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Contemporary Clinical Trials Jun 2024Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last... (Review)
Review
BACKGROUND
Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last steps in the evaluation process for a new drug, have been recommended to all be RCTs. Nevertheless, single-arm phase 3 trials still appear to be in use.
METHODS
We performed a PubMed search to identify the use of a single-arm design in phase 3 trials, excluding only non-English articles. Three categories were distinguished: past use of an RCT, of any other trial design, or no previous trial; and according to diagnosis (oncology, infection, others).
RESULTS
A total of 176 single-arm phase 3 trials (19 oncology, 43 infections and 114 others) were identified by the search, with exponential growth since 1994, in parallel with that of RCTs. Among them, 64 (36%) were preceded by an RCT, 58 (33%) by a non-randomized trial, and 54 (31%) had no previous trial, with no main influence of the diagnosis setting. Justification of the design was reported in 30 (18%) of those trials, with ethical concerns comprising one-third of those justifications. This was similar in the 14 single-arm phase 2-3 trials, with about one-third in each group, and 17% justification of a non-comparative design.
CONCLUSION
The use of a single-arm phase 3 trial is heterogeneous, ranging from first trials up to confirmatory trials after a previously conducted RCT. Justification for these single-arm designs as confirmatory evidence should be more clearly reported, along with potential sources of bias.
Topics: Humans; Research Design; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic; Non-Randomized Controlled Trials as Topic
PubMed: 38508234
DOI: 10.1016/j.cct.2024.107506 -
American Journal of Respiratory and... Mar 2024Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with...
Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy...
Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Three themes emerged: ) consensus on endpoints mirroring the lived experiences of patients with IPF; ) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; ) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.
Topics: Humans; Idiopathic Pulmonary Fibrosis; National Institutes of Health (U.S.); Patient Advocacy; Quality of Life; Reproducibility of Results; United States; Vital Capacity; Clinical Trials as Topic
PubMed: 38174955
DOI: 10.1164/rccm.202312-2213SO -
Journal of Cardiology Feb 2024Heart failure (HF) is a growing, global public health issue. Despite advances in HF care, many challenges remain and HF outcomes are poor. Some of the major reasons for... (Review)
Review
Heart failure (HF) is a growing, global public health issue. Despite advances in HF care, many challenges remain and HF outcomes are poor. Some of the major reasons for this are the lack of understanding and treatment for certain HF sub-types as well as the lack of implementation of treatment in areas where effective treatment exists. HF registries provide the opportunity to transform clinical research and patient care. Recently the registry-based randomized clinical trial has emerged as a pragmatic and inexpensive alternative to the gold standard in clinical trial design, the randomized controlled trial. Registries may also provide platforms for strategy trials, implementation trials, and screening. Using examples from the Swedish Heart Failure Registry and others, the present review provides insights into how registry-based research can address many of the unmet needs in HF.
Topics: Humans; Heart Failure; Treatment Outcome; Hospitalization; Registries; Sweden; Randomized Controlled Trials as Topic
PubMed: 37844799
DOI: 10.1016/j.jjcc.2023.10.006 -
The Annals of Pharmacotherapy Jul 2023To evaluate clinical data using oral n-acetylcysteine (NAC) in obsessive-compulsive and related disorders (OCDRD) treatment. (Review)
Review
OBJECTIVE
To evaluate clinical data using oral n-acetylcysteine (NAC) in obsessive-compulsive and related disorders (OCDRD) treatment.
DATA SOURCES
PubMed, Ovid MEDLINE (1946-July 2022), and the Cochrane Library database were searched using the terms NAC, children, adolescent, obsessive-compulsive disorder (OCD), trichotillomania (TTM), excoriation, hoarding disorder, and body dysmorphic disorder. Bibliographies were reviewed for relevant trials and case studies.
STUDY SELECTION AND DATA EXTRACTION
English language, clinical trials, or case studies analyzing NAC use in patients aged 3 to 21 years old with OCDRD as determined by the , 5th Edition.
DATA SYNTHESIS
Three randomized double-blind placebo-controlled trials of NAC in children and adolescents studied 121 patients with OCDRD. Trials assessed symptom severity from baseline to 10 to 12 weeks of NAC therapy. Two OCD trials identified statistically significant improvements, with only 1 trial demonstrating a clear clinically relevant difference from placebo. One trial in TTM found no difference between the NAC and placebo. Adverse effects were mild and included nausea, blurred vision, fatigue, tremor, and sweats. N-acetylcysteine titrated to 2400 or 2700 mg/day in divided doses was the most studied regimen.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Many OCDRD patients fail to completely respond to first-line treatment with cognitive behavioral therapy (CBT) and/or selective serotonin reuptake inhibitors (SSRIs) leaving practitioners with few additional treatment options. Preliminary efficacy and safety data are presented in this review.
CONCLUSIONS
Limited evidence suggests children and adolescents with OCD refractory to SSRIs or CBT may benefit from NAC augmentation.
Topics: Humans; Adolescent; Child; Child, Preschool; Young Adult; Adult; Acetylcysteine; Selective Serotonin Reuptake Inhibitors; Obsessive-Compulsive Disorder; Cognitive Behavioral Therapy; Drug-Related Side Effects and Adverse Reactions; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 36384314
DOI: 10.1177/10600280221138092 -
Heart, Lung & Circulation Sep 2023Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We... (Review)
Review
BACKGROUND
Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We aim to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive HCM.
METHODS
This systematic review of the literature followed the PRISMA guidelines. Title/abstract and topics were searched using the following term: "mavacamten". The electronic research literature databases included the Cochrane Library, MedLine, and clinicaltrials.gov from July to August 2022. Primary efficacy endpoint was to assess clinical response at the end of treatment compared with baseline, defined as, at least one New York Heart Association (NYHA) class reduction. Two secondary endpoints from baseline were determined. The first was defined as improvement in mixed venous oxygen pressure (pVO). The second was defined as reduction of the post-exercise left ventricular outflow tract (LVOT) gradient.
RESULTS
We included in our analyses data from four studies that met our review eligibility criteria. There were three randomised placebo-controlled clinical trials and one non-randomised open-label clinical trial. All four studies showed a reduction in NYHA class from mavacamten use. Three out of four studies demonstrated >1 NYHA functional class improvement ranging from 34% to 80%, while only one study showed a smaller percentage of patients remaining at class 3. Three out of four studies measured pVO as an outcome, and all three studies noticed an increase in peak oxygen consumption after mavacamten treatment. Additionally, three out of four studies measured post-exercise LVOT gradient reduction as an outcome and all three found significant reduction in the post-exercise LVOT gradient after treatment. The most commonly observed adverse side effects were atrial fibrillation and decreased left ventricular ejection fraction, but all participants recovered without long-term sequelae and only one patient dropped out of the trial.
CONCLUSIONS
Mavacamten has a greater efficacy than placebo in the treatment of HCM. It also showed promising tolerability and efficacy profiles in the treatment of HCM in adults. The three endpoints used in the evaluation of studies were reduction in NYHA class, increase in pVO, and post-exercise LVOT gradient reduction. Mavacamten showed greater reduction in NYHA, larger effects on increase of pVO, and significant reduction of the LVOT gradient. Mavacamten was also found to be well tolerated, like the placebo. The side effect profile was limited for the majority of individuals taking mavacamten. In the future, authors recommended dose-optimisation studies, and studies that evaluate mavacamten both in comparison to, and in conjunction with other current treatments.
Topics: Adult; Humans; Cardiomyopathy, Hypertrophic; Heart; Stroke Volume; Ventricular Function, Left; Clinical Trials as Topic
PubMed: 37453852
DOI: 10.1016/j.hlc.2023.05.019 -
Revue Medicale Suisse Jan 2024In this review of new developments in pulmonology for the year 2023, we look at two contributions in the diagnostic field: the optimal way of comparing a spirometry... (Review)
Review
In this review of new developments in pulmonology for the year 2023, we look at two contributions in the diagnostic field: the optimal way of comparing a spirometry measurement with the expected normal values, and a new tool for identifying dysfunctional breathing. On the therapeutic front, a new molecule, ensifentrine, has been shown to be effective in a phase 3 study involving COPD patients. Finally, and still for patients with severe COPD, volume reduction, either surgically or endoscopically, can lead to an improvement in function and severity scores.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Pulmonary Medicine; Spirometry; Clinical Trials, Phase III as Topic
PubMed: 38299959
DOI: 10.53738/REVMED.2024.20.859.262 -
Journal of Oncology Pharmacy Practice :... Apr 2024Multiple myeloma cells resist standard therapies due to overexpression of the transport protein, exportin 1. Selinexor is a novel drug that targets the Exportin 1... (Review)
Review
OBJECTIVE
Multiple myeloma cells resist standard therapies due to overexpression of the transport protein, exportin 1. Selinexor is a novel drug that targets the Exportin 1 protein in these cells.
DATA SOURCE
A comprehensive search was done, and data showing the efficacy and safety of selinexor in relapsed/refractory multiple myeloma was collected using PubMed, Google Scholar, and clincialtrials.gov.
DATA SUMMARY
Results from the clinical trials STORM, BOSTON, and STOMP were included. Parts I and II of the STORM trial revealed a progression-free survival (PFS) of 4.7 and 3.7 months, a median duration of response of 6.2 and 4.4 months, and an overall survival of 7.3 and 8.4 months, respectively. BOSTON trial's SVd arm (selinexor, bortezomib, and dexamethasone) had a median follow-up period of 13.2 months and an mPFS of 13.93 months. The Vd arm (bortezomib and dexamethasone) had a median follow-up duration of 16.5 months and an mPFS of 9.46 months. The STOMP trial is still active and has limited data available. The SKd arm (selinexor, carfilzomib, and dexamethasone) reported an overall response rate of 66.7% in patients with triple refractory multiple myeloma, and 82% in patients with high-risk cytogenetics. The SPd arm (selinexor, pomalidomide, and dexamethasone) shows an overall response rate of 54.30% in pomalidomide naïve-nonrefractory, 35.70% in pomalidomide refractory and 60% in those dosed at RP2D. SRd arm (selinexor, lenalidomide, and dexamethasone) shows an overall response rate of 91.7% in lenalidomide naïve and 12.5% in lenalidomide refractory patients. SVd (selinexor, bortezomib, and dexamethasone) arm reported an overall response rate of 63% in all patients while the SDd arm (selinexor, daratumumab, and dexamethasone) showed an overall response rate of 73%.
CONCLUSION
To improve the outcome of patients with relapsed/refractory multiple myeloma, it is critical to develop new therapies, assess potential therapeutic synergies, and overcome drug resistance by determining the efficacy of multiple myeloma therapies across multiple disease subgroups.
Topics: Humans; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Exportin 1 Protein; Hydrazines; Karyopherins; Multiple Myeloma; Neoplasm Recurrence, Local; Progression-Free Survival; Receptors, Cytoplasmic and Nuclear; Triazoles; Clinical Trials as Topic
PubMed: 38454813
DOI: 10.1177/10781552241235902 -
Obstetrics and Gynecology Sep 2023
Topics: Female; Humans; Genital Neoplasms, Female; Clinical Trials as Topic
PubMed: 37548377
DOI: 10.1097/AOG.0000000000005307 -
Seminars in Radiation Oncology Oct 2023Optimal management of cancer patients relies heavily on late-phase oncology randomized controlled trials. A comprehensive understanding of the key considerations in... (Review)
Review
Optimal management of cancer patients relies heavily on late-phase oncology randomized controlled trials. A comprehensive understanding of the key considerations in designing and interpreting late-phase trials is crucial for improving subsequent trial design, execution, and clinical decision-making. In this review, we explore important aspects of late-phase oncology trial design. We begin by examining the selection of primary endpoints, including the advantages and disadvantages of using surrogate endpoints. We address the challenges involved in assessing tumor progression and discuss strategies to mitigate bias. We define informative censoring bias and its impact on trial results, including illustrative examples of scenarios that may lead to informative censoring. We highlight the traditional roles of the log-rank test and hazard ratio in survival analyses, along with their limitations in the presence of nonproportional hazards as well as an introduction to alternative survival estimands, such as restricted mean survival time or MaxCombo. We emphasize the distinctions between the design and interpretation of superiority and noninferiority trials, and compare Bayesian and frequentist statistical approaches. Finally, we discuss appropriate utilization of phase II and phase III trial results in shaping clinical management recommendations and evaluate the inherent risks and benefits associated with relying on phase II data for treatment decisions.
Topics: Humans; Bayes Theorem; Clinical Decision-Making; Medical Oncology; Neoplasms; Randomized Controlled Trials as Topic
PubMed: 37684072
DOI: 10.1016/j.semradonc.2023.06.007 -
International Journal of Molecular... Aug 2023The long-term survival of Hodgkin lymphoma (HL) patients treated according to the current standard of care is excellent. Combined-modality schedules (ABVD plus... (Review)
Review
The long-term survival of Hodgkin lymphoma (HL) patients treated according to the current standard of care is excellent. Combined-modality schedules (ABVD plus radiotherapy) in early-stage disease, along with treatment intensity adaptation to early metabolic response assessed by PET/CT in advanced stage HL, have been the cornerstones of risk stratification and treatment decision-making, minimizing treatment-related complications while keeping efficacy. Nevertheless, a non-negligible number of patients are primary refractory or relapse after front-line treatment. Novel immunotherapeutic agents, namely Brentuximab Vedotin (BV) and immune checkpoint inhibitors (CPI), have already shown outstanding efficacy in a relapsed/refractory setting in recent landmark studies. Several phase 2 single-arm studies suggest that the addition of these agents in the frontline setting could further improve long-term disease control permitting one to reduce the exposure to cytotoxic drugs. However, a longer follow-up is needed. At the time of this writing, the only randomized phase 3 trial so far published is the ECHELON-1, which compares 1 to 1 BV-AVD (Bleomycin is replaced by BV) with standard ABVD in untreated advanced-stage III and IV HL. The ECHELON-1 trial has proven that BV-AVD is safe and more effective both in terms of long-term disease control and overall survival. Just recently, the results of the S1826 SWOG trial demonstrated that the combination nivolumab-AVD (N-AVD) is better than BV-AVD, while preliminary results of other randomized ongoing phase 3 trials incorporating anti-PD-1 in this setting will be soon available. The aim of this review is to present the recent data regarding these novel agents in first-line treatment of HL and to highlight current and future trends which will hopefully reshape the overall management of this disease.
Topics: Humans; Antibodies, Monoclonal; Hodgkin Disease; Antineoplastic Combined Chemotherapy Protocols; Positron Emission Tomography Computed Tomography; Bleomycin; Dacarbazine; Doxorubicin; Vinblastine; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 37685994
DOI: 10.3390/ijms241713187