Multiple Randomized Controlled Trials Research Articles

Endoscopic Artificial Intelligence for Image Analysis in Gastrointestinal Neoplasms.

Artificial intelligence (AI) using deep learning systems has recently been utilized in various medical fields. In the field of gastroenterology, AI is primarily implemented in image recognition and utilized in the realm of gastrointestinal (GI) endoscopy. In GI endoscopy, computer-aided detection/diagnosis (CAD) systems assist endoscopists in GI neoplasm detection or differentiation of cancerous or non-cancerous lesions. Several AI systems for colorectal polyps have already been applied in colonoscopy clinical practices. In esophagogastroduodenoscopy, a few CAD systems for upper GI neoplasms have been launched in Asian countries. The usefulness of these CAD systems in GI endoscopy has been gradually elucidated. In this review, we outline recent articles on several studies of endoscopic AI systems for GI neoplasms, focusing on esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cancer (GC), and colorectal polyps. In ESCC and EAC, computer-aided detection (CADe) systems were mainly developed, and a recent meta-analysis study showed sensitivities of 91.2% and 93.1% and specificities of 80% and 86.9%, respectively. In GC, a recent meta-analysis study on CADe systems demonstrated that their sensitivity and specificity were as high as 90%. A randomized controlled trial (RCT) also showed that the use of the CADe system reduced the miss rate. Regarding computer-aided diagnosis (CADx) systems for GC, although RCTs have not yet been conducted, most studies have demonstrated expert-level performance. In colorectal polyps, multiple RCTs have shown the usefulness of the CADe system for improving the polyp detection rate, and several CADx systems have been shown to have high accuracy in colorectal polyp differentiation. Most analyses of endoscopic AI systems suggested that their performance was better than that of non-expert endoscopists and equivalent to that of expert endoscopists. Thus, Endoscopic AI systems may be useful for reducing the risk of overlooking lesions and improving the diagnostic ability of endoscopists.

Triptans in the Acute Migraine Management of Children and Adolescents: An Update.

To summarize recent findings regarding triptan use in the acute treatment of pediatric migraine. Prevalence of pediatric migraine is rising. The American Headache Society and American Academy of Neurology updated guidelines to provide evidence-based recommendations for the treatment of acute migraine in youth. In the setting of a dearth of new randomized controlled trials (RCTs), we review current guidelines, triptan use in the emergency department, and an era of secondary analyses. Measuring the efficacy of triptans in pediatric migraine has been challenged by high placebo response rates. Secondary analyses, combining data from multiple RCTs, support that triptans are safe and effective in the treatment of migraine. Triptans are a vital tool and the only FDA-approved migraine-specific treatment available in pediatrics. There is a need for further studies and funding support in pediatric headache medicine.

538 - Physician-assessed effectiveness and patient-reported outcomes in adult and adolescent patients with atopic dermatitis in the Asian subpopulation treated with dupilumab: real-world insights 1 year into the GLOBOSTAD multinational prospective observational study

Abstract Introduction In multiple randomized controlled clinical trials, dupilumab demonstrated robust efficacy in patients with moderate-to-severe atopic dermatitis (AD). Long-term effectiveness of dupilumab in real-world AD treatment is one of the main objectives of the ongoing GLOBOSTAD study. Comprehensive data on Asian patients with moderate-to-severe AD treated with dupilumab are limited. Objectives To report patient-reported outcomes and physician-assessed AD clinical measures to evaluate disease characteristics, severity, and treatment effectiveness 1 year after initiating dupilumab treatment in Asian patients. The baseline disease severity and patient demographics have been reported previously1. Methods This 5-year, multinational, multicentre, prospective, observational study (GLOBOSTAD; NCT03992417) included Asian patients ≥12 years-old with moderate-to-severe AD who initiated dupilumab treatment based on country-specific prescribing criteria. Eczema Area and Severity Index (EASI), Scoring Atopic Dermatitis (SCORAD), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS) and Dermatology Life Quality Index (DLQI) were assessed at baseline, 3 months (± 1 month), 6 months (± 2 months), and 12 months (± 2 months). Data are reported as observed in patients self-reported as Asian for enrolment/safety (N = 204; data cutoff: March 2023) and follow-up (N = 194) populations. Results During the study, EASI (>21 = severe; ≤7 = mild/no disease) score improved from 28.0 (12.1), mean (SD) at baseline to 7.4 (8.5) at 3 months, 5.7 (6.9) at 6 months, and was sustained until the end of observation period, 12 months, at 4.7 (7.1). Similarly, SCORAD (>50 = severe; <25 = mild/no disease) score improved from 61.5 (16.9) at baseline to 25.4 (16.6) at 3 months, 22.5(14.8) at 6 months, and further improved to 18.6 (13.3) at 12 months. During the study, patients also reported early improvements in POEM, mean (SD) from 19.1 (7.3) at baseline to 8.0 (5.8) at 3 months, 7.6 (5.5) at 6 months, and to 7.2 (5.0) at end of observation period (12 months); PP-NRS decreased from 5.7 (2.3) to 2.1 (2.2) to 1.7 (1.8), and to 1.4 (1.7) at 3 months, 6 months, and 12 months respectively; and DLQI improved from 13.2 (7.4) to 4.9 (4.6) to 4.0 (3.8), and to 4.1 (4.0) at 3 months, 6 months and 12 months respectively. Dupilumab-related adverse events were reported in 44 (21.5%) patients while 4 (2.0%) reported dupilumab-related severe adverse events. Conclusion In Asian patients, the initiation of dupilumab treatment led to early improvements in all AD outcome measures, sustained throughout the 1-year observational period. Safety and treatment effectiveness were consistent with overall population.

Strategic Multimodal Intervention in at‐risk Elderly Indians for Prevention of Dementia (SMRUTHI INDIA): A cohort multiple randomised controlled trial (cmRCT)

AbstractBackgroundThe major burden of dementia will be falling on Low and middle‐income countries in the next few decades. One of the major strategies to counter the rise in dementia burden is primary prevention, especially in at‐risk elderly individuals.MethodStrategic Multimodal Intervention in at‐risk Elderly Indians for Prevention of Dementia (SMRUTHI INDIA) is designed as a Cohort Multiple Randomised Controlled Trial (cmRCT) under a prospective community‐based cohort in rural India with long‐term follow‐up over many years. The rural cohort will be established in four zones of India, under the Indian Council of Medical Research (ICMR), Model Rural Health Research Units (MRHRUs) at Himachal Pradesh (North), Tripura (East), Rajasthan (West) and Karnataka (South). We plan to recruit 10000 participants with age > = 55 years and CAIDE score > = 6. SMRUTHI INDIA will be established in 2 phases. Phase 1 involves establishing a cohort (phase 1a) and development, followed by validation of the multimodal care bundle (phase 1 b). The care bundle preparation will have a development phase, acceptability and adaptability phase followed by feasibility testing involving a pilot RCT in a single centre. Phase 2 involves testing multiple interventions in cmRCT, and the first intervention to be tested will be the multimodal care bundle. The primary outcome will be the incidence of all‐cause dementia.ResultSMRUTHI INDIA will establish in parallel a large prospective rural cohort of at‐risk elderly in India and develop a culturally adapted and context‐specific multimodal care bundle. At the end of Phase 1, we will have the results of the pilot RCT on the feasibility of multimodal care bundle.ConclusionSMRUTHI INDIA is a landmark cohort multiple randomised controlled trial (cmRCT) which will assess multiple interventions for the primary prevention of dementia for the first time in India.Funding: Department of Health Research, Indian Council of Medical Research (ICMR)

A Real-World Experience of Azathioprine Versus First-Line Disease-Modifying Therapy in Relapsing-Remitting Multiple Sclerosis-A Prospective Cohort Study.

Azathioprine (AZA) has demonstrated efficacy in multiple randomized control trials (RCTs) for Relapsing-Remitting Multiple Sclerosis (RRMS). However, we still need comparative real-world data with other first-line disease-modifying therapies (DMTs). We aimed to assess AZA's effectiveness regarding relapses, disability progression, time to the first relapse, magnetic resonance imaging (MRI) activity, and safety compared with other approved first-line DMTs in an Indian population in a real-world setting. We conducted a single-center prospective study of treatment-naive RRMS patients between 2017 and 2019. We evaluated the effects of AZA and other approved DMTs on clinical and radiological measures. Among 192 eligible patients (F:M ratio 2.84:1), 68 patients (35.4%) were on AZA, 68 patients (35.4%) were on dimethyl fumarate (DMF), 32 patients (16.7%) on interferon (IFN beta-1a), and 16 patients (8.3%) on teriflunomide (TFL). Four treatment groups were comparable: AZA v/s DMF v/s TFL v/s IFN beta-1a. In primary outcomes, there was no significant difference between the groups in terms of change in the Expanded Disability Status Scale (EDSS) score at three months (p-value = 0.169), six months (p-value = 0.303), 12 months (p-value = 0.082), and 24 months (p-value = 0.639), the number of relapses (p-value = 0.229), and time to the first relapse (p-value > 0.05 in all groups). In the secondary outcome, there was no significant difference between the treatment groups on serial MRI parameters used according to "Magnetic Resonance Imaging in Multiple Sclerosis" (MAGNIMS) 2016 criteria (p-value > 0.05). In safety outcomes, leukopenia was significantly more common in the AZA group (p-value = 0.025), flu-like symptoms (p-value = 0.0001), and injection site reactions (p-value = 0.035) were significantly more common in the IFN beta-1a group. Our study suggests AZA is as effective as other approved DMTs and a good alternative as a first-line treatment for multiple sclerosis's clinical and radiological activity in real-world settings on short follow-up. Based on these results, more randomized controlled trials of AZA v/s DMF or other DMTs are needed for more robust outcomes.

493-P: SCS for the Treatment of Painful DPN—Consistent Outcomes from Multiple RCTs

Pain associated with diabetic peripheral neuropathy (DPN) is treated medically with gabapentin/pregabalin, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors1 which are often not satisfactory long-term. Spinal Cord Stimulation (SCS) is an effective alternative per 3 randomized controlled trials (RCTs)2,3,4. We reviewed and compared 3 published RCTs2,3,4 comparing SCS to conventional treatments for painful DPN in subjects with mostly type 2 diabetes (Table 1). Study outcome measures included a composite primary endpoint where patients could be identified as treatment responders by reduction in pain diary scores or Patient Global Impression of Change, ≥50% reduction in VAS measurement for pain, and a compound primary endpoint of ≥50% reduction in pain score and no neurologic decline. EQ5D questionnaires were used to assess Quality of Life. The difference in treatment success between SCS and control for the primary endpoint in the Intention-to-Treat populations ranged from 52 - 58%. Improvement in EQ5D index scores at 6 months ranged from 0.124 - 0.380. The similarity of outcomes in 3 RCTs2,3,4 demonstrate that SCS is an effective treatment modality for DPN pain compared with conventional medical approaches. Patients from 1 study4 have been followed-up to 18 months8 and patients in another2 up to 10 years9 with similar outcomes, demonstrating long-term benefits of SCS for patients with painful DPN. Disclosure B.W.Bode: Advisory Panel; Ascensia Diabetes Care, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Research Support; Abbott Diabetes, Abvance Therapeutics, Better Therapeutics, Inc, Dexcom, Inc., Diasome, Dompé, Insulet Corporation, Lilly Diabetes, Medtronic, Novo Nordisk, Sanvita Medical, Senseonics, Provention Bio, Inc., REMD Biotherapeutics, ViaCyte, Inc., Xeris Pharmaceuticals, Inc., vTv Therapeutics, Speaker's Bureau; Abbott Diabetes, American Diabetes Association, Boehringer Ingelheim and Eli Lilly Alliance, Insulet Corporation, Lilly Diabetes, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; Glytec, LLC. G.Grunberger: Advisory Panel; CeQur SA, Nevro Corp., LifeScan Diabetes Institute, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. M.Fishman: Consultant; Abbott, Biotronik, Medtronic, Nevro Corp., Other Relationship; Medtronic, Abbott, Research Support; Abbott, Boston Scientific Corporation, Medtronic, Nalu, SGX Medical, Thermaquil, Biotronik, Stock/Shareholder; Celeri Health, Thermaquil. M.Murphy: Consultant; Medtronic, Relievant. R.A.Vigersky: Employee; Medtronic. L.Johanek: Employee; Medtronic. M.Larue: Employee; Medtronic. Funding Medtronic

Guideline-Directed Medical Therapy for the Treatment of Heart Failure with Reduced Ejection Fraction.

Guideline-directed medical therapy (GDMT) is the cornerstone of pharmacological therapy for patients with heart failure with reduced ejection fraction (HFrEF) and consists of the four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors. The recommendation for use of GDMT is based on the results of multiple major randomized controlled trials demonstrating improved clinical outcomes in patients with HFrEF who are maintained on this therapy. The effect is most beneficial when medications from the four main drug classes are used in conjunction. Despite this, there is an underutilization of GDMT, partially due to lack of awareness of how to safely and effectively initiate and titrate these medications. In this review article, we describe the different drug classes included in GDMT and offer an approach to initiation and effective titration in both the inpatient as well as outpatient setting.

Feasibility and first results of the ‘Trials-within-Cohorts’ (TwiCs) design in patients undergoing radiotherapy for lung cancer

Background: ‘Trials-within-Cohorts’ (TwiCs), previously known as ‘cohort multiple randomized controlled trials’ is a pragmatic trial design, supporting an efficient and representative recruitment of patients for (future) trials. To our knowledge, the ‘COhort for Lung cancer Outcome Reporting and trial inclusion’ (COLOR) is the first TwiCs in lung cancer patients. In this study we aimed to assess the feasibility and first year results of COLOR.Material and Methods: All patients diagnosed with lung cancer referred to the Radiotherapy department were eligible to participate in the ongoing prospective COLOR study. At inclusion, written informed consent was requested for use of patient data, participation in patient-reported outcomes (PROs), and willingness to participate in (future) trials. Feasibility was studied by assessing participation and comparing baseline PROs to EORTC reference values. First-year results of PROs at baseline and 3 months after inclusion were evaluated separately for stereotactic body radiotherapy (SBRT) and conventional radiotherapy patients.Results: Of the 338 eligible patients between July 2020 and July 2021, 169 (50%) participated. Among these, 127 (75%) gave informed consent to PROs participation and 110 (65%) were willing to participate in (future) trials. The inclusion percentage dropped from 77% to 33% when the information procedure was switched from in-person to by phone (due to COVID-19 pandemic measures). Baseline PROs for physical and cognitive functioning were comparable in COLOR patients compared to the EORTC reference values. No significant changes in PROs were observed 3 months after inclusion, except for a slight increase in pain scores in the SBRT group (n = 97).Conclusions: The TwiCs-design appears feasible in lung cancer patients with fair participation rates (although negatively impacted by the COVID-19 pandemic). With a planned expansion to other centers, the COLOR-study is expected to enable multiple (randomized) evaluations of experimental interventions with important advantages for recruitment, generalizability, and long-term outcome data collection.

THERAPEUTIC HYPOTHERMIA OF NEWBORNS: RECOMMENDATIONS OF UNIVERSITÄTSKLINIKUM CARL-GUSTAV-CARUS (DRESDEN, GERMANY)

Therapeutic hypothermia (TH) is a modern standard of care for newborns with gestational age ≥36 weeks who have moderate to severe hypoxic-ischemic encephalopathy. The introduction of TH is based on evidence-based medicine, and multiple randomized controlled trials confirm its efficiency in significantly reducing the risk of death or severe infant disability. Recent practice emphasizes the vital importance of clearly defined protocols for TH and its use in neonatal care settings with facilities for multidisciplinary care and adequate resources for comprehensive monitoring and treatment.The article reports on the local protocol of TH in the neonatal intensive care unit of the University Hospital at Carl-Gustav-Carus at the Technical University Dresden (Dresden, Germany). TH is administered to newborns with moderate or severe hypoxic-ischemic encephalopathy who were born at a gestational age of ≥ 36+0 weeks, are less than 6 hours old and have no signs of massive intracranial hemorrhage. Exclusion criteria are threat to life, congenital malformations, severe intracranial hemorrhage and poor prognosis. Whole-body cooling to an internal body temperature of 33.5°C is preferred. The cooling period is 72 hours, with warming at a rate of 0.2°C per hour, followed by normothermia over the next 48 hours.Comprehensive assessment of the infant's status includes the Thompson score, amplitude and standard electroencephalography, magnetic resonance imaging, control of blood coagulation, acid-base status and blood gases, etc. Follow-up therapy is aimed at providing adequate ventilatory support to prevent hypocapnia, sufficient fluid supply, effective analgesia and anticonvulsant therapy, etc. Emphasis is placed on the need for further cathemnestic monitoring of infants who underwent TH.

PSMA-PET/CT-Guided Intensification of Radiation Therapy for Prostate Cancer (PSMAgRT): Findings of Detection Rate, Effect on Cancer Management, and Early Toxicity From a Phase 2 Randomized Controlled Trial

Prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET) is increasingly integrated in prostate cancer management because of its diagnostic performance. We sought to evaluate the effect of PSMA-PET/computed tomography (CT)-guided intensification of radiation therapy (PSMAgRT) on patient outcomes. Here, we report secondary trial endpoints including the rate of new lesion detection, effect on prostate cancer management, and treatment-related toxicities. In this phase 2 cohort multiple randomized controlled trial across 2 institutions, men with prostate cancer planned for RT were randomly selected for PSMAgRT across 4 strata: oligometastatic, high risk (Cancer of the Prostate Risk Assessment ≥6 or cN1), salvage post-RT, and salvage postprostatectomy (RP). Primary endpoint was failure-free survival at 5 years, with analysis pending further follow-up. Secondary endpoints included new lesion detection yield of PSMA-PET/CT, acute and delayed toxicities, effect on prostate cancer management, and health-related quality-of-life outcomes. This trial is registered with ClinicalTrials.gov, identifier NCT03525288, companion to registry NCT03378856. Between May 2018 and February 2021, 262 patients were enrolled and randomized. Nine patients were later excluded (5 control, 4 PSMAgRT), leaving 253 patients for analysis (23 oligometastatic, 86 high risk, 16 salvage post-RT, and 128 salvage post-RP). New lesions were detected in 45.5% of oligometastatic, 39.5% of high risk, 14.3% of salvage post-RT, and 51.6% of salvage post-RP. Overall, PSMA-PET/CT led to intensification of RT in over half of patients (52.0%), with minimal intensification of systemic therapy (4.0%). With a median follow-up of 12.9 months, this intensification was associated with 3 attributable grade 3+ events (2.5% of patients undergoing PSMAgRT) but no difference in the rate of grade 2+ events attributable to RT compared with controls (43%, both arms). In this randomized trial, PSMA-PET/CT led to intensification of RT in more than half of patients. Longer follow-up is required to determine whether this intensification translates to effect on cancer control and long-term toxicity and health-related quality-of-life outcomes.

The Efficacy of Conservative Management in Uncomplicated Acute Appendicitis - A Single-Center Retrospective Study.

Background Acute appendicitis remains the most common cause of lower abdominal pain leading to emergency visits. Even though the standard treatment of acute appendicitis remains appendectomy, in recent times, multiple randomized control trials and meta-analyses have deduced conservative treatment as a successful alternative treatment.During the coronavirus disease (COVID) pandemic, with a shortage of staff and resources, treatment with conservative management of uncomplicated acute appendicitis became very beneficial under certain circumstances and conditions. This study aimed to assess whether it is effective to manage patients with uncomplicated acute appendicitis with antibiotic therapy. Methodology This was a single hospital based retrospective, cross-sectional study from Jan 2015 to May 2020. Patients with clinical and radiological features of uncomplicated acute appendicitis with Alvarado's score >6 were included in the study. Patients were kept on antibiotics, intravenous fluids, and analgesia as part of a conservative regime. Those who failed to respond to conservative therapy were managed surgically. The follow-up period was six months. Results One hundred eighty-two cases of uncomplicated acute appendicitis were included and managed conservatively, of which 52.2% were males while 47.8% were females. The median age of the patients was 26 years. Conservative treatment was successful in 26.2% of the patients, with a recurrence of 5.5% in the six-month follow-up period. The mean number of days of hospital stay was three days in patients treated with conservativeor surgical treatment. Conclusion Conservative management is gaining popularity, and many centers are inclined towards non-operative management; however, appendectomy remains the gold standard treatment for appendicitis.

Randomized controlled trial of an internet-based self-guided hand exercise program to improve hand function in people with systemic sclerosis: the Scleroderma Patient-centered Intervention Network Hand Exercise Program (SPIN-HAND) trial

BackgroundSystemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. Functional impairment of hands is common. The Scleroderma Patient-centered Intervention Network (SPIN)-HAND trial compared effects of offering access to an online self-guided hand exercise program to usual care on hand function (primary) and functional health outcomes (secondary) in people with SSc with at least mild hand function limitations.MethodsThe pragmatic, two-arm, parallel-group cohort multiple randomized controlled trial was embedded in the SPIN Cohort. Cohort participants with Cochin Hand Function Scale (CHFS) scores ≥ 3 and who indicated interest in using the SPIN-HAND Program were randomized (3:2 ratio) to an offer of program access or to usual care (targeted N = 586). The SPIN-HAND program consists of 4 modules that address (1) thumb flexibility and strength; (2) finger bending; (3) finger extension; and (4) wrist flexibility and strength. The primary outcome analysis compared CHFS scores 3 months post-randomization between participants offered versus not offered the program. Secondary outcomes were CHFS scores 6 months post-randomization and functional health outcomes (Patient-Reported Outcomes Measurement Information System profile version 2.0 domain scores) 3 and 6 months post-randomization.ResultsIn total, 466 participants were randomized to intervention offer (N = 280) or usual care (N = 186). Of 280 participants offered the intervention, 170 (61%) consented to access the program. Of these, 117 (69%) viewed at least one hand exercise instruction video and 77 (45%) logged into the program website at least 3 times. In intent-to-treat analyses, CHFS scores were 1.2 points lower (95% CI − 2.8 to 0.3) for intervention compared to usual care 3 months post-randomization and 0.1 points lower (95% CI − 1.8 to 1.6 points) 6 months post-randomization. There were no statistically significant differences in other outcomes.ConclusionThe offer to use the SPIN-HAND Program did not improve hand function. Low offer uptake, program access, and minimal usage among those who accessed the program limited our ability to determine if using the program would improve function. To improve engagement, the program could be tested in a group format or as a resource to support care provided by a physical or occupational therapist.Trial registrationNCT03419208. Registered on February 1, 2018.

Psychopharmacological Treatment Algorithms of Manic/Mixed and Depressed Episodes in Pediatric Bipolar Disorder.

Introduction: Pediatric bipolar disorder (PBD) is a severe psychiatric illness diagnosed before the age of 18, which is associated with extreme shifts in mood characterized by manic and depressive episodes. In 2005, AACAP published algorithms to guide pharmacological treatment of manic/mixed episodes associated with PBD. At that time, lithium was the only Food and Drug Administration (FDA)-approved treatment for pediatric bipolar manic/mixed episodes. The goal of this article is to review evidence that has emerged since the AACAP algorithm in 2005. Methods: Literature searches were conducted through PubMed and limited to studies published between 2005 and 2021, using keywords that focused on randomized controlled trials (RCTs) for available psychopharmacological medications. In addition, the authors conducted in-depth searches for articles providing evidence for agents included in the 2005 AACAP algorithm. Results: Since the publication of the AACAP algorithm in 2005, multiple RCTs have been conducted in PBD, leading to FDA approval of five medications (aripiprazole, asenapine, olanzapine, quetiapine, and risperidone) for the treatment of manic/mixed episodes and two medications (lurasidone and olanzapine-fluoxetine combination) for the treatment of depressed episodes. Divalproex sodium and oxcarbazepine were studied in pediatric RCTs and failed to separate from placebo. Conclusions: We offer an update to the 2005 AACAP algorithms for the treatment of pediatric bipolar mixed/manic episodes and added an evidence-based algorithm for the treatment of depression in PBD. In addition to treatment algorithms, we review current evidence for efficacy of agents proposed in the AACAP algorithm and provide tables summarizing medication side effects and efficacy.

From the identification of biopsychosocial risk factors to an increase in pain-related self-efficacy (IDRIS) – The online-based conveyance of an explanatory model for chronic back pain: Study protocol of a cohort multiple randomized controlled trial

BackgroundBack pain has a high global prevalence and carries a substantial risk for chronification. Biopsychosocial factors are assumed to be critical in the transition from acute to chronic back pain. Digital interventions are a promising tool to educate patients about their complaints. Thus, providing patients with an explanatory model regarding their individual risk factors in the early stage of their complaints via the internet might thus be a valuable approach in treatment. ObjectivesThe objectives of the present online study are to investigate the influence of a personalized psychoeducational intervention on self-efficacy and functioning and to examine biopsychosocial risk factors for symptom chronification. The intervention is based on a current model summarizing the empirical knowledge on relevant factors for persistent somatic symptoms, which has not been studied in back pain patients yet. MethodsAn observational cohort of patients with acute and subacute back pain (N = 564) will be asked about biopsychosocial risk factors via online survey at baseline, 4-week, and 12-week follow-up. Within this cohort, a randomly selected group of 132 participants (intervention group) with psychological burden (MCS-12 score of the SF-12 ≤ 50) and relevant somatic symptom intensity and interference (mean sum score of two numeric rating scales ≥5) and no prior psychotherapeutic treatment will be offered a personalized explanatory model in the form of an animated psychoeducational video. The video will be personalized in terms of participants' individual symptom profile and will be made accessible to watch online for 7 days. Participants will be compared to a control group receiving no treatment regarding change in pain-specific self-efficacy after 1 month as primary outcome, and change in functioning after 1 and 3 months, respectively, as secondary outcomes. Acceptance and usefulness of the intervention will be evaluated using the number of video views and a numeric rating scale. DiscussionThis is the first investigation of a personalized, video-animated online psychoeducation based on patients' individual risk factors for the chronification of back pain and the first systematic evaluation of the risk factors included in a comprehensive aetiological model on persistent somatic symptoms in back pain patients. This way, this study contributes to the understanding of cross-disorder psychopathological factors and a stronger consideration of biopsychosocial factors in the treatment of persistent somatic symptoms. If proven effective, the internet-based intervention will make an important contribution to the early treatment of back pain. Ethical approvalThe study was approved by the Local Psychological Ethics Committee (LPEK) at the Center for Psychosocial Medicine of the University Medical Center Hamburg-Eppendorf. Trial registrationThe study was registered at the German Clinical Trials Register in December 2021 (registration trial number: DRKS00025445).

Should serum biomarker monitoring replace primary antifungal chemoprophylaxis in patients with acute leukaemia receiving systemic anti-cancer therapy? A PRO/CON debate.

Fungal infection exacts a severe burden on patients with acute leukaemia. Azole prophylaxis attempts to mitigate this impact but is associated with toxicity and cost as well as the potential to select for resistance. The development of biomarkers including galactomannan and β-1,3-d-glucan may improve detection of early disease and thus reduce the need for prophylaxis, though these assays also have their limitations. In this debate, Howard et al. argue in favour of continuing chemoprophylaxis in patients with acute leukaemia receiving systemic chemotherapy, citing the multiple randomized control trials and meta-analyses that demonstrate its efficacy. Taynton et al. argue that fungal biomarker surveillance in the absence of primary antifungal chemoprophylaxis is a safe alternative that could reduce antifungal use and the development of resistance.

Rethinking about the treatment of polypoidal choroidal vasculopathy

Polypoidal Choroidal Vasculopathy (PCV) is now categorized as a subtype of neovascular Age-related Macular Degeneration (nAMD), though the ocular manifestation and prognosis of PCV patients are quite distinct from nAMD. Due to its high prevalence in Asian population, retina specialists have implemented multiple randomized control trials (RCT) in recent years, aiming at providing grade 1 clinical evidence for current therapies and exploring efficient and affordable regimens for long-term management of PCV. Here we summarised current problems existed in available RCTs and prognostic biomarkers, and presented our thoughts based on previous clinical experiences which may be helpful for clinical management of PCV.

158P Predictors of response to neoadjuvant checkpoint inhibition with chemotherapy in triple-negative breast cancer (TNBC): A meta-analysis of randomized control trials (RCTs)

Multiple RCTs have analyzed the effect of addition of checkpoint inhibitors to neoadjuvant chemotherapy (NACT) in TNBC, however there is a paucity of biomarkers to identify patients who would benefit from neoadjuvant chemoimmunotherapy (NACI), given significant immune-related toxicities observed with the combination. Therefore, we performed a meta-analysis to identify predictors of response to NACI as well as evaluate the efficacy of this combination approach.

Machine learning approaches to predict the 1-year-after-initial-AMI survival of elderly patients

BackgroundWhile multiple randomized controlled trials (RCTs) are available, their results may not be generalizable to older, unhealthier or less-adherent patients. Observational data can be used to predict outcomes and evaluate treatments; however, exactly which strategy should be used to analyze the outcomes of treatment using observational data is currently unclear. This study aimed to determine the most accurate machine learning technique to predict 1-year-after-initial-acute-myocardial-infarction (AMI) survival of elderly patients and to identify the association of angiotensin-converting- enzyme inhibitors and angiotensin-receptor blockers (ACEi/ARBs) with survival.MethodsWe built a cohort of 124,031 Medicare beneficiaries who experienced an AMI in 2007 or 2008. For analytical purposes, all variables were categorized into nine different groups: ACEi/ARB use, demographics, cardiac events, comorbidities, complications, procedures, medications, insurance, and healthcare utilization. Our outcome of interest was 1-year-post-AMI survival. To solve this classification task, we used lasso logistic regression (LLR) and random forest (RF), and compared their performance depending on category selection, sampling methods, and hyper-parameter selection. Nested 10-fold cross-validation was implemented to obtain an unbiased estimate of performance evaluation. We used the area under the receiver operating curve (AUC) as our primary measure for evaluating the performance of predictive algorithms.ResultsLLR consistently showed best AUC results throughout the experiments, closely followed by RF. The best prediction was yielded with LLR based on the combination of demographics, comorbidities, procedures, and utilization. The coefficients from the final LLR model showed that AMI patients with many comorbidities, older ages, or living in a low-income area have a higher risk of mortality 1-year after an AMI. In addition, treating the AMI patients with ACEi/ARBs increases the 1-year-after-initial-AMI survival rate of the patients.ConclusionsGiven the many features we examined, ACEi/ARBs were associated with increased 1-year survival among elderly patients after an AMI. We found LLR to be the best-performing model over RF to predict 1-year survival after an AMI. LLR greatly improved the generalization of the model by feature selection, which implicitly indicates the association between AMI-related variables and survival can be defined by a relatively simple model with a small number of features. Some comorbidities were associated with a greater risk of mortality, such as heart failure and chronic kidney disease, but others were associated with survival such as hypertension, hyperlipidemia, and diabetes. In addition, patients who live in urban areas and areas with large numbers of immigrants have a higher probability of survival. Machine learning methods are helpful to determine outcomes when RCT results are not available.

Commentary on: A call for better reporting of trials using surrogate primary endpoints.

Drs. Manyara, Ciani, and Taylor make the important point that randomized controlled trials (RCTs) using a primary surrogate endpoint should be more transparent in their reporting details of biomarkers in trials. They suggest a clear statement concerning use of a surrogate primary endpoint and providing information on validity and limitations of the surrogate. They announce a new project to develop SPIRIT and CONSORT extensions specific to surrogate endpoints SPIRIT-SURROGATE and CONSORT-SURROGATE. There are no fully qualified and validated surrogate biomarkers for Alzheimer's disease (AD) RCTs and none that could serve as a primary RCT endpoint. As described by the US Food and Drug Administration (FDA) a surrogate endpoint is a clinical trial endpoint used as a substitute for a direct measure of how a patient feels, functions, or survives.1 A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict clinical benefit. Epidemiologic, therapeutic, pathophysiologic, or other scientific data provide the evidentiary basis for establishing a biomarker as a surrogate. A surrogate must change in response to multiple therapies across multiple RCTs and must explain the change in clinical outcome as well as correlate with it.2 Designation as a surrogate requires substantial statistical evidence based on trial meta-analyses.3 Robert Califf, US Commissioner of Food and Drugs, makes the point that “the single most common and serious error in the evaluation of biomarkers is the assumption that a correlation between the measured level of a biomarker and a clinical outcome means that the biomarker constitutes a valid surrogate.”2 The primary outcome of the RCTs of the aducanumab trials was the Clinical Dementia Rating–Sum of Boxes (CDR-SB; NCT02484547; NCT02477800) and the primary endpoint was the drug–placebo difference on this outcome at week 76. Accelerated approval of aducanumab was based on amyloid plaque lowering as shown by amyloid positron emission tomography (PET) considered reasonably likely to predict clinical benefit.4 Reasonably likely surrogate endpoints are supported by a strong mechanistic and/or epidemiologic rationale, but the amount of clinical data available is not sufficient to support them as a validated surrogate endpoint (defined above). Reasonably likely surrogate endpoints are used to support the FDA's Accelerated Approval program, which is intended to provide patients with serious diseases more rapid access to promising therapies.5 Accelerated approval is followed by post-marketing studies to determine whether the reasonably likely surrogate endpoint, in fact, predicts the clinical benefit. The aducanumab trials would not have been included in reporting requirements for trials using surrogate primary endpoints; their primary endpoints were drug–placebo differences on clinical measures; amyloid lowering was not a primary or a secondary endpoint and was not included in the sequential testing rank order implemented (NCT02484547; NCT024778006). I concur with Drs. Manyara, Ciani, and Taylor that biomarkers should be described in greater detail in the SPIRIT and CONSORT criteria. Using the FDA biomarker lexicon, these measures would be described as risk/susceptibility, diagnosis, monitoring, pharmacodynamic/response, predictive, prognostic, or safety biomarkers.7, 8 Candidate surrogate biomarkers or biomarkers that might be considered reasonably likely to predict clinical benefit are pharmacodynamic biomarkers. Biomarkers that have been qualified for a specific context of use in the RCT should be described in the SPIRIT and CONSORT reporting framework.9 The SPIRIT-SURROGATE and CONSORT-SURROGATE initiative is important and might be more broadly conceived as a SPIRIT-BIOMARKER and CONSORT-BIOMARKER initiatives. Another important adjustment to the SPIRIT and CONSORT criteria is to require the reporting of ethnicity and race among trial participants. These data are sometimes not collected and often omitted from clinical trial reports.10 They are critically important to assess our success in increasing the diversity of clinical trial populations. JC is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P20AG068053; NIA grant P30AG072959; NIA grant R35AG71476; Alzheimer’s Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; and the Joy Chambers-Grundy Endowment. J.C. has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Biogen, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Signant Health, Suven, and United Neuroscience pharmaceutical, assessment, and investment companies. Author disclosures are available in the supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program: protocol for a two-arm parallel partially nested randomized controlled feasibility trial with progression to full-scale trial

BackgroundSystemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary).MethodsThis study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort (http://www.spinsclero.com/en/cohort) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited.DiscussionThe SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge.Trial registrationClinicalTrials.govNCT04246528. Registered on 27 January 2020