Pivotal Randomized Clinical Trials Research Articles

Acute Appendicitis After COVID-19 Vaccines in Italy: A Self-Controlled Case Series Study.

Cases of appendicitis were identified in the pivotal randomized clinical trial on BNT162b2 mRNA vaccine and reported from coronavirus disease 2019 (COVID-19) vaccine pharmacovigilance systems. Three cohort studies and two self-controlled case series (SCCS) studies evaluating the association between mRNA vaccines and appendicitis reported discordant results. To address this uncertainty, the present study examines in a large population, with a SCCS design, the association between mRNA (BNT162b2 and mRNA-1273) and, for the first time, viral vector (ChAdOx1-S and Ad26.COV2-S) COVID-19 vaccines and acute appendicitis. The SCCS study design was used to evaluate the association between COVID-19 vaccination and subsequent onset of acute appendicitis. The study was based on record linkage of health archives through TheShinISS application, a statistical tool that locally processes data from regional health care databases according to ad hoc, study-tailored and common data model. The study population included all vaccinated subjects ≥ 12 years old between 27 December 2020 and 30 September 2021. The acute appendicitis was identified through discharge diagnoses of hospital admissions or emergency department visits. Incident cases were defined as those who experienced a first event of acute appendicitis in the study period, excluding subjects with a diagnosis of appendicitis in the previous 5 years. Exposure was defined as the first or second dose of BNT162b2, mRNA-1273 and ChAdOx1-S and the single dose of Ad26.COV2-S. The risk interval was defined as 42 days from the first or second vaccination dose and divided into pre-specified risk subperiods; the reference period was the observation time outside the risk interval. Relative incidences (RI) and 95% confidence intervals (95% CI) were estimated with the SCCS method 'modified for event-dependent exposures', through unbiased estimating equations. The seasonal component was considered as a time-dependent covariate. In the 42-day risk interval 1285 incident cases of acute appendicitis occurred: 727 cases after the first dose and 558 cases after the second dose. In the main analysis, no increased risks of acute appendicitis were observed in subjects vaccinated with BNT162b, mRNA-1273, ChAdOx1-S and Ad26.COV2-S. The subgroup analyses by sex showed an increased risk in the 14-27 day risk interval, in males after the first dose of mRNA-1273 (RI of 1.71; 95% CI 1.08-2.70, p = 0.02) and in females after the single dose of Ad26.COV2-S (RI of 4.40; 95% CI 1.29-15.01, p = 0.02). There was no evidence of association of BNT162b, ChAdOx1-S, mRNA-1273 and Ad26.COV2-S with acute appendicitis in the general population. The results of the subgroup analyses by sex needs to be considered with caution. The multiplicity issue cannot be excluded being these hypotheses two of several hypotheses tested. In addition, relevant literature on the biological mechanism of the disease and evidence of similar effects with other vaccines or with the same vaccines are still lacking to provide strong support for a conclusion that there is an harmful effect in males and females with mRNA-1273 and Ad26.COV2-S.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest

BackgroundCardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established.MethodsThis study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures.DiscussionIn vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms.Trial registrationClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Patients with atrial fibrillation and common exclusion criteria from clinical trials are at high risk of clinical events: the Murcia AF Project II (MAFP-II) cohort study.

Some clinical characteristics and comorbidities in atrial fibrillation (AF) patients are exclusion criteria in randomized clinical trials (RCTs) investigating oral anticoagulants (OAC). However, these conditions are present also in everyday clinical practice patients. We compared the risk of adverse clinical outcomes between patients with and without RCT exclusion criteria. The Murcia AF Project II was an observational cohort study including AF outpatients starting vitamin K antagonists (VKAs) from July 2016 to June 2018. For the selection of the exclusion criteria, the four pivotal RCTs of direct-acting OAC (DOACs) were used as reference. During 2years, all ischemic strokes/transient ischemic attacks, major adverse cardiovascular events (MACEs), major bleeds, and all-cause deaths were recorded. 1050 patients (51.5% female, median age 77years) were included, of whom 368 (35%) met at least one exclusion criterion for RCTs. During follow-up, the incidence rate ratios for major bleeding, MACE and all-cause mortality were higher among patients with exclusion criteria (all p < 0.001). Patients fulfilling at least one exclusion criterion had increased risks of major bleeding (aHR 1.48; 95% CI 1.22-1.81; p < 0.001), MACE (aHR 1.51, 95% CI 1.10-2.09, p = 0.012), and mortality (aHR 3.22, 95% CI 2.32-4.48, p < 0.001), as well as a lower event-free survival (all log-rank p < 0.001). In this AF cohort taking VKAs, more than one-third had at least one RCT exclusion criteria, which translates into higher risk of major bleeding, MACE, and death. These observations should be considered when translating RCTs results to AF patients for a proper and a more patient-centered management.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. ClinicalTrials.gov (NCT04217551, 2019-12-30).

Effectiveness of COVID-19 vaccines against severe COVID-19 among patients with cancer in Catalonia, Spain

Patients with cancer were excluded from pivotal randomized clinical trials of COVID-19 vaccine products, and available observational evidence on vaccine effectiveness (VE) focused mostly on mild, and not severe COVID-19, which is the ultimate goal of vaccination for high-risk groups. Here, using primary care electronic health records from Catalonia, Spain (SIDIAP), we built two large cohorts of vaccinated and matched control cancer patients with a primary vaccination scheme (n = 184,744) and a booster (n = 108,534). Most patients received a mRNA-based product in primary (76.2%) and booster vaccination (99.9%). Patients had 51.8% (95% CI 40.3%−61.1%) and 58.4% (95% CI 29.3%−75.5%) protection against COVID-19 hospitalization and COVID-19 death respectively after full vaccination (two-doses) and 77.9% (95% CI 69.2%−84.2%) and 80.2% (95% CI 63.0%−89.4%) after booster. Compared to primary vaccination, the booster dose provided higher peak protection during follow-up. Calibration of VE estimates with negative outcomes, and sensitivity analyses with slight different population and COVID-19 outcomes definitions provided similar results. Our results confirm the role of primary and booster COVID-19 vaccination in preventing COVID-19 severe events in patients with cancer and highlight the need for the additional dose in this population.

Evidence into practice: Changes in haploidentical versus double umbilical cord blood graft utilization for hematopoietic cell transplantation in the U.S. in relation to a pivotal randomized clinical trial.

e23306 Background: Randomized clinical trials are the “gold standard”, but expensive and not always practice changing. Umbilical cord blood (UCB) and haploidentical (haplo) are donor sources for hematopoietic cell transplant (HCT) patients who do not have a fully matched donor. The Blood and Marrow Transplant Clinical Trials Network (CTN) 1101 trial (2012-2018) compared outcomes of double UCB and haplo bone marrow (BM) transplantation. The trial showed a lower two-year overall survival after UCB compared to haplo (46% vs 57%, p = 0.04). Here, we quantified the change in graft selection in clinical practice in the U.S. after publication of the trial’s primary results. Methods: 11,190 U.S. HCT recipients 18-70 years of age who received either UCB (single or double units) or haplo transplants (BM or peripheral blood stem cells), for leukemias, lymphomas, myelodysplastic syndrome, myeloproliferative neoplasms, who reported to the Center for International Blood and Marrow Transplant Research database, were analyzed. Graft utilization was analyzed in 3 time periods: 2010-2012 (pre-study), 2013-2018 (during study), and 2019-2022 (post-study), using Chi-square test and multivariable logistic regression. Results: Over the 3 time periods, there was a practice change with an increasing proportion of haplo transplants vs UCB (32%, 68% and 91% of transplants, p &lt; 0.001; odds ratio (OR) of 4.67 and 21.38 for during-study and post-study periods, respectively, both with p &lt; 0.001, compared to pre-study period). Males and older patients were more likely to receive haplo (OR = 1.32, p &lt; 0.001, and OR = 1.74, p &lt; 0.001, respectively). Compared to White recipients, Black recipients were more likely to receive haplo (OR = 1.74, p &lt; 0.001), whereas Asian recipients were less likely to receive haplo (OR = 0.75, p = 0.002). Hispanic recipients had a similar likelihood of receiving haplo to White patients (OR = 1.03, p = 0.665). Conclusions: Practice change toward haploidentical graft utilization had begun before the CTN 1101 trial’s publication and continued to increase over time. Black patients were more likely than White patients to receive haplo, and Asian patients were more likely than White patients to receive UCB. Availability of both UCB and haplo as alternative graft sources allowed for HCT for a diverse population. [Table: see text]

Optimizing warfarin dosing for patients with atrial fibrillation using machine learning

While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0–3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R2 = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally.

Streamlining Randomized Clinical Trials for Device Therapies in Heart Failure: Bayesian Borrowing of External Data.

The Breakthrough Devices Program of the US Food and Drug Administration has accelerated the development and evaluation of medical devices for patients with heart failure. One such device is the Optimizer Smart System, which the US Food and Drug Administration approved in 2019. The Optimizer device was evaluated in a pivotal randomized clinical trial (FIX-HF-5C [Confirmatory Randomized Trial Evaluating the Optimizer System]) that leveraged Bayesian borrowing of external data to reduce the sample size and determine therapeutic device benefit versus continued medical therapy. Bayesian borrowing is explained in the context of the FIX-HF-5C trial, including an overview of the statistical methodologies, regulatory considerations, and interpretations of trial results. The US Food and Drug Administration Breakthrough Devices Program and novel Bayesian statistical methodology accelerated the path to regulatory approval and patient access to a potentially lifesaving device and may serve as a model for future clinical trials.

Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients’ characteristics and median treatment duration of biologics approved for IMIDs between RCTs’ and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8–1.9) compared to RCTs (F/M ratio: 0.5–0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4–100 vs. 6–167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Long-term effectiveness and tolerability of galcanezumab in patients with migraine excluded from clinical trials: real world evidence of 1055 patients with 1 year follow-up from the Galca-Only registry

BackgroundGalcanezumab has shown efficacy and effectiveness in the treatment of episodic and chronic migraine (CM), however, the population represented in randomized clinical trials (RCTs) differs from the population observed in real-world setting. To describe the long-term effectiveness and tolerability of galcanezumab in clinical practice in patients excluded from RCTs.MethodsMulticenter prospective cohort study of consecutive patients with chronic and high-frequency episodic migraine (HFEM) with prior failure to three or more migraine preventive drugs, treated with galcanezumab and followed up for 12 months.ResultsWe enrolled 1055 patients, aged 50 (IQR: 42–58), 82.9% female, 76.4% chronic migraine, 69% with at least one exclusion criteria for RCTs, including age > 65 (n = 121), concomitant use of onabotulinumtoxinA (n = 185), daily headache at baseline (n = 347), chronic painful syndromes (n = 206), fibromyalgia (n = 101) or treatment resistance (n = 957). The median number of prior preventive treatments was 4 (IQR: 3–5). The retention rate was 90.8%, 76.8% and 71.4% at 3, 6 and 12 months. The main reasons for treatment discontinuation were lack of effectiveness (21.1%) and inadequate tolerability (6.6%).The 30%, 50% and 75% responder rates were 62.6%, 49.8% and 24.2% between weeks 8–12; 60.9%, 48.8% and 24.6% between weeks 20–24; and 59.7%, 48.3% and 24.6% between weeks 44–48. Daily headache at baseline (OR: 0.619; 95%CI: 0.469–0.817) and patient’s age (OR: 1.016; 95%CI: 1.005–1.026) were associated with 50% response at weeks 20–24. The variables that were associated with a higher reduction of headache days between weeks 20–24 were patient’s age (0.068; 95% CI: 0.018–0.119) and headache days per month at baseline (0.451; 95% CI: 0.319–0.583), while psychiatric comorbidity (-1.587; 95% CI: -2.626—0.538) and daily headache at baseline (-2.718; 95% CI: -4.58—0.869) were associated with fewer reduction in the number of headache days between weeks 20–24.ConclusionThis study provides class III evidence of effectiveness and tolerability of galcanezumab in patients with HFEM and CM with comorbidities that would result in exclusion of the pivotal RCTs. Nonetheless, the clinical results over a 12-month period were similar to the efficacy observed in randomized controlled trials. Few patients discontinued the drug due to inadequate tolerability.

Endovascular therapy versus best medical management for isolated posterior cerebral artery occlusion: A systematic review and meta-analysis.

Isolated posterior cerebral artery occlusions (iPCAO) were underrepresented in pivotal randomized clinical trial (RCTs) of endovascular thrombectomy (EVT) in ischemic stroke, and the benefit of EVT in this population is still indeterminate. We performed a systematic review and a meta-analysis to compare the safety and efficacy of EVT compared to best medical management (BMM) in patients with iPCAO. We searched Medline/PubMed, Embase, Web of Science, and the Cochrane databases up to May 2023 for eligible studies reporting outcomes of patients with iPCAO treated with EVT or BMM. We pooled odds ratios (ORs) with corresponding 95% confidence intervals (CI) using a random-effects model. Seven studies involving 2560 patients were included. EVT was associated with significantly higher likelihood of early neurological improvement (OR, 2.31 [95% CI, 1.38-2.91]; p < 0.00001) and visual field normalization (OR, 3.08 [95% CI, 1.76-5.38]; p < 0.0001) compared to BMM. Rates of good functional outcomes (mRS 0-2) were comparable between the two arms (OR, 0.88 [95% CI, 0.70-1.10]; p = 0.26). Symptomatic intracranial hemorrhage (sICH) was comparable between the two groups (OR, 1.94 [95% CI, 0.96-3.93]; p = 0.07). Mortality was also similar between the two groups (OR, 1.36; [95% CI, 0.77-2.42]; p = 0.29). In patients with iPCAO, EVT was associated with visual and early neurological improvement but with a strong trend toward increased sICH. Survival and functional outcomes may be slightly poorer. The role of EVT in iPCAO remains uncertain.

Deep learning based automatic detection algorithm for acute intracranial haemorrhage: a pivotal randomized clinical trial

Acute intracranial haemorrhage (AIH) is a potentially life-threatening emergency that requires prompt and accurate assessment and management. This study aims to develop and validate an artificial intelligence (AI) algorithm for diagnosing AIH using brain-computed tomography (CT) images. A retrospective, multi-reader, pivotal, crossover, randomised study was performed to validate the performance of an AI algorithm was trained using 104,666 slices from 3010 patients. Brain CT images (12,663 slices from 296 patients) were evaluated by nine reviewers belonging to one of the three subgroups (non-radiologist physicians, n = 3; board-certified radiologists, n = 3; and neuroradiologists, n = 3) with and without the aid of our AI algorithm. Sensitivity, specificity, and accuracy were compared between AI-unassisted and AI-assisted interpretations using the chi-square test. Brain CT interpretation with AI assistance results in significantly higher diagnostic accuracy than that without AI assistance (0.9703 vs. 0.9471, p < 0.0001, patient-wise). Among the three subgroups of reviewers, non-radiologist physicians demonstrate the greatest improvement in diagnostic accuracy for brain CT interpretation with AI assistance compared to that without AI assistance. For board-certified radiologists, the diagnostic accuracy for brain CT interpretation is significantly higher with AI assistance than without AI assistance. For neuroradiologists, although brain CT interpretation with AI assistance results in a trend for higher diagnostic accuracy compared to that without AI assistance, the difference does not reach statistical significance. For the detection of AIH, brain CT interpretation with AI assistance results in better diagnostic performance than that without AI assistance, with the most significant improvement observed for non-radiologist physicians.

Current approach to the treatment of vasovagal syncope in adults.

Vasovagal syncope (VVS) is the most common cause of transient loss of consciousness. Although not associated with mortality, it causes injuries, reduces quality of life, and is associated with anxiety and depression. The European and North American cardiac societies recently published syncope clinical practice guidelines. Most patients with VVS do well after specialist evaluation, reassurance and education. Adequate hydration, increased salt intake when not contraindicated, and careful withdrawal of diuretics and specific hypotension-inducing drugs are a reasonable initial strategy. Physical counterpressure maneuvers might be helpful but can be of limited efficacy in older patients and those with short or no prodromes. Orthostatic training lacks long term efficacy and is troubled by non-compliance. Yoga might be helpful, although the biomedical mechanism is unknown. Almost a third of VVS patients continue to faint despite these conservative measures. Metoprolol was not helpful in a pivotal randomized clinical trial. Fludrocortisone and midodrine significantly reduce syncope recurrences with tolerable side effects, when titrated to target doses. Pacing therapy with specialized sensors appears promising in carefully selected population who have not responded conservative measures. Cardioneuroablation may be helpful but has not been studied in a formal clinical trial.

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy

Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. ClinicalTrials.gov Identifier: NCT03439670.

Comprehensive assessments of immuno-oncology drug-based combination therapies as first-line treatment for advanced renal cell carcinoma.

Over the last decade, there have been substantial progress in the field of systemic therapy for advanced renal cell carcinoma. Through the transition from treatment with cytokines to molecular-targeted agents, and currently to immuno-oncology drugs, the prognostic outcomes of patients with advanced renal cell carcinoma have been markedly improved. In particular, based on the promising outcomes of recently conducted pivotal randomized clinical trials, immuno-oncology drug-based combination therapy by either dual immune checkpoint inhibition or combined inhibition of an immune checkpoint and tyrosine kinase, is currently regarded as a standard of care for treatment-naïve advanced renal cell carcinoma patients. However, insufficient data are available with respect to the selection of optimal systemic therapies for advanced renal cell carcinoma in the first-line setting due to the lack of a head-to-head comparison between approved immuno-oncology drug-based combination therapies. In this review, therefore, we summarize interesting findings associated with first-line combination therapies for advanced renal cell carcinoma obtained from both randomized clinical trials and real-world clinical practices, in order to present useful guidance to help make treatment decisions for patients with treatment-naïve advanced renal cell carcinoma.

Risk assessment tools for survival prognosis: An era of new surrogacy endpoints for clinical outcome measurement in pulmonary arterial hypertension clinical trials?

Developing a new medication in a rare disease indication like pulmonary arterial hypertension (PAH) is very challenging. This is especially true now that clinical trials often employ time to clinical worsening (TTCW) as an endpoint (thus requiring a relatively large and lengthy trial) and since patients are more frequently prescribed combination therapy. During the last few decades, several tools have been developed to predict mortality in PAH and have demonstrated generally good discrimination. The objective of this review article is to assess the available data on the different tools and methods described in the literature and identify potential candidates that could be used as surrogate endpoints in pivotal randomized clinical trials in future. Some of these tools have been validated in various registries and in post-hoc analyses of clinical trial data, but none have been assessed in a prospective clinical trial and we still lack the evidence necessary for endorsement by health authorities. In this review, we identify several promising options that warrant further investigation as potential surrogate endpoints in clinical trials to replace TTCW or 6-minute walk distance. Prospective inclusion of such tools in new clinical trials may help build a stronger surrogacy for prognosis of disease progression and mortality.

Early- and subsequent- response of cognitive functioning in Alzheimer's disease: Individual-participant data from five pivotal randomized clinical trials of donepezil

The association between early improvement and subsequent change in cognition is unexamined in antidementia clinical trials. We aimed to examine the consequences of early-response to antidementia medication in Alzheimer's disease. Participant-level data were analyzed from five pivotal clinical trials of donepezil for Alzheimer's disease lasting up to 24 weeks (N = 1917). Early-response was based on Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) change scores under minus four from baseline to week six, otherwise classified non-response; then subgrouped by donepezil or placebo. The primary analysis tested the group differences in ADAS-Cog change from baseline for the interval after week six up to 24, based on a three-level mixed-effects model repeated measures (MMRM) model. Four models of increasing complexity were tested, and the most parsimonious model was examined in the primary analysis. The remaining models were tested in sensitivity analysis. In the analytic sample, 32.09% (N = 396/1234) of donepezil and 24.01% (N = 164/683) of placebo participants were classified as early responders, and 67.91% donepezil (N = 838/1234), 75.99% (N = 519/683) placebo participants were not. MMRM identified a statistically significant (P < 0.05) responder group effect. Marginal means (MM) demonstrated more improvement for the early responders (donepezil: MM = −4.13, 95% CI = -5.93, −2.32; placebo MM = 1.81, 95% CI = −4.12, 0.50), compared to non-early responders (donepezil MM = 0.05, 95% CI = -1.40, 1.51; placebo MM = 2.59, 95% CI = 0.99, 4.19). Results replicated in sensitivity analysis. Our results inform clinicians regarding the extent and consequences of early improvement in cognitive functioning and potentially contribute to treatment monitoring and the design of clinical trials for Alzheimer's disease.

Quantification of infarct core signal using CT imaging in acute ischemic stroke

In stroke care, the extent of irreversible brain injury, termed infarct core, plays a key role in determining eligibility for acute treatments, such as intravenous thrombolysis and endovascular reperfusion therapies. Many of the pivotal randomized clinical trials testing those therapies used MRI Diffusion-Weighted Imaging (DWI) or CT Perfusion (CTP) to define infarct core. Unfortunately, these modalities are not available 24/7 outside of large stroke centers. As such, there is a need for accurate infarct core determination using faster and more widely available imaging modalities including Non-Contrast CT (NCCT) and CT Angiography (CTA).Prior studies have suggested that CTA provides improved predictions of infarct core relative to NCCT; however, this assertion has never been numerically quantified by automatic medical image computing pipelines using acquisition protocols not confounded by different scanner manufacturers, or other protocol settings such as exposure times, kilovoltage peak, or imprecision due to contrast bolus delays. In addition, single-phase CTA protocols are at present designed to optimize contrast opacification in the arterial phase. This approach works well to maximize the sensitivity to detect vessel occlusions, however, it may not be the ideal timing to enhance the ischemic infarct core signal (ICS).In this work, we propose an image analysis pipeline on CT-based images of 88 acute ischemic stroke (AIS) patients drawn from a single dynamic acquisition protocol acquired at the acute ischemic phase. We use the first scan at the time of the dynamic acquisition as a proxy for NCCT, and the rest of the scans as a proxy for CTA scans, with bolus imaged at different brain enhancement phases. Thus, we use the terms “NCCT” and “CTA” to refer to them. This pipeline enables us to answer the questions “Does the injection of bolus enhance the infarct core signal?” and “What is the ideal bolus timing to enhance the infarct core signal?” without being influenced by aforementioned factors such as scanner model, acquisition settings, contrast bolus delay, and human reader errors. We use reference MRI DWI images acquired after successful recanalization acting as our gold standard for infarct core.The ICS is quantified by calculating the difference in intensity distribution between the infarct core region and its symmetrical healthy counterpart on the contralateral hemisphere of the brain using a metric derived from information theory, the Kullback-Leibler divergence (KL divergence). We compare the ICS provided by NCCT and CTA and retrieve the optimal timing of CTA bolus to maximize the ICS.In our experiments, we numerically confirm that CTAs provide greater ICS compared to NCCT. Then, we find that, on average, the ideal CTA acquisition time to maximize the ICS is not the current target of standard CTA protocols, i.e., during the peak of arterial enhancement, but a few seconds afterward (median of 3 s; 95% CI [1.5, 3.0]). While there are other studies comparing the prediction potential of ischemic infarct core from NCCT and CTA images, to the best of our knowledge, this analysis is the first to perform a quantitative comparison of the ICS among CT based scans, with and without bolus injection, acquired using the same scanning sequence and a precise characterization of the bolus uptake, hence, reducing potential confounding factors.

Cost-Effectiveness Analysis of Omalizumab for Severe Allergic Asthma in Japan Using Real-World Evidence

ObjectivesOmalizumab is a recommended add-on therapy for patients with severe allergic asthma who remain uncontrolled despite treatment with standard of care (SoC). This study evaluated the cost-effectiveness of omalizumab compared with SoC applying real-world clinical outcomes in adult patients with severe allergic asthma in Japan. MethodsA validated Markov model was adapted for Japan and compared the cost-effectiveness of omalizumab as an add-on therapy to SoC versus SoC alone using the most recently updated price of omalizumab. A Japanese real-world postmarketing surveillance and a pivotal randomized clinical trial were used as inputs for clinical effectiveness. Japanese life tables and literature were accessed for mortality data and unit costs were extracted from a Japanese insurance claims database. Quality of life data were retrieved from the clinical trial. ResultsIn the base case, the incremental cost-effectiveness ratio for omalizumab add-on therapy was ¥2.85 million per quality-adjusted life-year gained (approximately €21 000; 1€ = ¥133.26) compared with SoC alone. The model appeared to be most sensitive to changes in clinically significant severe exacerbation fatality, day-to-day asthma symptom utilities for SoC, discount rates for benefits, day-to-day asthma symptom utilities for omalizumab responders, time horizon, and the annual cost of omalizumab. The results of the probabilistic sensitivity analysis showed that the probability of omalizumab being cost-effective was 93% to 98% at a threshold of ¥5 to ¥6 million (willingness-to-pay for 1 quality-adjusted life-year). ConclusionsOmalizumab add-on therapy is cost-effective compared with SoC alone in Japan in severe allergic asthma population who are uncontrolled with high-dose inhaled corticosteroid and other controllers.

Uptake and Survival Outcomes Following Immune Checkpoint Inhibitor Therapy Among Trial-Ineligible Patients With Advanced Solid Cancers

Immune checkpoint inhibitors (ICIs) are part of standard of care for patients with many advanced solid tumors. Patients with poor performance status or organ dysfunction are traditionally ineligible to partake in pivotal randomized clinical trials of ICIs. To assess ICI use and survival outcomes among patients with advanced cancers who are traditionally trial ineligible based on poor performance status or organ dysfunction. This retrospective cohort study was conducted in 280 predominantly community oncology practices in the US and included 34 131 patients (9318 [27.3%] trial ineligible) who initiated first-line systemic therapy from January 2014 through December 2019 for newly diagnosed metastatic or recurrent nontargetable non-small cell lung, urothelial cell, renal cell, or hepatocellular carcinoma. Data analysis was performed from December 1, 2019, to June 1, 2021. Trial ineligibility (Eastern Cooperative Oncology Group performance status ≥2 or the presence of kidney or liver dysfunction); first-line systemic therapy. The association between trial ineligibility and ICI monotherapy uptake was assessed using inverse probability-weighted (IPW) logistic regressions. The comparative survival outcomes following ICI and non-ICI therapy among trial-ineligible patients were assessed using treatment IPW survival analyses. Because we observed nonproportional hazards, we reported 12-month and 36-month restricted mean survival times (RMSTs) and time-varying hazard ratios (HRs) of less than 6 months and 6 months or greater. Among the overall cohort (n = 34 131), the median (IQR) age was 70 (62-77) years; 23 586 (69%) were White individuals, and 14 478 (42%) were women. Over the study period, the proportion of patients receiving ICI monotherapy increased from 0% to 30.2% among trial-ineligible patients and 0.1% to 19.4% among trial-eligible patients. Trial ineligibility was associated with increased ICI monotherapy use (IPW-adjusted odds ratio compared with non-ICI therapy, 1.8; 95% CI, 1.7-1.9). Among trial-ineligible patients, there were no overall survival differences between ICI monotherapy, ICI combination therapy, and non-ICI therapy at 12 months (RMST, 7.8 vs 7.7 vs 8.1 months) or 36 months (RMST, 15.0 vs 13.9 vs 14.4 months). Compared with non-ICI therapy, ICI monotherapy showed evidence of early harm (IPW-adjusted HR within 6 months, 1.2; 95% CI, 1.1-1.2) but late benefit (adjusted HR among patients who survived 6 months, 0.8; 95% CI, 0.7-0.8). In this cohort study, compared with trial-eligible patients, trial-ineligible patients with advanced cancers preferentially received first-line ICI therapy. A survival difference was not detected between ICI and non-ICI therapies among trial-ineligible patients. Positive results for ICI in phase 3 trials may not translate to this vulnerable population.