Why do phase III trials of promising heart failure drugs often fail? the contribution of “regression to the truth”

2003 ◽  
Vol 9 (5) ◽  
pp. 364-367 ◽  
Author(s):  
Henry Krum ◽  
Andrew Tonkin
Keyword(s):  
Heart Failure ◽  
Phase Iii ◽  
Phase Iii Trials

Promise of autologous CD34+ stem/progenitor cell therapy for treatment of cardiovascular disease

2020 ◽  
Vol 116 (8) ◽  
pp. 1424-1433 ◽  
Author(s):  
Megha Prasad ◽  
Michel T Corban ◽  
Timothy D Henry ◽  
Allan B Dietz ◽  
Lilach O Lerman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Therapy ◽  
Therapeutic Potential ◽  
Microvascular Disease ◽  
Microvascular Dysfunction ◽  
Therapeutic Angiogenesis ◽  
Phase Iii ◽  
Potential Safety ◽  
Cd34 Cells ◽  
Phase Iii Trials

Abstract CD34+ cells are haematopoietic stem cells used therapeutically in patients undergoing radiation or chemotherapy due to their regenerative potential and ability to restore the haematopoietic system. In animal models, CD34+ cells have been associated with therapeutic angiogenesis in response to ischaemia. Several trials have shown the potential safety and efficacy of CD34+ cell delivery in various cardiovascular diseases. Moreover, Phase III trials have now begun to explore the potential role of CD34+ cells in treatment of both myocardial and peripheral ischaemia. CD34+ cells have been shown to be safe and well-tolerated in the acute myocardial infarction (AMI), heart failure, and angina models. Several studies have suggested potential benefit of CD34+ cell therapy in patients with coronary microvascular disease as well. In this review, we will discuss the therapeutic potential of CD34+ cells, and describe the pertinent trials that have used autologous CD34+ cells in no-options refractory angina, AMI, and heart failure. Lastly, we will review the potential utility of autologous CD34+ cells in coronary endothelial and microvascular dysfunction.

The disconnect between phase II and phase III trials of drugs for heart failure

2013 ◽  
Vol 10 (2) ◽  
pp. 85-97 ◽  
Author(s):  
Muthiah Vaduganathan ◽  
Stephen J. Greene ◽  
Andrew P. Ambrosy ◽  
Mihai Gheorghiade ◽  
Javed Butler
Keyword(s):  
Heart Failure ◽  
Phase Ii ◽  
Phase Iii ◽  
Phase Iii Trials

Cardiovascular events (CVEs) associated with tyrosine kinase inhibitor (TKI) therapy in patients with metastatic renal cell carcinoma (mRCC) at a regional cancer center

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16040-e16040
Author(s):  
J. McGhie ◽  
M. J. Mackenzie ◽  
E. Winquist ◽  
S. Ernst ◽  
L. Sax ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Kinase Inhibitor ◽  
Cardiac Risk ◽  
Phase Iii ◽  
Cancer Center ◽  
True Rate ◽  
Cardiac Risk Factors ◽  
Coronary Syndrome ◽  
Phase Iii Trials

e16040 Background: Recent studies suggest the incidence of CVEs associated with TKIs has been underestimated. Phase III trials have reported low incidences of heart failure, cardiac ischemia and hypertension. A recent observational study reported that one third of patients taking sunitinib or sorafenib experienced a cardiovascular event often without symptoms. We assessed the incidence of CVEs in mRCC patients who received TKIs at our centre. Methods: Eligible mRCC patients were identified from a mRCC database between January 2006 and November 2008. Data was retrospectively extracted including age, sex, diagnosis, histology, past cardiac history, cardiac risk factors, number and type of TKI regimens, and CVEs. A CVE was defined as unexplained death, acute coronary syndrome (ACS), heart failure, or arrhythmia requiring intervention. We also identified any new or exacerbated cases of hypertension after the start of TKI therapy, as a CVE. Results: Eighty-five eligible patients were identified. Average age was 61 years (range, 23–78), 72% were male and 80% were clear cell in origin. A total of 31 CVEs occurred in 28 patients (33%). These events occurred at a median of 5 weeks of TKI therapy (range, 1 - 64 weeks). There were 8 cases of ACS, 2 of heart failure, 2 of arrhythmia, and 3 unknown causes of death. Only 2 of these particular CVEs were associated with new or increased hypertension. There were 16 cases of hypertension alone. Those who had CVEs had a higher mean number of cardiac risk factors. They were also more likely to have an echocardiogram during treatment, and less likely to receive sorafenib following sunitinib. Conclusions: Our study suggests a lower rate of CVEs than recent studies, but the true rate may be underestimated, as routine cardiac studies were not performed in all patients. Rational surveillance strategies for patients receiving TKI therapies should be developed. Prospective trials should address predictive and prognostic factors for CVEs. [Table: see text] [Table: see text]

Clinical implications and outcomes of the ORION Phase III trials

2020 ◽  
Author(s):  
Julia Brandts ◽  
Kausik K Ray
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Phase Iii ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density Lipoprotein Cholesterol ◽  
Clinical Safety ◽  
Phase Iii Trials ◽  
Phase Ii And Iii ◽  
Ongoing Phase

Inclisiran is a siRNA inhibiting hepatic PCSK9 synthesis. As a first-in-class therapy, inclisiran has been assessed within the ORION trial program for its low-density lipoprotein cholesterol (LDL-C) lowering efficacy and clinical safety. Phase II and III trials have shown that inclisiran lowers LDL-C by about 50% with an infrequent dosing schedule in patients with established atherosclerotic cardiovascular disease and those at high risk, including patients with heterozygous familial hypercholesterolemia. Ongoing Phase III trials will provide evidence on longer-term safety and effectiveness, and inclisiran’s efficacy in patients with homozygous familial hypercholesterolemia. Furthermore, the ORION-4 trial will assess inclisiran’s impact on cardiovascular outcomes.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

Interaction of neurovascular protection of erythropoietin with age, sepsis, and statin therapy following aneurysmal subarachnoid hemorrhage

2010 ◽  
Vol 112 (6) ◽  
pp. 1235-1239 ◽  
Author(s):  
Ming-Yuan Tseng ◽  
Peter J. Hutchinson ◽  
Peter J. Kirkpatrick
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Statin Therapy ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Potential Interaction ◽  
Repeated Measurements ◽  
Unfavorable Outcome ◽  
Phase Iii ◽  
Neurovascular Protection ◽  
Phase Iii Trials

Object In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy. Methods The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-β or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or ≥ 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements. Results Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 × 109/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO. Conclusions Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.

Sign in / Sign up

Export Citation Format

Share Document