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Journal of the American College of... Mar 2023Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF).
OBJECTIVES
This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF.
METHODS
This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity.
RESULTS
The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L).
CONCLUSIONS
The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.
Topics: Humans; Heart Failure; C-Reactive Protein; Stroke Volume; Ventricular Function, Left; Myocardial Infarction; Stroke; Inflammation; Cell- and Tissue-Based Therapy
PubMed: 36858705
DOI: 10.1016/j.jacc.2022.11.061 -
Arthritis Research & Therapy Sep 2023To compare a treat-to-target (T2T) approach and routine care (RC) in adults with active to severely active rheumatoid arthritis (RA) initiating subcutaneous abatacept. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
To compare a treat-to-target (T2T) approach and routine care (RC) in adults with active to severely active rheumatoid arthritis (RA) initiating subcutaneous abatacept.
METHODS
A 12-month cluster-randomized trial in active RA patients treated with abatacept was conducted. Physicians were randomized to RC or T2T with a primary endpoint of achieving sustained Clinical Disease Activity Index (CDAI) low disease activity (LDA) at two consecutive assessments approximately 3 months apart. Additional outcomes included Simple Disease Activity Index (SDAI), Disease Activity Score 28-CRP (DAS28-CRP), Routine Assessment of Patient Index Data 3 (RAPID3), and the Health Assessment Questionnaire-Disability Index (HAQ-DI). Time to achieve therapeutic endpoints was assessed with survival analysis.
RESULTS
Among the 284 enrolled patients, 130 were in the T2T group and 154 in RC. Primary endpoint was achieved by 36.9% and 40.3% of patients in T2T and RC groups, respectively. No significant between-group differences were observed in the odds of achieving secondary outcomes, except for a higher likelihood of CDAI LDA in the T2T group vs. RC (odds ratio [95% confidence interval]: 1.33 [1.03-1.71], p = 0.0263). Compared with RC, patients in the T2T group achieved SDAI remission significantly faster (Kaplan-Meier-estimated mean [standard error]: 14.0 [0.6] vs. 19.3 [0.8] months, p = 0.0428) with a trend toward faster achievement of CDAI LDA/remission, DAS28-CRP remission, and HAQ-DI minimum clinically important difference.
CONCLUSIONS
Patients managed per T2T and those under RC experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with higher odds of CDAI LDA and a shorter time to achieving therapeutic endpoints.
TRIAL REGISTRATION
Name of the registry: ClinicalTrials.gov.
TRIAL REGISTRATIONS
NCT03274141 . Date of registration: September 6, 2017.
Topics: Adult; Humans; Abatacept; Arthritis, Rheumatoid; Kaplan-Meier Estimate; Minimal Clinically Important Difference; Odds Ratio
PubMed: 37759330
DOI: 10.1186/s13075-023-03151-2 -
Frontiers in Cardiovascular Medicine 2024Cardiovascular (CV) disease remains a leading cause of mortality despite statin therapy. Statin add-on lipid-lowering therapies have been investigated for CV risk... (Review)
Review
INTRODUCTION
Cardiovascular (CV) disease remains a leading cause of mortality despite statin therapy. Statin add-on lipid-lowering therapies have been investigated for CV risk reduction, but their effect on CV mortality has not been reviewed.
METHODS
This review describes CV outcomes trials of add-on therapies to statins, highlighting findings related to the primary composite CV endpoints and the more patient-centric endpoint of CV-related mortality.
RESULTS
Add-on ezetimibe met its primary composite CV endpoint vs. statin alone (= 0.016); however, the individual endpoint of death from CV causes did not differ between groups. Add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors achieved the primary composite CV endpoints in the respective CV outcomes trials for alirocumab (< 0.001) and evolocumab (< 0.001); however, neither CV outcomes trial found a difference vs. placebo in CV-related mortality. In its CV outcomes trial, icosapent ethyl added to statin therapy significantly reduced the occurrence of the primary composite CV endpoint (< 0.001) and the individual endpoint of risk of CV-related death (= 0.03) vs. placebo. A CV outcomes trial of bempedoic acid monotherapy achieved its primary composite CV endpoint vs. placebo (= 0.004) but not the endpoint of death from CV causes.
DISCUSSION
Statin add-on therapies achieved their CV outcomes trial composite CV endpoints. Proprotein convertase subtilisin/kexin type 9 inhibitors and icosapent ethyl have approved indications for CV risk reduction. Only add-on therapy with icosapent ethyl demonstrated a significant reduction in CV mortality in the overall intent-to-treat population, possibly due to the unique pleiotropic mechanisms of eicosapentaenoic acid independent of lipid-lowering effects.
PubMed: 38545344
DOI: 10.3389/fcvm.2024.1308695 -
Cancers Sep 2023Immunotherapy with checkpoint inhibitors (CPIs) and cell-based products has revolutionized the treatment of various solid tumors and hematologic malignancies. These... (Review)
Review
Immunotherapy with checkpoint inhibitors (CPIs) and cell-based products has revolutionized the treatment of various solid tumors and hematologic malignancies. These agents have shown unprecedented response rates and long-term benefits in various settings. These clinical advances have also pointed to the need for new or adapted approaches to trial design and assessment of efficacy and safety, both in the early and late phases of drug development. Some of the conventional statistical methods and endpoints used in other areas of oncology appear to be less appropriate in immuno-oncology. Conversely, other methods and endpoints have emerged as alternatives. In this article, we discuss issues related to trial design in the early and late phases of drug development in immuno-oncology, with a focus on CPIs. For early trials, we review the most salient issues related to dose escalation, use and limitations of tumor response and progression criteria for immunotherapy, the role of duration of response as an endpoint in and of itself, and the need to conduct randomized trials as early as possible in the development of new therapies. For late phases, we discuss the choice of primary endpoints for randomized trials, review the current status of surrogate endpoints, and discuss specific statistical issues related to immunotherapy, including non-proportional hazards in the assessment of time-to-event endpoints, alternatives to the Cox model in these settings, and the method of generalized pairwise comparisons, which can provide a patient-centric assessment of clinical benefit and be used to design randomized trials.
PubMed: 37760636
DOI: 10.3390/cancers15184669 -
Pulmonary Circulation Jul 2023Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations... (Review)
Review
Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations of patients, clinicians, and regulators in this evolving therapy area. The most commonly used primary endpoint in PAH trials has been 6-min walk distance (6MWD), leading to the approval of several targeted therapies. However, single surrogate endpoints such as 6MWD or hemodynamic parameters may not correlate with clinical outcomes. Composite endpoints of clinical worsening have been developed to reflect patients' overall condition more accurately, although there is no standard definition of worsening. Recently there has been a shift to composite endpoints assessing clinical improvement, and risk scores developed from registry data are increasingly being used. Biomarkers are another area of interest, although brain natriuretic peptide and its -terminal prohormone are the only markers used for risk assessment or as endpoints in PAH. A range of other genetic, metabolic, and immunologic markers is currently under investigation, along with conventional and novel imaging modalities. Patient-reported outcomes are an increasingly important part of evaluating new therapies, and several PAH-specific tools are now available. In the future, alternative statistical techniques and trial designs, such as patient enrichment strategies, will play a role in evaluating PAH-targeted therapies. In addition, modern sequencing techniques, imaging analyses, and high-dimensional statistical modeling/machine learning may reveal novel markers that can play a role in the diagnosis and monitoring of PAH.
PubMed: 37554146
DOI: 10.1002/pul2.12271 -
Journal of Inherited Metabolic Disease Mar 2022There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia... (Review)
Review
There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of C-propionate (exhaled CO ), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.
Topics: Amino Acid Metabolism, Inborn Errors; Biomarkers; Drug Development; Humans; Methylmalonic Acid; Propionic Acidemia
PubMed: 35038174
DOI: 10.1002/jimd.12478 -
Contemporary Clinical Trials... Dec 2019The purpose of late phase clinical trials is to generate evidence of sufficient validity and generalisability to be translated into practice and policy to improve health... (Review)
Review
The purpose of late phase clinical trials is to generate evidence of sufficient validity and generalisability to be translated into practice and policy to improve health outcomes. It is therefore crucial that the chosen endpoints are meaningful to the clinicians, patients and policymakers that are the end-users of evidence generated by these trials. The choice of endpoints may be improved by understanding their characteristics and properties. This narrative review describes the evolution, range and relative strengths and weaknesses of endpoints used in late phase trials. It is intended to serve as a reference to assist those designing trials when choosing primary endpoint(s), and for the end-users charged with interpreting these trials to inform practice and policy.
PubMed: 31799474
DOI: 10.1016/j.conctc.2019.100486 -
Lung Feb 2020Until recently, many clinical trials in patients with pulmonary arterial hypertension (PAH) evaluated exercise capacity with 6-minute walk distance (6MWD) as the primary... (Review)
Review
BACKGROUND
Until recently, many clinical trials in patients with pulmonary arterial hypertension (PAH) evaluated exercise capacity with 6-minute walk distance (6MWD) as the primary endpoint. Common secondary endpoints include PAH functional class (FC), which assesses symptoms, and either brain natriuretic peptide (BNP) or the inactive N-terminal cleavage product of its prohormone (NT-proBNP), which assesses cardiac function.
OBJECTIVE
Examine the relationships among 6MWD, FC, and BNP/NT-proBNP measured at baseline or follow-up with long-term outcomes in PAH studies.
METHODS
Relevant literature from January 1990 to April 2018 were obtained by searching PubMed, Embase, and Cochrane. Articles in English reporting on associations between 6MWD, FC, or BNP/NT-proBNP and outcomes in PAH were identified. Each endpoint was evaluated individually. Prespecified inclusion and exclusion criteria were applied at level 1 (titles/abstracts) and level 2 (full-text review).
RESULTS
The database search yielded 836 unique records; 65 full-text articles were reviewed. Twenty-five studies were eligible for inclusion. Findings supported the importance of measuring PAH noninvasive endpoints in predicting long-term outcomes. Patients with shorter or decreased 6MWD, poor (III/IV) or declining FC (e.g., from II to III), or elevated or increasing BNP/NT-proBNP had a higher risk of death and costly events (e.g., hospitalization, lung transplant). FC also predicted health care resource utilization and costs. Collectively, these endpoints establish risk groups that predict likelihood of complications from PAH or death.
CONCLUSION
Assessment of 6MWD, FC, and BNP/NT-proBNP provides low-cost, efficient, and noninvasive means of predicting long-term health and economic outcomes in patients with PAH.
Topics: Biomarkers; Disease Progression; Functional Status; Hospitalization; Humans; Lung Transplantation; Mortality; Natriuretic Peptide, Brain; Outcome Assessment, Health Care; Peptide Fragments; Prognosis; Pulmonary Arterial Hypertension; Severity of Illness Index; Walk Test
PubMed: 31722043
DOI: 10.1007/s00408-019-00289-2 -
Transplant International : Official... 2022Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials,...
Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials, given the pathophysiological similarities between both conditions. Kidney dysfunction is reflected in the glomerular filtration rate (GFR), and although a predefined (e.g., 50%) reduction in GFR was recommended as an endpoint by the European Medicines Agency (EMA) in 2016, many other endpoints are also included in clinical trials. End-stage renal disease is strongly associated with a change in estimated (e)GFR, and eGFR trajectories or slopes are increasingly used as endpoints in clinical intervention trials in chronic kidney disease (CKD). Similar approaches could be considered for clinical trials in kidney transplantation, although several factors should be taken into account. The present Consensus Report was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the EMA in 2020. This paper provides a contemporary discussion of primary endpoints used in clinical trials involving CKD, including proteinuria and albuminuria, and evaluates the validity of these concepts as endpoints for clinical trials in kidney transplantation.
Topics: Albuminuria; Allografts; Disease Progression; Glomerular Filtration Rate; Humans; Kidney Transplantation; Renal Insufficiency, Chronic
PubMed: 35669976
DOI: 10.3389/ti.2022.10139 -
RMD Open Jan 2023Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, were evaluated in a 6-month, double-blind, phase 3 study in Chinese patients with active... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, were evaluated in a 6-month, double-blind, phase 3 study in Chinese patients with active (polyarthritic) psoriatic arthritis (PsA) and inadequate response to ≥1 conventional synthetic disease-modifying antirheumatic drug.
METHODS
Patients were randomised (2:1) to tofacitinib 5 mg twice daily (N=136) or placebo (N=68); switched to tofacitinib 5 mg twice daily after month (M)3 (blinded).
PRIMARY ENDPOINT
American College of Rheumatology (ACR50) response at M3. Secondary endpoints (through M6) included: ACR20/50/70 response; change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI); ≥75% improvement in Psoriasis Area and Severity Index (PASI75) response, and enthesitis and dactylitis resolution. Safety was assessed throughout.
RESULTS
The primary endpoint was met (tofacitinib 5 mg twice daily, 38.2%; placebo, 5.9%; p<0.0001). M3 ACR20/ACR70/PASI75 responses, and enthesitis and dactylitis resolution rates, were higher and HAQ-DI reduction was greater for tofacitinib 5 mg twice daily versus placebo. Incidence of adverse events (AEs)/serious AEs (M0-3): 68.4%/0%, tofacitinib 5 mg twice daily; 75.0%/4.4%, placebo. One death was reported with placebo→tofacitinib 5 mg twice daily (due to accident). One serious infection, non-serious herpes zoster, and lung cancer case each were reported with tofacitinib 5 mg twice daily; four serious infections and one non-serious herpes zoster case were reported with placebo→tofacitinib 5 mg twice daily (M0-6). No non-melanoma skin cancer, major adverse cardiovascular or thromboembolism events were reported.
CONCLUSION
In Chinese patients with PsA, tofacitinib efficacy was greater than placebo (primary and secondary endpoints). Tofacitinib was well tolerated; safety outcomes were consistent with the established safety profile in PsA and other indications.
TRIAL REGISTRATION NUMBER
NCT03486457.
Topics: Humans; Arthritis, Psoriatic; East Asian People; Piperidines; Enthesopathy; Herpes Zoster
PubMed: 36720560
DOI: 10.1136/rmdopen-2022-002559