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The Lancet. Oncology May 2024The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation... (Review)
Review
The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.
Topics: Humans; Early Detection of Cancer; Neoplasms; Biomarkers, Tumor; Clinical Trials as Topic; Research Design; Biomarkers; Endpoint Determination
PubMed: 38697164
DOI: 10.1016/S1470-2045(24)00015-9 -
Circulation. Cardiovascular Quality and... Jun 2024
Topics: Humans; Cardiovascular Diseases; Practice Guidelines as Topic; Observational Studies as Topic; Clinical Trials as Topic; Evidence-Based Medicine; Treatment Outcome; Risk Assessment
PubMed: 38682334
DOI: 10.1161/CIRCOUTCOMES.124.010979 -
BMJ Open Nov 2023There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic...
Randomised, placebo-controlled, phase 3 trial of the effect of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases: EPA for Metastasis Trial 2 (EMT2) study protocol.
INTRODUCTION
There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis.
METHODS AND ANALYSIS
The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6 monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%.
ETHICS AND DISSEMINATION
Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently.
TRIAL REGISTRATION NUMBER
NCT03428477.
Topics: Humans; Eicosapentaenoic Acid; Quality of Life; Treatment Outcome; Neoplasm Recurrence, Local; Colorectal Neoplasms; Double-Blind Method; Liver Neoplasms; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic
PubMed: 38030258
DOI: 10.1136/bmjopen-2023-077427 -
The Annals of Pharmacotherapy Aug 2023This article reviews clinical trials to assess the efficacy, safety, and clinical application of once-daily roflumilast 0.3% cream for the treatment of plaque psoriasis. (Review)
Review
OBJECTIVE
This article reviews clinical trials to assess the efficacy, safety, and clinical application of once-daily roflumilast 0.3% cream for the treatment of plaque psoriasis.
DATA SOURCES
A systematic review of the literature was performed using the terms OR OR in MEDLINE (PubMed) and EMBASE databases between January 2012 and October 2022. Bibliographies and the ClinicalTrials.gov website were also searched to identify further studies.
STUDY SELECTION AND DATA EXTRACTION
Studies written in English and relevant to pharmacology, clinical trials, and safety were considered for inclusion.
DATA SYNTHESIS
In two 8-week phase III clinical trials, disease severity as assessed by a score of "clear" or "almost clear" and a 2-point improvement on Investigator Global Assessment (IGA) was 42.4% and 37.5% at week 8 in DERMIS-1 and DERMIS-2, respectively, compared to 6.1% and 6.9% in the control groups. In the 52-week phase III trial, treatment success rates for plaque psoriasis and intertriginous psoriasis were similar to the 8-week data with 45% of patients in the treatment group were evaluated as an IGA of "clear" or "almost clear" at week 52.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS
Roflumilast is a new US Food and Drug Administration (FDA)-approved topical phosphodiesterase inhibitor that shows promise for the treatment of mild-severe plaque psoriasis. It is an effective and safe topical nonsteroidal alternative to currently available topical corticosteroids, but there are currently no comparative studies with other psoriasis treatments.
CONCLUSION
Roflumilast is effective and safe for the treatment of plaque psoriasis and intertriginous psoriasis. Future trials should compare its efficacy and tolerability with that of the older, clinically established topical corticosteroids. Prohibitive factors may include limited patient adherence to topical treatments and cost.
Topics: Humans; Adrenal Cortex Hormones; Aminopyridines; Dermatologic Agents; Immunoglobulin A; Psoriasis; Severity of Illness Index; Treatment Outcome; Clinical Trials as Topic
PubMed: 36420929
DOI: 10.1177/10600280221137750 -
Current Opinion in Ophthalmology May 2024To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON). (Review)
Review
PURPOSE OF REVIEW
To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON).
RECENT FINDINGS
Results of G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy show good safety and unexpected bilateral partial improvements of BCVA (best-corrected visual acuity) with mean logMAR BCVA improvements of up to near ∼0.3 logMAR (3 lines) in the treated eyes and ∼0.25 logMAR (2.5 lines) in the sham-treated or placebo-treated fellow eyes. Final mean BCVA levels after gene therapy were in the range of ∼1.3 logMAR (20/400) bilaterally.
SUMMARY
Bilateral partial improvement with unilateral LHON gene therapy was unanticipated and may be due to treatment efficacy, natural history, learning effect, and other mediators. The overall efficacy is limited given the final BCVA levels. The sequential progressive visual loss and varied occurrence of spontaneous partial improvement in LHON confound trial results. Future clinical trials with randomization of patients to a group not receiving gene therapy in either eye would help to assess treatment effect. Promising future LHON gene therapy strategies include mitochondrially-targeted-sequence adeno-associated virus ('MTS-AAV') for direct delivery of the wild-type mitochondrial DNA into the mitochondria and CRISPR-free, RNA-free mitochondrial base editing systems. Signs of anatomical optic nerve damage and objective retinal ganglion cell dysfunction are evident in the asymptomatic eyes of LHON patients experiencing unilateral visual loss, indicating the therapeutic window is narrowing before onset of visual symptoms. Future treatment strategies utilizing mitochondrial base editing in LHON carriers without optic neuropathy holds the promise of a more advantageous approach to achieve optimal visual outcome by reducing disease penetrance and mitigating retinal ganglion cell loss when optic neuropathy develops.
Topics: Humans; DNA, Mitochondrial; Electroretinography; Genetic Therapy; Optic Atrophy, Hereditary, Leber; Tomography, Optical Coherence; Vision Disorders; Visual Fields; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 38117686
DOI: 10.1097/ICU.0000000000001028 -
BMJ Open Sep 2023Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI...
INTRODUCTION
Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results for weight loss in small single arm studies. LGAE could be a treatment option in between our current tier-3 and tier-4 services for obesity. EMBIO is a National Institute for Health Research funded trial, a multicentre double-blinded randomised controlled trial between Imperial College National Health Service Trust and University College London Hospital, comparing LGAE versus Placebo procedure. The key aims of the trial is to evaluate LGAE efficacy on weight loss, its mechanism of action, safety profile and obesity-related comorbidities.
METHODS AND ANALYSIS
76 participants will be recruited from the existing tier-3 database after providing informed consent. Key inclusion criteria include adults aged 18-70 with a body mass index 35-50 kg/m and appropriate anatomy of the left gastric artery and coeliac plexus on CT Angiogram. Key exclusion criteria included previous major abdominal and bariatric surgery, weight >150 kg, type 2 diabetes on any medications other than metformin and the use of weight modifying medications. Participants will undergo mechanistic visits 1 week prior to the intervention and 3, 6 and 12 months postintervention. Informed consent will be received from each participant and they will be randomised in a 1:1 ratio to left gastric artery embolisation and placebo treatment. Blinding strategies include the use of moderate doses of sedation, visual and auditory isolation. All participants will enter a tier-3 weight management programme postintervention. The primary analysis will estimate the difference between the groups in the mean per cent weight loss at 12 months.
ETHICS AND DISSEMINATION
This trial shall be conducted in full conformity with the 1964 Declaration of Helsinki and all subsequent revisions. Local research ethics approval was granted by London-Central Research Ethics Committee, (Reference 19/LO/0509) on 11 October 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) issued the Letter of No Objection on 8 April 2022 (Reference CI/2022/0008/GB). The trial's development and progress are monitored by an independent trial steering committee and data monitoring and ethics committee. The researchers plan to disseminate results at conferences, in peer- reviewed journals as well as lay media and to patient organisations.
TRIAL REGISTRATION NUMBER
ISRCTN16158402.
Topics: Adult; Humans; COVID-19; SARS-CoV-2; Body Mass Index; Gastric Artery; Diabetes Mellitus, Type 2; State Medicine; Obesity; Treatment Outcome; Weight Loss; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37770263
DOI: 10.1136/bmjopen-2023-072327 -
Journal of Pediatric Gastroenterology... Dec 2023The objective of this study was to evaluate the efficacy and safety of budesonide oral suspension (BOS) in adolescents with eosinophilic esophagitis (EoE).
OBJECTIVES
The objective of this study was to evaluate the efficacy and safety of budesonide oral suspension (BOS) in adolescents with eosinophilic esophagitis (EoE).
METHODS
This post hoc analysis pooled data from two 12-week, randomized, double-blind, placebo-controlled studies of BOS 2.0 mg twice daily (b.i.d.) (phase 2, NCT01642212; phase 3, NCT02605837) in patients aged 11-17 years with EoE and dysphagia. Efficacy endpoints included histologic (≤6, ≤1, and <15 eosinophils per high-power field [eos/hpf]), dysphagia symptom (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] scores from baseline), and clinicopathologic (≤6 eos/hpf and ≥30% reduction in DSQ scores from baseline) responses at week 12. Change from baseline to week 12 in peak eosinophil counts, DSQ scores, EoE Histology Scoring System (EoEHSS) grade (severity) and stage (extent) total score ratios (TSRs), and total EoE Endoscopic Reference Scores (EREFS) were assessed. Safety outcomes were also examined.
RESULTS
Overall, 76 adolescents were included (BOS, n = 45; placebo, n = 31). Significantly more patients who received BOS than placebo achieved histologic responses (≤6 eos/hpf: 46.7% vs 6.5%; ≤1 eos/hpf: 42.2% vs 0.0%; <15 eos/hpf: 53.3% vs 9.7%; P < 0.001) and a clinicopathologic response (31.1% vs 3.2%; P = 0.003) at week 12. More BOS-treated than placebo-treated patients achieved a dysphagia symptom response at week 12 (68.9% vs 58.1%; not statistically significant P = 0.314). BOS-treated patients had significantly greater reductions in EoEHSS grade and stage TSRs ( P < 0.001) and total EREFS ( P = 0.021) from baseline to week 12 than placebo-treated patients. BOS was well tolerated, with no clinically meaningful differences in adverse events versus placebo.
CONCLUSIONS
BOS 2.0 mg b.i.d. significantly improved most efficacy outcomes in adolescents with EoE versus placebo.
Topics: Adolescent; Humans; Budesonide; Deglutition Disorders; Eosinophilic Esophagitis; Esophagoscopy; Suspensions; Treatment Outcome; Child; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic
PubMed: 37718471
DOI: 10.1097/MPG.0000000000003948 -
Current Heart Failure Reports Jun 2024To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure. (Review)
Review
PURPOSE OF REVIEW
To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure.
RECENT FINDINGS
Intentional weight loss via semaglutide among persons with heart failure and preserved ejection fraction and obesity significantly improves weight loss and health status as assessed by the KCCQ-CSS score and is associated with improvements in 6-min walk test. Ongoing and planned trials will explore the role of intentional weight loss with treatments such as semaglutide or tirzepatide for individuals with heart failure across the entire ejection fraction spectrum.
Topics: Humans; Heart Failure; Obesity; Weight Loss; Clinical Trials as Topic; Stroke Volume
PubMed: 38619690
DOI: 10.1007/s11897-024-00655-z -
Osteoarthritis and Cartilage Oct 2023Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has... (Review)
Review
Reflections from the OARSI 2022 clinical trials symposium: The pain of OA-Deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design.
OBJECTIVE
Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field.
METHOD
The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development.
RESULTS
Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions.
CONCLUSIONS
The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.
Topics: Humans; Clinical Trials as Topic; Osteoarthritis; Knee Joint; Pain; Patient Reported Outcome Measures; Osteoarthritis, Knee; Treatment Outcome
PubMed: 37380011
DOI: 10.1016/j.joca.2023.06.006 -
Expert Review of Clinical Immunology 2023Despite ongoing efforts to develop effective therapeutics, no disease-modifying drugs have been officially licensed for the indication of Sjögren's disease (SjD). This... (Review)
Review
INTRODUCTION
Despite ongoing efforts to develop effective therapeutics, no disease-modifying drugs have been officially licensed for the indication of Sjögren's disease (SjD). This is partly due to heterogeneity in disease manifestations, which complicates drug target selection, trial design and interpretation of clinical efficacy in SjD.
AREAS COVERED
Here, we summarize developments and comment on challenges in 1) identifying the right target for treatment, 2) selection of the primary study endpoint for trials and definition of clinically relevant response to treatment, 3) inclusion criteria and patient stratification, 4) distinguishing between disease activity and damage and 5) establishing the effect of treatment considering measurement error, natural variation, and placebo or nocebo responses.
EXPERT OPINION
Targets that are involved in both the immune cell response and dysregulation of glandular epithelial cells (e.g. B-lymphocytes, type-I interferon) are of particular interest to treat both glandular and extra-glandular manifestations of SjD. The recent development of composite study endpoints (CRESS and STAR) may be a crucial step forward in the search for clinically effective systemic treatment of patients with SjD. Important additional areas for future research are symptom-based and/or molecular pathway-based patient stratification, prevention of irreversible damage, and establishing the effect of treatment.
Topics: Humans; Clinical Trials as Topic; Sjogren's Syndrome; Treatment Outcome; Research Design
PubMed: 37551702
DOI: 10.1080/1744666X.2023.2234641