evaluation, had low quality in reporting outcomes and certain risk of bias in methodology. For objective assessment of the efficacy and safety of TCM in treating CHF secondary to CHD, future research should be rigorous designed, set end points as primary outcome measures and pay more attention to safety evaluation throughout the trial.

Abstract P310: Predictors of Phase III Enrollment in Participants Completing Phase II Cardiac Rehabilitation in a Large Urban Cardiac Rehabilitation Center

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
Harsha V Ganga ◽  
Jennifer Jantz ◽  
Gaurav Choudhary ◽  
Wen-Chih Wu
Keyword(s):  
Weight Loss ◽  
Logistic Regression ◽  
Cardiac Rehabilitation ◽  
Exercise Capacity ◽  
Phase Ii ◽  
Temporal Trends ◽  
College Education ◽  
Phase Iii ◽  
Metabolic Equivalents ◽  
Multivariable Logistic Regression

Background: Short duration of outpatient Phase II cardiac rehabilitation (CR) program is not sufficient to sustain benefits of CR. Participation in long-term Phase III CR improves exercise capacity and lipoprotein profile. Hypothesis: We examined the factors predicting Phase III CR enrollment in those who have successfully completed Phase II CR in a large urban CR center. Methods: 4714 participants who completed structured 36-session Phase II CR program from the year 2000 to 2014 were included in this retrospective study. Multivariable logistic regression model was used to identify demographic, socio-economic factors predicting Phase III CR enrollment. The Cochran-Armitage test was used to assess temporal trends in Phase III CR enrollment. Results: A total of 901, out of 4714 participants completing Phase II CR, enrolled into Phase III CR. Mean age was 65 years and 31% were females. Univariate predictors include age, race, education, occupation, income, return to work obligation, insurance status, weight loss, depression and anxiety, exercise duration, and metabolic equivalents (METs). On multivariable logistic regression, those with at least college education (Odds Ratio [OR] 1.5,95% confidence interval [CI], 1.07-2), depression (OR,1.5, 95% CI, 1.07-1.96), weight loss (OR, 1.03, 95% CI, 1.01-1.05) and attending more Phase II sessions (OR,1.06, 95% CI, 1.02-1.10) were more likely to enroll whereas those living > 30 minutes from CR center (OR, 0.40, 95% CI, 0.20-0.75), with higher METs (OR,0.93, 95% CI, 0.87-0.99) and exercising longer (OR, 0.96, 95% CI, 0.93-0.99) were less likely to enroll. There is significantly increased temporal trend for Phase III CR enrollment (Z=11.34, P<0.0001). Conclusion: In participants completing Phase II CR, higher education, depression and weight loss predict increased Phase III CR enrollment whereas increased distance from CR center or better exercise capacity predict decreased Phase III CR enrollment.

scholarly journals Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease

2020 ◽  
Vol 126 (9) ◽  
pp. 1260-1280 ◽  
Author(s):  
Antonio Abbate ◽  
Stefano Toldo ◽  
Carlo Marchetti ◽  
Jordana Kron ◽  
Benjamin W. Van Tassell ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Cardiovascular Diseases ◽  
Phase Ii ◽  
Nlrp3 Inflammasome ◽  
Wide Spectrum ◽  
Phase Iii ◽  
Intracellular Sensing ◽  
Inflammasome Inhibitors

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment–elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.

scholarly journals MICS-Asia III: Overview of model inter-comparison and evaluation of acid deposition over Asia

2019 ◽  
Author(s):  
Syuichi Itahashi ◽  
Baozhu Ge ◽  
Keiichi Sato ◽  
Joshua S. Fu ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Acid Deposition ◽  
Phase Ii ◽  
Wet Deposition ◽  
Lessons Learned ◽  
Phase Iii ◽  
Anthropogenic Emissions ◽  
Observation Data ◽  
Total Deposition ◽  
North Asia ◽  
Phase Iii Study

Abstract. The Model Inter-Comparison Study for Asia (MICS-Asia) Phase III was conducted to promote understanding of regional air quality and climate change in Asia, which have received growing attention due to the huge amount of anthropogenic emissions worldwide. This study provides an overview of acid depositions. Specifically, dry and wet depositions of the following species were analyzed: S (sulfate aerosol, sulfur dioxide (SO2), and sulfuric acid (H2SO4)), N (nitrate aerosol, nitrogen monoxide (NO), nitrogen dioxide (NO2), and nitric acid (HNO3)), and A (ammonium aerosol and ammonia (NH3)). The wet deposition simulated by a total of nine models was analyzed and evaluated using ground observation data from the Acid Deposition Monitoring Network in East Asia (EANET). In this Phase III study, the number of observation sites was increased to 54 from 37 in the Phase II study, and Southeast Asian countries were newly added. Additionally, whereas the analysis period was limited to representative months of each season in MICS-Asia Phase II, this Phase III study analyzed the full year of 2010. The scope of this overview mainly focuses on the annual accumulated depositions. In general, models can capture the observed wet depositions over Asia but underestimate the wet deposition of S and A and show large differences in the wet deposition of N. Furthermore, the ratio of wet deposition to the total deposition (the sum of dry and wet deposition) was investigated in order to understand the role of important processes in the total deposition. The general dominance of wet deposition over Asia and attributions from dry deposition over land were consistently found in all models. Then, total deposition maps over 13 countries participating in EANET were produced, and the balance between deposition and anthropogenic emissions was calculated. Excesses of deposition, rather than of anthropogenic emissions, were found over Japan, North Asia, and Southeast Asia, indicating the possibility of long-range transport within and outside Asia, as well as other emission sources. To improve the ability of models to capture the observed wet deposition, two approaches were attempted, namely, ensemble and precipitation adjustment. The ensemble approach was effective at modulating the differences in performance among models, and the precipitation-adjusted approach demonstrated that the model performance for precipitation played a key role in better simulating wet deposition. Finally, the lessons learned from this Phase III study and future perspectives for Phase IV are summarized.

A phase II study of atezolizumab as neoadjuvant and adjuvant therapy in patients (pts) with resectable non-small cell lung cancer (NSCLC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS8580-TPS8580
Author(s):  
Dwight Hall Owen ◽  
Paul A. Bunn ◽  
Bruce E. Johnson ◽  
David J. Kwiatkowski ◽  
Mark G. Kris ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Surgical Resection ◽  
Phase Ii ◽  
Response Rate ◽  
Early Stage ◽  
The United States ◽  
Pathologic Response ◽  
Phase Iii ◽  
End Points ◽  
Early Stage Disease

TPS8580 Background: Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with early stage disease. Atezolizumab is a humanized IgG1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. In the OAK trial, a randomized phase III trial of patients with metastatic NSCLC who progressed on platinum based chemotherapy, atezolizumab improved overall survival in patients regardless of PD-L1 expression compared with docetaxel (13.8 months vs. 9.6 months, HR 0.73 [95% CI 0.62 – 0.87]) with a manageable safety profile. Methods: NCT02927301 is a phase II, open-label, single-arm study designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant and adjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. The study has two parts: the primary part will evaluate the ability of neoadjuvant atezolizumab to produce pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit in Part 1. The primary endpoint is major pathologic response rate (defined as ≤ 10% of viable tumor tissue) based on surgical resection. Secondary end points include overall response rate by status of mutation load, neoantigen score and gene expression signatures. OS and DFS are exploratory end points. This trial presents a unique opportunity to evaluate exploratory biomarkers given the availability of pre- and post-treatment biopsy specimens for assessment of evolution of immune related markers associated with response. The study opened to accrual in January 2017. Clinical trial information: NCT02927301.

scholarly journals Phase II trials in heart failure: The role of cardiovascular imaging

2011 ◽  
Vol 162 (1) ◽  
pp. 3-15.e3 ◽  
Author(s):  
Sanjiv J. Shah ◽  
Gregg C. Fonarow ◽  
Mihai Gheorghiade ◽  
Roberto M. Lang
Keyword(s):  
Heart Failure ◽  
Phase Ii ◽  
Cardiovascular Imaging ◽  
Phase Ii Trials

scholarly journals Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

2015 ◽  
Vol 33 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Manish R. Sharma ◽  
Elizabeth Gray ◽  
Richard M. Goldberg ◽  
Daniel J. Sargent ◽  
Theodore G. Karrison
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Phase Iii ◽  
Rank Test ◽  
Phase Ii Trials ◽  
End Points ◽  
End Point ◽  
Randomized Phase Ii ◽  
Log Ratio

Purpose The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]). Methods Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS. Results For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm. Conclusion TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.

scholarly journals Spontaneous Intracerebral and Intraventricular Hemorrhage

Neurosurgery ◽  
2014 ◽  
Vol 74 (suppl_1) ◽  
pp. S142-S150 ◽  
Author(s):  
Mahua Dey ◽  
Agnieszka Stadnik ◽  
Issam A. Awad
Keyword(s):  
Randomized Trials ◽  
Lessons Learned ◽  
National Institutes Of Health ◽  
Phase Iii ◽  
Recent Experience ◽  
Preliminary Treatment ◽  
Phase Ii Trials ◽  
Invasive Techniques ◽  
The Impact

Abstract Optimal management of spontaneous intracerebral hemorrhage (ICH) remains one of the highly debated areas in the field of neurosurgery. Earlier studies comparing open surgical intervention with best medical management failed to show a clear benefit. More recent experience with minimally invasive techniques has shown greater promise. Well-designed phase II trials have confirmed the safety and preliminary treatment effect of thrombolytic aspiration and clearance of spontaneous ICH and associated intraventricular obstructive hemorrhage. Those trials are reviewed, including respective protocols and technical nuances, and lessons learned regarding patient selection, the concept of hemorrhage stabilization, optimization of the surgical procedure, and thrombolytic dosing decisions. These concepts have been incorporated in the design of ongoing definite phase III randomized trials (MISTIE and CLEAR) funded by the National Institutes of Health. These are presented including the role of surgical leadership in the training and monitoring of the surgical task and quality assurance. The impact of these techniques on neurosurgical practice is discussed.

scholarly journals Drug Development in Alzheimer’s Disease—The Role of Default Mode Network Assessment in Phase II

US Neurology ◽  
2017 ◽  
Vol 13 (02) ◽  
pp. 67 ◽  
Author(s):  
Jeffrey Cummings ◽  
Kate Zhong ◽  
Dietmar Cordes ◽  
◽  
◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Phase Ii ◽  
Default Mode Network ◽  
Phase Iii ◽  
Human Cognition ◽  
Default Mode ◽  
Disease Modifying Agents ◽  
New Treatments

Alzheimer’s disease (AD) is rapidly becoming more common as the global population ages. New treatments are needed and new approaches to drug development are warranted. The phase II challenge for AD treatment development programs is how to provide proof-of-concept (POC) of the candidate agent without a large long trial equivalent to phase III. We propose that the available data support measures of the default mode network (DMN) using functional magnetic resonance imaging (fMRI) as demonstrating the effect of treatment on cognitive circuits critical to human cognition. Improved DMN function with symptomatic cognitive enhancing agents or decreased deterioration of DMN function compared to placebo in trials of disease-modifying agents would support POC and allow progression to phase III with greater confidence.

Exercise Training and Physical Activity in Patients with Heart Failure

2018 ◽  
Vol 66 (3) ◽  
Keyword(s):  
Physical Activity ◽  
Heart Failure ◽  
Exercise Training ◽  
Phase Ii ◽  
Left Ventricular ◽  
Phase Iii ◽  
Ventricular Assist Devices ◽  
Implantable Cardioverter Defibrillators ◽  
Left Ventricular Assist Devices ◽  
Supervised Exercise

Abstract: Heart failure is a clinical syndrome with different etiologies and phenotypes. For all forms, supervised exercise training and individual physical activity are class IA recommendations in current guidelines. Exercise training can start in the hospital, immediately after stabilization of acute heart failure (phase I). After discharge, it can continue in a stationary or ambulatory prevention and rehabilitation program (phase II). Typical components are endurance, resistance and respiratory training. Health insurances cover costs for three to six months. Patients with implantable cardioverter defibrillators or left ventricular assist devices may train in experienced centers. Besides muscular reconditioning, a major goal of phase II is to increase health literacy to improve long-term adherence to physical activity. In phase III, heart groups offer support.

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