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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 -
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 -
Journal of Medicinal Food Feb 2020The purpose of this randomized, placebo-controlled, triple-blind trial on 60 healthy female volunteers was to assess the cosmetic effects on skin quality of a food... (Randomized Controlled Trial)
Randomized Controlled Trial
A Dermonutrient Containing Special Collagen Peptides Improves Skin Structure and Function: A Randomized, Placebo-Controlled, Triple-Blind Trial Using Confocal Laser Scanning Microscopy on the Cosmetic Effects and Tolerance of a Drinkable Collagen Supplement.
The purpose of this randomized, placebo-controlled, triple-blind trial on 60 healthy female volunteers was to assess the cosmetic effects on skin quality of a food supplement containing special collagen peptides together with acerola extract, vitamin C, vitamin E, biotin, and zinc after an intake of 12 weeks (Elasten, QUIRIS Healthcare, Germany). To reduce assessment bias maximally and increase the accuracy and objectivity of the outcomes, the trial design was triple blinded in a manner that neither the subjects nor the person administering the products nor the person who assessed the primary outcomes knew which subjects had received the test product and which had received the placebo. The expert grader assessing the confocal laser scanning microscopy images was additionally blinded regarding the time when the image was taken (on days 1 or 85). The objective, blinded, and validated image analyses using confocal laser scanning microscopy showed a significant improvement of the collagen structure of facial skin (primary endpoint) after intake of the test product, while no improvements were found after intake of the placebo. The proven positive nutritional effect on the collagen structure was fully consistent with positive subjective evaluations of relevant skin parameters such as elasticity, crinkliness/wrinkliness, and evenness in different body areas such as face, hands, décolleté, neck, backside, legs, and belly, all serving as secondary endpoints. The test product was found to be safe and very well tolerated. A cosmetically relevant improvement of the facial skin was demonstrated after administration of the collagen supplement.
Topics: Collagen; Dietary Supplements; Double-Blind Method; Female; Humans; Microscopy, Confocal; Middle Aged; Skin; Skin Aging; Vitamins
PubMed: 32017646
DOI: 10.1089/jmf.2019.0197 -
Vaccine Aug 2019Well-established, validated and clinically meaningful primary and secondary endpoints are critical in advancing vaccines through proof of principal studies, licensure... (Review)
Review
Well-established, validated and clinically meaningful primary and secondary endpoints are critical in advancing vaccines through proof of principal studies, licensure and pre-qualification. To that end, the field of vaccine development for Shigella, enterotoxigenic Escherichia coli (ETEC) as well as other enteric pathogens would benefit greatly from a focused review of clinical endpoints and the use of common endpoints across the field to enable study-to-study comparisons as well as comparative assessments between vaccine candidates. A workshop was conducted to review clinical endpoints from controlled human challenge studies, field studies in naïve adult travelers and pediatric studies in low-middle income countries and to develop a consensus on clinical endpoints for future vaccine trials. Following sequential presentations on different study designs (CHIM, travelers' efficacy and pediatric efficacy), workshop participants broke into three simultaneous workgroups focused on those study designs to discuss a number of topics key to clinical endpoints specific to each study design. Previously utilized endpoints were reviewed with an eye towards potentially novel endpoints for future studies and consideration of the disease parameters and spectrum of disease targeted for prevention. The strength of support among workshop participants for the use of various endpoints is summarized as are recommendations for additional endpoints to be considered in future studies. It is anticipated that this report will facilitate endpoint determination in future efficacy trials of vaccine candidates.
Topics: Adult; Child, Preschool; Clinical Trials as Topic; Congresses as Topic; Developing Countries; Diarrhea; Dysentery, Bacillary; Endpoint Determination; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Humans; Immunization; Immunogenicity, Vaccine; Models, Immunological; Shigella; Shigella Vaccines; Travel
PubMed: 30981626
DOI: 10.1016/j.vaccine.2019.03.051 -
Clinical and Experimental Rheumatology Dec 2022In the last decade, many randomised controlled trials (RCTs) with biological DMARDs (bDMARDs) have been performed in patients with primary Sjögren's syndrome (pSS).... (Observational Study)
Observational Study
In the last decade, many randomised controlled trials (RCTs) with biological DMARDs (bDMARDs) have been performed in patients with primary Sjögren's syndrome (pSS). Unfortunately, no bDMARD has yet been approved for systemic treatment of pSS. The heterogeneity of disease manifestations raises two essential questions: 1) which outcome measure is valid, reliable and responsive to demonstrate treatment efficacy and should be used as primary study endpoint? and 2) which pSS patients should be included in clinical trials? Both the selection of the primary study endpoint and the selection of patients are crucial and evolving issues in clinical trial design in pSS. This article summarises the history and comments the selection of primary study endpoints including the novel development of composite endpoints. Furthermore, this article gives an overview of inclusion criteria used for phase II and III trials, and illustrates by data-analysis based on two prospective observational cohorts that each additional selection criterion will (largely) decrease the number of eligible patients in daily clinical practice.
Topics: Humans; Sjogren's Syndrome; Antirheumatic Agents; Treatment Outcome; Outcome Assessment, Health Care; Reproducibility of Results
PubMed: 36305355
DOI: 10.55563/clinexprheumatol/yagocb -
Journal of the National Cancer Institute Oct 2022Randomized clinical trials are critical for evaluating the safety and efficacy of interventions in oncology and informing regulatory decisions, practice guidelines, and...
Randomized clinical trials are critical for evaluating the safety and efficacy of interventions in oncology and informing regulatory decisions, practice guidelines, and health policy. Patient-reported outcomes (PROs) are increasingly used in randomized trials to reflect the impact of receiving cancer therapies from the patient perspective and can inform evaluations of interventions by providing evidence that cannot be obtained or deduced from clinicians' reports or from other biomedical measures. This commentary focuses on how PROs add value to clinical trials by representing the patient voice. We employed 2 previously published descriptive frameworks (addressing how PROs are used in clinical trials and how PROs have an impact, respectively) and selected 9 clinical trial publications that illustrate the value of PROs according to the framework categories. These include 3 trials where PROs were a primary trial endpoint, 3 trials where PROs as secondary endpoints supported the primary endpoint, and 3 trials where PROs as secondary endpoints contrast the primary endpoint findings in clinically important ways. The 9 examples illustrate that PROs add valuable data to the care and treatment context by informing future patients about how they may feel and function on different treatments and by providing clinicians with evidence to support changes to clinical practice and shared decision making. Beyond the patient and clinician, PROs can enable administrators to consider the cost-effectiveness of implementing new interventions and contribute vital information to policy makers, health technology assessors, and regulators. These examples provide a strong case for the wider implementation of PROs in cancer trials.
Topics: Drug Development; Health Policy; Humans; Neoplasms; Patient Reported Outcome Measures
PubMed: 35900186
DOI: 10.1093/jnci/djac128 -
Cureus Sep 2021Primary myelofibrosis (PMF) is the most aggressive type of chronic myeloproliferative neoplasm, characterized by a disarray of hematopoietic stem cells and bone marrow... (Review)
Review
Primary myelofibrosis (PMF) is the most aggressive type of chronic myeloproliferative neoplasm, characterized by a disarray of hematopoietic stem cells and bone marrow fibrosis. The estimated incidence is 1.5 per 100,000 individuals per year with a median survival of less than six years. This statistic can vary by risk category, primarily based on clinical and cytogenetic features. Death can result from many causes, including leukemic transformation, cachexia, vascular events, and infection. Currently, allogeneic hematopoietic cell transplant is the only curative method for those at high risk. Unfortunately, only about 10% are eligible for this therapy. JAK2 kinase inhibitors are commonly used for high-risk patients with symptomatic splenomegaly or systemic symptoms from PMF. In clinical trials, the major endpoint is a reduction of spleen size by 35%. Secondary endpoints have included amelioration of symptomatic PMF and overall survival, which can be difficult to determine because of frequent co-morbid conditions. Current Food and Drug Administration (FDA)-approved JAK2 inhibitors have not shown increased survival or reduced risk of leukemic transformation. In relapsed or refractory disease, there is currently no standard of care. In this paper, we discuss the role of a new anti-apoptotic B cell leukemia 2 (Bcl-2) inhibitor, Navitoclax, for the treatment of myelofibrosis. The clinical data thus far for Navitoclax, especially in synergistic combination with traditional JAK2 inhibitors, have been promising for those with a refractory or relapsing disease on prior therapies. Following the encouraging results of phase II trials, ongoing phase III trials will primarily evaluate splenic size reduction versus the standard of care and evaluate secondary endpoints such as symptom reduction and overall survival. These studies may establish a new standard of care for refractory or relapsed myelofibrosis.
PubMed: 34667663
DOI: 10.7759/cureus.17976