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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 -
Annals of the Rheumatic Diseases Feb 2022To evaluate risankizumab, a biological therapy that inhibits interleukin 23, in patients with active psoriatic arthritis (PsA) who have responded inadequately or are... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate risankizumab, a biological therapy that inhibits interleukin 23, in patients with active psoriatic arthritis (PsA) who have responded inadequately or are intolerant to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD).
METHODS
In the randomised, placebo-controlled, double-blind KEEPsAKE 1 trial, 964 patients with active PsA were randomised (1:1) to receive risankizumab 150 mg or placebo at weeks 0, 4 and 16. The primary endpoint was the proportion of patients achieving ≥20% improvement in American College of Rheumatology criteria (ACR20) at week 24. Here, we report the results from the 24-week double-blind period; the open-label period with all patients receiving risankizumab is ongoing.
RESULTS
At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (57.3% vs placebo, 33.5%; p<0.001). Significant differences were also observed for risankizumab versus placebo for the first eight ranked secondary endpoints, including skin and nail psoriasis endpoints, minimal disease activity and resolution of enthesitis and dactylitis (p<0.001). Adverse events and serious adverse events were reported at similar rates in the risankizumab and placebo groups. Serious infections were reported for 1.0% and 1.2% of patients receiving risankizumab and placebo, respectively. There was one death in the risankizumab group (urosepsis deemed unrelated to the study drug).
CONCLUSIONS
Risankizumab treatment results in significantly greater improvement of signs and symptoms of PsA compared with placebo and is well tolerated in patients with active PsA who have responded inadequately or are intolerant to ≥1 csDMARD.
TRIAL REGISTRATION NUMBER
NCT03675308.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Psoriatic; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Outcome
PubMed: 34911706
DOI: 10.1136/annrheumdis-2021-221019 -
The Journal of Steroid Biochemistry and... Apr 2020Whether supplemental vitamin D reduces risk of cancer or cardiovascular disease (CVD) is relatively unexplored in randomized trial settings. The VITamin D and OmegA-3... (Randomized Controlled Trial)
Randomized Controlled Trial
Whether supplemental vitamin D reduces risk of cancer or cardiovascular disease (CVD) is relatively unexplored in randomized trial settings. The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, placebo-controlled, 2 × 2 factorial trial of daily vitamin D (2000 IU) and marine omega-3 fatty acids (1 g) in the primary prevention of cancer and CVD among 25,871 U.S. men aged ≥50 and women aged ≥55, including 5106 African Americans. Median treatment duration was 5.3 years. Vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR] = 0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR = 0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR = 0.79 [0.63-0.99]) or first 2 years (HR = 0.75 [0.59-0.96]) of follow-up. Vitamin D did not significantly reduce the co-primary endpoint of major CVD events (HR = 0.97 [0.85-1.12]), other cardiovascular endpoints, or all-cause mortality (HR = 0.99 [0.87-1.12]). Updated meta-analyses that include VITAL and other recent vitamin D trials indicate a significant reduction in cancer mortality but not in cancer incidence or CVD endpoints. Additional research is needed to determine which individuals may be most likely to derive a net benefit from vitamin D supplementation. (VITAL clinicaltrials.gov identifier: NCT01169259).
Topics: Aged; Cardiovascular Diseases; Cholecalciferol; Fatty Acids, Omega-3; Female; Humans; Male; Middle Aged; Neoplasms; Placebo Effect; Vitamins
PubMed: 31733345
DOI: 10.1016/j.jsbmb.2019.105522 -
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 -
International Journal of Cardiology Dec 2022Despite evidence of hemodynamic benefit of sodium nitroprusside (SNP) treatment for acute heart failure (AHF), there are limited data about its efficacy and safety. This...
AIMS
Despite evidence of hemodynamic benefit of sodium nitroprusside (SNP) treatment for acute heart failure (AHF), there are limited data about its efficacy and safety. This study aimed to assess the effectiveness and safety of SNP treatment, to explore the impact of N-terminal pro-B natriuretic peptide (NT-proBNP) reduction on clinical endpoints and to identify possible predictors of clinical response.
METHODS AND RESULTS
Multicenter retrospective cohort study of 200 patients consecutively admitted for AHF in 2 Italian Centers. Primary endpoint was the reduction of NT-proBNP levels ≥25% from baseline values within 48 h from the onset of SNP infusion. Secondary and safety endpoints included all-cause mortality, rehospitalization for HF at 1, 3 and 6 months, length of hospital stay (LOS) and severe hypotension. 131 (66%) patients experienced a NT-proBNP reduction ≥25% within 48 h from treatment onset, irrespective of initial systolic blood pressure (SBP). Left ventricular end diastolic diameter (LVEDD) was the only independent predictor of treatment efficacy. Patients who achieved the primary endpoint (i.e., 'responders') had lower LOS (median 15 [IQR:10-27] vs 19 [IQR:12-35] days, p-value = 0.033) and a lower incidence of all-cause mortality and rehospitalization for HF at 1 and 3 months compared to "non responders" (p-value <0.050). Severe hypotension was observed in 10 (5%) patients, without any adverse clinical consequence.
CONCLUSION
SNP is a safe and effective treatment of AHF, particularly in patients with dilated left ventricle. Reduced NT-proBNP levels in response to SNP is associated to shorter LOS and lower risk of 1- and 3-month re-hospitalizations for HF.
CLINICAL TRIAL REGISTRATION
http://www.
CLINICALTRIALS
gov. Unique identifier: NCT05027360.
Topics: Biomarkers; Cohort Studies; Heart Failure; Humans; Hypotension; Natriuretic Peptide, Brain; Nitroprusside; Peptide Fragments; Prognosis; Retrospective Studies; Stroke Volume
PubMed: 35944767
DOI: 10.1016/j.ijcard.2022.08.009 -
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 -
JACC. Clinical Electrophysiology Jan 2023Treatment of cardioinhibitory vasovagal syncope (VVS) is difficult. Recently, cardioneuroablation (CNA) has emerged as a new therapeutic option. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Treatment of cardioinhibitory vasovagal syncope (VVS) is difficult. Recently, cardioneuroablation (CNA) has emerged as a new therapeutic option.
OBJECTIVES
This study sought to assess the effects of CNA on syncope recurrences in patients with VVS.
METHODS
This study was a prospective, open, randomized, controlled, investigator-initiated trial comparing CNA versus optimal nonpharmacologic therapy in patients with cardioinhibitory VVS. Patients were included if they had documented symptomatic cardioinhibitory or mixed VVS and positive atropine test. CNA was performed using radiofrequency ablation of the ganglionated plexi from the left and right atria. Follow-up lasted 2 years. Primary endpoint was time to first syncope recurrence. Secondary endpoints included changes in sinus rhythm and heart rate variability measured in Holter electrocardiography at baseline and 3, 12, and 24 months after CNA, as well as changes in quality of life at baseline and after completion of follow-up.
RESULTS
A total of 48 patients (17 male, mean age 38 ± 10 years, 24 in CNA group, 24 in control group) entered the study. The primary endpoint occurred in 2 patients (8%) from the CNA group versus 13 control patients (54%) (P = 0.0004). After CNA the mean sinus rhythm at 24-hour Holter electrocardiography was significantly faster and heart rate variability parameters significantly changed toward parasympathetic withdrawal compared with baseline values. Quality of life significantly improved in the CNA group (30 ± 10 points vs 10 ± 7 points; P = 0.0001), whereas it remained stable in control patients (31 ± 10 points vs 30 ± 10 points; P = 0.5501).
CONCLUSIONS
This is the first randomized study documenting efficacy of CNA in patients with cardioinhibitory VVS. Larger studies are needed to confirm these findings. (Cardioneuroablation for Reflex Syncope [ROMAN]; NCT03903744).
Topics: Humans; Male; Adult; Middle Aged; Heart Rate; Syncope, Vasovagal; Prospective Studies; Quality of Life; Arrhythmias, Cardiac; Reflex
PubMed: 36114133
DOI: 10.1016/j.jacep.2022.08.011 -
European Heart Journal Dec 2023Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality.
METHODS
Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (i) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and (ii) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined.
RESULTS
Three FCM trials with a total of 4501 patients were included. Ferric carboxymaltose was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio 0.86; 95% confidence interval 0.75-0.98; P = .029; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (rate ratio 0.87; 95% confidence interval 0.75-1.01; P = .076; Cochran Q: 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well tolerated.
CONCLUSIONS
In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality.
Topics: Humans; Anemia, Iron-Deficiency; Stroke Volume; Ventricular Function, Left; Iron Deficiencies; Ferric Compounds; Heart Failure
PubMed: 37632415
DOI: 10.1093/eurheartj/ehad586