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American Journal of Cancer Research 2021Clinical endpoints are essential for assessing the safety and efficacy of new cancer therapies. They are used by oncologists to help guide clinical decision making.... (Review)
Review
Clinical endpoints are essential for assessing the safety and efficacy of new cancer therapies. They are used by oncologists to help guide clinical decision making. While overall survival (OS) has frequently been regarded as the "gold standard" primary clinical endpoint, it's utility is constrained by several disadvantages. The time-consuming nature of trials using OS has led to a recent push to explore surrogate clinical endpoints and their potential to serve as primary clinical endpoints in lieu of OS. Additionally, it is becoming evident that other endpoints add valuable information about quality of life and treatment failure as their use is becoming increasingly prevalent in oncology clinical trials. Without a doubt, the use of clinical endpoints will continue to expand and evolve as new cancer therapies are developed and novel treatments, including immunotherapy, draw interest. This review explores the roles of primary and surrogate clinical endpoints as well as the benefits and drawbacks of each specific endpoint. In addition, it directly compares the unique features of each suggesting some of the specific uses each one fulfills.
PubMed: 33948349
DOI: No ID Found -
Multiple Sclerosis and Related Disorders Dec 2022Exercise studies including only fatigued persons with multiple sclerosis (PwMS) with fatigue as primary endpoint are lacking. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Exercise studies including only fatigued persons with multiple sclerosis (PwMS) with fatigue as primary endpoint are lacking.
OBJECTIVE
To evaluate the effects of high-intensity resistance training (HIRT) on self-reported fatigue in fatigued PwMS in a single center randomised controlled trial.
METHODS
We recruited 71 PwMS scoring ≥ 53 on the Fatigue Scale for Motor and Cognitive Functions (FSMC), who were randomised 1:1 to either twice (group A) or once (group B) weekly supervised HIRT for twelve weeks. A non-randomised FSMC score-matched group (n=69) served as non-intervention control.
RESULTS
Between HIRT-group differences were non-significant for primary and most secondary endpoints. Mean difference in FSMC score (95% confidence intervals) was -10.9 (-14.8; -6.9) in group A and -9.8 (-13.2; -6.3) in group B. Corresponding values for combined HIRT groups vs non-intervention control were -10.3 (-12.9; -7.7) and 1.5 (-0.6;3.6), respectively, p<0.001. Secondary endpoints also improved in both HIRT groups, though only Hospital Anxiety and Depression Scale anxiety and MS Impact Scale-29 psychological subscales significantly favoured the twice a week HIRT (group A). As an exploratory endpoint, changes in plasma inflammatory protein markers were associated with reduced FSMC scores in the pooled material.
CONCLUSION
The finding that HIRT in fatigued PwMS leads to clinically relevant reductions in self-reported fatigue, associated with changes in plasma inflammatory protein levels, provide evidence for recommending HIRT for fatigued PwMS.
Topics: Humans; Multiple Sclerosis; Resistance Training; Exercise Therapy; Cognitive Behavioral Therapy; Fatigue; Quality of Life
PubMed: 36037752
DOI: 10.1016/j.msard.2022.104106 -
American Heart Journal Jan 2023The main objective of the Danish German Cardiogenic Shock trial (DanGer Shock ClinicalTrials.gov Identifier: NCT01633502) is to assess the efficacy of the trans valvular...
BACKGROUND
The main objective of the Danish German Cardiogenic Shock trial (DanGer Shock ClinicalTrials.gov Identifier: NCT01633502) is to assess the efficacy of the trans valvular axial flow device Impella CP in treating patients with AMICS shock due to STEMI undergoing emergency percutaneous coronary intervention.
METHODS
This statistical analysis plan represents an overview of the statistical methods which will be used for analyzing the DanGer Shock trial.
RESULTS
The primary study endpoint is death from all causes through 180 days in the intention to treat population (all randomized consented patients). The secondary endpoints comprise; composite event of the need for additional mechanical support, need for cardiac transplantation, and death of all causes whichever comes first; and days alive and out of hospital. As exploratory analyses an as treated analysis of primary endpoint will be performed. Composite safety endpoint will comprise of major bleeding, vascular complications, device malfunction, damage to the aortic valve, and significant hemolysis. The primary endpoint death rate at 180 days will be analyzed using Cox proportional hazards analysis. The result will be reported as hazard ratio and corresponding 95% confidence interval (95% CI). No imputation of missing values will be performed. Additional statistical analyses for predefined hemodynamic, metabolic, renal, hematological, and health economics substudies will be specified in separate protocols.
CONCLUSION
Main analyses of the primary and secondary outcomes of the DanGer Shock trial will be conducted according to this publication.
Topics: Humans; Shock, Cardiogenic; Heart-Assist Devices; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Hemodynamics; Treatment Outcome
PubMed: 36272450
DOI: 10.1016/j.ahj.2022.10.078 -
Journal of Clinical Epidemiology Dec 2020Studies often combine several events, for example, death or myocardial infarction or stroke, into a single study outcome. This is called a composite endpoint. Composite... (Review)
Review
Studies often combine several events, for example, death or myocardial infarction or stroke, into a single study outcome. This is called a composite endpoint. Composite endpoints make doing trials easier by reducing the sample size or follow-up period required to demonstrate the effectiveness of an intervention. However, interpreting the results of composite endpoints can be confusing. To avoid misleading conclusions about the effectiveness of an intervention, it is important for readers of studies reporting a composite endpoint to ascertain that the clinical importance, the frequency of events, and the effect of the intervention on each component of the composite endpoint are similar.
Topics: Endpoint Determination; Epidemiologic Research Design; Humans; Sample Size
PubMed: 32739473
DOI: 10.1016/j.jclinepi.2020.07.017 -
Journal of Hepatology Nov 2023Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD)... (Review)
Review
Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference.
Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level <100 IU/mL and HBV DNA
endpoint for chronic hepatitis D, but HDV RNA primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase level. Suitable candidates for phase II/III trials would be treatment-naiive or experienced patients with quantifiable HDV RNA. Novel biomarkers (hepatitis B core-related antigen [HBcrAg] and HBV RNA) remain exploratory, while nucleos(t)ide analogs and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs. PubMed: 37377088
DOI: 10.1016/j.jhep.2023.06.002 -
Journal of Hepatology Mar 2020Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV... (Review)
Review
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV 'functional cure', the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
Topics: Alanine Transaminase; Antiviral Agents; Biomarkers; Clinical Trials, Phase III as Topic; Coinfection; DNA, Viral; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans; Research Design; Sustained Virologic Response
PubMed: 31730789
DOI: 10.1016/j.jhep.2019.11.003 -
Gastroenterology Dec 2022Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury.
METHODS
This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine.
RESULTS
Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002.
CONCLUSIONS
IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).
Topics: Humans; Glutens; Celiac Disease; Peptide Hydrolases; Intestinal Mucosa
PubMed: 35931103
DOI: 10.1053/j.gastro.2022.07.071 -
Renal Failure Dec 2022Diabetic kidney disease (DKD) is emerging rapidly as the leading cause of chronic kidney disease (CKD) worldwide. In this 3-year prospective, multicenter cohort study, a...
Prognosis and risk factors of chronic kidney disease progression in patients with diabetic kidney disease and non-diabetic kidney disease: a prospective cohort CKD-ROUTE study.
Diabetic kidney disease (DKD) is emerging rapidly as the leading cause of chronic kidney disease (CKD) worldwide. In this 3-year prospective, multicenter cohort study, a total of 1138 pre-dialysis CKD patients were recruited. Patients were categorized into two groups according to the etiologies of DKD and non-diabetic kidney disease (NDKD). Propensity score matching was performed to adjust for confounding factors, resulting in 197 patients being assigned to DKD and NDKD groups, respectively. The primary endpoints were 50% estimated glomerular filtration rate (eGFR) decline and initiation of kidney replacement therapy (KRT). The secondary endpoints were all-cause death and the development of cardiovascular disease (CVD) events. We found that DKD patients have a higher risk to develop 50% eGFR decline endpoint (HR:2.30, 95%CI [1.48-3.58], < 0.001) and KRT endpoint (HR:1.64, 95%CI [1.13-2.37], < 0.05) than NDKD patients. The 3-year cumulative incidence of 50% eGFR decline and KRT endpoint was significantly higher in DKD patients (26.90% 13.71% and 35.03% 22.34%, respectively). The Cox regression analyses showed that the increased systolic blood pressure (SBP), DKD, decreased serum albumin (Alb), and higher CKD stages were risk factors for the 50% eGFR decline endpoint; the increased SBP, DKD, decreased serum Alb, serum creatinine (Scr), higher CKD stages, presence of proteinuria and CVD were risk factors for KRT endpoint; the increased age, decreased hemoglobin (Hb), decreased serum Alb were risk factors for all-cause death endpoint; the increased age, decreased serum Alb were risk factors for CVD events endpoint. Appropriate preventive or therapeutic interventions should be taken to control these predictive factors to delay the development of CKD complications, thereby improving the prognosis and reducing the disease burden of the high-risk populations.
Topics: Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Glomerular Filtration Rate; Humans; Prognosis; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors
PubMed: 35938702
DOI: 10.1080/0886022X.2022.2106872 -
Hepatology (Baltimore, Md.) Nov 2023Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD)...
Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference.
Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level < 100 IU/mL and HBV DNA < LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg positive or negative CHB, who are treatment-naive or virally suppressed on nucleos(t)ide analogs. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA < LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA < LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase level. Suitable candidates for phase II/III trials would be treatment-naiive or experienced patients with quantifiable HDV RNA. Novel biomarkers (hepatitis B core-related antigen [HBcrAg] and HBV RNA) remain exploratory, while nucleos(t)ide analogs and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.
Topics: Humans; Hepatitis B, Chronic; Hepatitis B virus; Hepatitis B Surface Antigens; Antiviral Agents; DNA, Viral; Hepatitis B Core Antigens; RNA; Hepatitis B e Antigens
PubMed: 37326326
DOI: 10.1097/HEP.0000000000000431 -
European Heart Journal Dec 2023Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process...
Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.
Topics: Humans; Myocardial Infarction; Ischemic Attack, Transient; Hemorrhage; Heart Failure; Angina, Unstable
PubMed: 37935635
DOI: 10.1093/eurheartj/ehad718