-
Journal of Neuro-oncology Dec 2023To date, immunotherapeutic approaches in glioblastoma (GBM) have had limited clinical efficacy as compared to other solid tumors. Here we explore autologous cell... (Review)
Review
PURPOSE
To date, immunotherapeutic approaches in glioblastoma (GBM) have had limited clinical efficacy as compared to other solid tumors. Here we explore autologous cell treatments that have the potential to circumvent treatment resistance to immunotherapy for GBM.
METHODS
We performed literature review and assessed clinical outcomes in phase 1 safety trials as well as phase 2 and 3 autologously-derived vaccines for the treatment of newly-diagnosed GBM. In one recent review of over 3,000 neuro-oncology phase 2 and phase 3 clinical trials, most trials were nonblinded (92%), single group (65%), nonrandomized (51%) and almost half were GBM trials. Only 10% involved a biologic and only 2.2% involved a double-blind randomized trial design.
RESULTS
With this comparative literature review we conclude that our autologous cell product is uniquely antigen-inclusive and antigen-agnostic with a promising safety profile as well as unexpected clinical efficacy in our published phase 1b trial. We have since designed a rigorous double-blinded add-on placebo-controlled trial involving our implantable biologic drug device. We conclude that IGV-001 provides a novel immunotherapy platform for historically intransigent ndGBM in this ongoing phase 2b trial (NCT04485949).
Topics: Humans; Glioblastoma; Brain Neoplasms; Treatment Outcome; Immunotherapy; Cancer Vaccines; Craniotomy; Randomized Controlled Trials as Topic
PubMed: 38017340
DOI: 10.1007/s11060-023-04491-4 -
Alzheimer's & Dementia : the Journal of... May 2024We conducted a rapid systematic review of minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) trial endpoints.
INTRODUCTION
We conducted a rapid systematic review of minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) trial endpoints.
METHODS
Two reviewers searched EMBASE, MEDLINE, and PubMed from inception to June 4, 2023.
RESULTS
Ten articles were retrieved. For mild cognitive impairment (MCI), a change of +2 to +3 points on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), +1 points on the Clinical Dementia Rating scale sum of boxes (CDR-SB), -5 points on the integrated Alzheimer's Disease Rating Scale (iADRS), or -1 to -2 points on the Mini-Mental State Examination (MMSE) was considered meaningful. For patients with mild AD, a change of +3 on the ADAS-Cog, +2 points on CDR-SB, -9 points on the iADRS, or -2 points on the MMSE was considered meaningful. For patients with moderate to severe AD, a change of +2 points on the CDR-SB or a change of -1.4 to -3 points on the MMSE was considered meaningful.
CONCLUSION
This review identified previously published MCIDs for AD trial endpoints. Input from patients and caregivers will be needed to derive more meaningful endpoints and thresholds.
HIGHLIGHTS
This systematic rapid review identified thresholds for minimal clinically important differences (MCIDs) for recently used Alzheimer's disease (AD) trial endpoints: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating scale sum of boxes (CDR-SB), integrated Alzheimer's Disease Rating Scale (iADRS), Mini-Mental State Examination (MMSE). MCIDs were higher for more severe stages of AD. Average treatment effects in recent trials of anti-amyloid disease modifying monoclonal antibodies are lower than previously published MCIDs. In future trials of disease modifying treatments for AD, the proportion of participants in each treatment group that experienced a clinically meaningful decline could be reported. More work is needed to incorporate the values and preferences of patients and care partners in deriving MCIDs.
Topics: Alzheimer Disease; Humans; Minimal Clinically Important Difference; Cognitive Dysfunction; Mental Status and Dementia Tests; Neuropsychological Tests; Clinical Trials as Topic
PubMed: 38561021
DOI: 10.1002/alz.13770 -
Journal of the American College of... Nov 2023Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is a frequent cause of hospital admission in older people, but clinical trials targeting this population are...
BACKGROUND
Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is a frequent cause of hospital admission in older people, but clinical trials targeting this population are scarce.
OBJECTIVES
The After Eighty Study assessed the effect of an invasive vs a conservative treatment strategy in a very old population with NSTE-ACS.
METHODS
Between 2010 and 2014, the investigators randomized 457 patients with NSTE-ACS aged ≥80 years (mean age 85 years) to an invasive strategy involving early coronary angiography with immediate evaluation for revascularization and optimal medical therapy or to a conservative strategy (ie, optimal medical therapy). The primary endpoint was a composite of myocardial infarction, need for urgent revascularization, stroke, and death. The long-term outcomes are presented.
RESULTS
After a median follow up of 5.3 years, the invasive strategy was superior to the conservative strategy in the reduction of the primary endpoint (incidence rate ratio: 0.76; 95% CI: 0.63-0.93; P = 0.0057). The invasive strategy demonstrated a significant gain in event-free survival of 276 days (95% CI: 151-400 days; P = 0.0001) at 5 years and 337 days (95% CI: 123-550 days; P = 0.0001) at 10 years. These results were consistent across subgroups of patients with respect to major cardiovascular prognostic factors.
CONCLUSIONS
In patients aged ≥80 years with NSTE-ACS, the invasive strategy was superior to the conservative strategy in the reduction of composite events and demonstrated a significant gain in event-free survival. (The After Eighty Study: a randomized controlled trial; NCT01255540).
Topics: Aged, 80 and over; Humans; Acute Coronary Syndrome; Coronary Angiography; Myocardial Infarction; Stroke; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37968019
DOI: 10.1016/j.jacc.2023.09.809 -
PloS One 2023Primarily, this study compares the efficacy of probiotic and acceptance and commitment therapy (ACT) in alleviating the severity of alcohol craving and alcohol use...
Research protocol of the efficacy of probiotics for the treatment of alcohol use disorder among adult males: A comparison with placebo and acceptance and commitment therapy in a randomized controlled trial.
BACKGROUND AND AIM
Primarily, this study compares the efficacy of probiotic and acceptance and commitment therapy (ACT) in alleviating the severity of alcohol craving and alcohol use disorder (AUD) among patients who had undergo two weeks of in-patient detoxification. Secondarily, this study compares the efficacy of probiotic and ACT in mitigating the severity of comorbid depression and anxiety symptoms; decreasing serum level of pro-inflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α); changing the event-related potential in electroencephalogram (EEG) and restoring microbiota flora in the gut of AUD patients.
METHODS AND ANALYSIS
Initially, during Phase I of the study, the serum level of IL-1β, IL-6 and TNF-α; ERP changes in the EEG and fecal microbiota content will be compared between 120 AUD patients and 120 healthy controls. Subsequently in Phase II of the study, 120 AUD patients will be randomized by stratified permuted block randomization into the probiotic, ACT and placebo groups in a 1:1:1 ratio. Participants in the probiotic and placebo groups will be administered one sachet per day of Lactobacillus spp. probiotic and placebo, respectively for 12 weeks. While those in the ACT group will receive one session per week of ACT for 8 weeks. Outcome measures will be administered at four timepoints, such as t0 = baseline assessment prior to intervention, t1 = 8 weeks after intervention began, t2 = 12 weeks after intervention and t3 = 24 weeks after intervention. Primary outcomes are the degrees of alcohol craving, alcohol withdrawal during abstinence and AUD. Secondary outcomes to be assessed are the severity of co-morbid depression and anxiety symptoms; the serum levels of IL-1β, IL-6 and TNF-α; changes in ERP and fecal microbiota content.
TRIAL REGISTRATION NUMBER
NCT05830708 (ClinicalTrials.gov). Registered on April 25, 2023.
Topics: Adult; Humans; Male; Acceptance and Commitment Therapy; Alcoholism; Clinical Trials, Phase II as Topic; Double-Blind Method; Interleukin-6; Probiotics; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 38051740
DOI: 10.1371/journal.pone.0294768 -
Medicine Jul 2023Glaucoma is the leading cause of irreversible blindness worldwide. The aim of this study was to evaluate the efficacy and safety of Fufang Xueshuantong Capsules (FFXST)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Glaucoma is the leading cause of irreversible blindness worldwide. The aim of this study was to evaluate the efficacy and safety of Fufang Xueshuantong Capsules (FFXST) in combination with conventional drugs in the treatment of glaucoma using meta-analysis and trial sequential analysis (TSA).
METHODS
Clinical trials of FFXST for glaucoma were identified in 8 databases until November 2022, and studies were included for meta-analysis and trial sequential analysis.
RESULTS
In terms of efficacy endpoints, meta-analysis showed that the combination group of FFXST significantly improved clinical effective rate (RR 1.29, 95% CI 1.20-1.39, P < .00001), visual function (MD 0.04, 95% CI 0.04-0.05, P < .00001), light sensitivity (MD 6.07, 95% CI 4.63-7.51, P < .00001), end-systolic blood flow velocity (MD 2.68, 95% CI 2.19-3.16, P < .00001) and end-diastolic blood flow velocity (MD 2.07, 95% CI 1.86-2.28, P < .00001), and significantly reduced total gray-scale value (MD -64.38, 95% CI -69.08 to -59.68, P < .00001) and defect of visual field (MD -3.40, 95% CI -4.11 to -2.69, P < .00001) compared with the conventional regimen group, while the pulsatility index and resistance index were comparable. The TSA indicated that these benefits were conclusive. In terms of safety endpoints, meta-analysis demonstrated that total drug-related adverse events in the combination group of FFXST were comparable to those in the conventional regimen group, with TSA showing that more studies are needed to validate the current results.
CONCLUSION
FFXST may be a safety and effective supplementary strategy for the treatment of glaucoma, which is worthy of further research.
Topics: Humans; Capsules; Drugs, Chinese Herbal; Glaucoma; Treatment Outcome; Clinical Trials as Topic
PubMed: 37443494
DOI: 10.1097/MD.0000000000034202 -
Trials Dec 2023Few large randomized controlled trials provide strong evidence to guide surgical repair of primary rhegmatogenous retinal detachment (RRD) repair. The purpose of this...
BACKGROUND
Few large randomized controlled trials provide strong evidence to guide surgical repair of primary rhegmatogenous retinal detachment (RRD) repair. The purpose of this factorial, single-blind, randomized controlled trial is to analyze and compare the surgical outcomes, functional visual outcomes, complications, and quality of life associated with RRD repair using (A) pars plana vitrectomy only (PPV) or PPV with scleral buckle (PPV-SB) and (B) sulfur hexafluoride gas (SF) or perfluoropropane gas (CF) tamponade.
METHODS
Eligible patients with moderately complex RRD will be randomized 1:1 to PPV or PPV-SB and 1:1 to SF or CF gas tamponade. Approximately 560 patients will be recruited to be able to detect a difference of around 10% in SSAS rate between the groups. Patients will be followed using multimodal imaging and quality of life questionnaires after the surgical repair until 1 year postoperative. The primary outcome will be a single-surgery anatomic success (SSAS), defined as the absence of reoperation for recurrent RRD in the operating room. Secondary outcomes will be pinhole visual acuity (PHVA) at 8-10 weeks and 6 months, final best-corrected visual acuity (BCVA), final retina status (i.e., attached or detached), time to onset of RRD recurrence, severity and number of complications, and questionnaire results.
DISCUSSION
This will be the first 2 × 2 factorial RCT examining repair techniques in primary RRD. It will also be the first RCT to compare gas tamponade between the two most common agents. Notably, it will be adequately powered to detect a clinically significant effect size. The use of multimodal imaging will also be a novel aspect of this study, allowing us to compare head-to-head the impact of adding an SB to the retina's recovery after RRD repair and of differing gas tamponades. Until now, the treatment of RRD has been largely guided by pragmatic retrospective cohort studies. There is a lack of strong evidence guiding therapeutic decisions and this trial will address (1) whether supplemental SB is justified and (2) whether longer duration gas tamponade with CF is necessary.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05863312. Registered on 18 May 2023.
Topics: Humans; Retinal Detachment; Retrospective Studies; Quality of Life; Single-Blind Method; Treatment Outcome; Visual Acuity; Vitrectomy; Randomized Controlled Trials as Topic
PubMed: 38124155
DOI: 10.1186/s13063-023-07815-x -
Scientific Reports Oct 2023In the recent JAVELIN Bladder 100 phase 3 trial, avelumab plus best supportive care significantly prolonged overall survival relative to best supportive care alone as...
In the recent JAVELIN Bladder 100 phase 3 trial, avelumab plus best supportive care significantly prolonged overall survival relative to best supportive care alone as first-line maintenance therapy following first-line platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). Discovering biomarkers using genomic profiling to understand potential patient heterogeneity is essential to help improve patient care with precision medicine. For the JAVELIN Bladder 100 trial, it is unclear which variable selection methods can most reliably identify biomarkers to inform patient care because the dataset is characterized by high collinearity and low signal. The aim of this paper was to evaluate available selection methods and their ability to discover prognostic and predictive biomarkers in patients with aUC receiving first-line maintenance therapy. A simulation study evaluated the performance of popular variable selection approaches for high-dimensional data, including penalized regression models, random survival forests, and Bayesian variable selection methods. For Bayesian variable selection methods, a modified Bayesian Information Criterion (BIC) thresholding rule was proposed in addition to the traditional BIC thresholding rule. These methods were applied to the JAVELIN Bladder 100 dataset to investigate potential biomarkers associated with survival benefit. Results from the simulations demonstrated the strengths and limitations of the different methods. The variable selection methods demonstrated low false discovery rates under different conditions. However, their performance declined in the presence of high collinearity. Using the JAVELIN Bladder 100 data, we identified some potentially significant biomarkers across multiple models. Several lasso-related methods were able to identify potentially biologically meaningful variables in the trial. Some variable selection methods (such as stochastic search variable selection and random survival forest) may not be well suited to this type of data due to the presence of extreme collinearity and low signal. Future research should explore novel variable selection methods that may be more suitable for identifying prognostic and predictive biomarkers in this population.Trial registration: ClinicalTrials.gov Identifier: NCT02603432.
Topics: Humans; Bayes Theorem; Biomarkers; Computer Simulation; Machine Learning; Prognosis; Clinical Trials, Phase III as Topic
PubMed: 37884606
DOI: 10.1038/s41598-023-45323-9 -
Cephalalgia : An International Journal... Feb 2024Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. (Review)
Review
BACKGROUND
Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice.
METHODS
An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1-12.
RESULTS
There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1-12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: -1.65 [-2.49, -0.81]; < 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles.
CONCLUSION
In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day.
Topics: Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Quality of Life; Spiro Compounds; Tablets; Treatment Outcome; Clinical Trials, Phase III as Topic; Clinical Trials, Phase II as Topic
PubMed: 38410850
DOI: 10.1177/03331024241235156 -
BMJ Open Oct 2023While limiting the tidal volume to 6 mL/kg during veno-venous extracorporeal membrane oxygenation (V-V ECMO) to ameliorate lung injury in patients with acute...
High versus low positive end-expiratory pressure setting in patients receiving veno-venous extracorporeal membrane oxygenation support for severe acute respiratory distress syndrome: study protocol for the multicentre, randomised ExPress SAVER Trial.
INTRODUCTION
While limiting the tidal volume to 6 mL/kg during veno-venous extracorporeal membrane oxygenation (V-V ECMO) to ameliorate lung injury in patients with acute respiratory distress syndrome (ARDS) is widely accepted, the best setting for positive end-expiratory pressure (PEEP) is still controversial. This study is being conducted to investigate whether a higher PEEP setting (15 cmHO) during V-V ECMO can decrease the duration of ECMO support needed in patients with severe ARDS, as compared with a lower PEEP setting.
METHODS AND ANALYSIS
The study is an investigator-initiated, multicentre, open-label, two-arm, randomised controlled trial conducted with the participation of 20 intensive care units (ICUs) at academic as well as non-academic hospitals in Japan. The subjects of the study are patients with severe ARDS who require V-V ECMO support. Eligible patients will be randomised equally to the high PEEP group or low PEEP group. Recruitment to the study will continue until a total of 210 patients with ARDS requiring V-V ECMO support have been randomised. In the high PEEP group, PEEP will be set at 15 cmHO from the start of V-V ECMO until the trials for liberation from V-V ECMO (or until day 28 after the allocation), while in the low PEEP group, the PEEP will be set at 5 cmHO. Other treatments will be the same in the two groups. The primary endpoint of the study is the number of ECMO-free days until day 28, defined as the length of time (in days) from successful libration from V-V ECMO to day 28. The secondary endpoints are mortality on day 28, in-hospital mortality on day 60, ventilator-free days during the first 60 days and length of ICU stay.
ETHICS AND DISSEMINATION
Ethics approval for the trial at all the participating hospitals was obtained on 27 September 2022, by central ethics approval (IRB at Hiroshima University Hospital, C2022-0006). The results of this study will be presented at domestic and international medical congresses, and also published in scientific journals.
TRIAL REGISTRATION NUMBER
The Japan Registry of Clinical Trials jRCT1062220062. Registered on 28 September 2022.
PROTOCOL VERSION
28 March 2023, version 4.0.
Topics: Humans; Extracorporeal Membrane Oxygenation; Positive-Pressure Respiration; Respiratory Distress Syndrome; Tidal Volume; Ventilators, Mechanical; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37852764
DOI: 10.1136/bmjopen-2023-072680 -
BMC Cancer Jul 2023Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially...
Hepatic arterial infusion in combination with systemic chemotherapy in patients with hepatic metastasis from colorectal cancer: a randomized phase II study - (NCT05103020) - study protocol.
BACKGROUND
Although 80% of patients with metastatic colorectal cancer (CRC) experience liver metastases, only 10-25% undergo resection at the time of diagnosis. Even in initially unresectable conditions, if appropriate treatment is provided, such as surgical conversion through a combination of hepatic arterial infusion (HAI) chemotherapy and systemic chemotherapy (sys-CT), better overall survival can be expected. Therefore, this study aims to evaluate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy in patients with unresectable CRC with liver-only metastasis.
METHODS
This is a single-center, randomized, open-label phase II trial (NCT05103020). Patients with untreated CRC, who have liver-only metastases and for whom liver resection is potentially possible but deemed infeasible at the time of initial diagnosis by a multidisciplinary team, will be eligible. Patients will be randomly assigned in a 1:1 ratio to either the combined HAI oxaliplatin and modified systemic 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus targeted therapy group or the systemic FOLFIRI plus targeted therapy group. Both regimens will be repeated every 2 weeks for a total of 12 cycles. The primary objective of this study is to compare the rate of conversion to liver resection. The surgical conversion rate is expected to increase by 25% with HAI oxaliplatin in combination with sys-CT plus targeted therapy (40% in the experimental arm versus 15% in the control arm) (power, 80%; two-sided alpha-risk, 5%). The secondary objectives include overall survival, progression-free survival, and objective response rate.
DISCUSSION
This is the first randomized controlled trial to investigate the efficacy of HAI oxaliplatin in combination with sys-CT plus targeted therapy as first-line treatment from the initial diagnosis in patients with unresectable CRC with liver-only metastasis, aiming to significantly increase the surgical conversion rate.
TRIAL REGISTRATION
ClinicalTrials.gov, (NCT05103020). Trial registration date: November 2, 2021.
Topics: Humans; Oxaliplatin; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Liver Neoplasms; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic
PubMed: 37481515
DOI: 10.1186/s12885-023-11085-w