Primary Time Point Research Articles

Randomised Controlled Trial of Intravenous Iron (ferric carboxymaltose) for Second Trimester Anaemia in Malawian Pregnant Women (REVAMP)

Introduction Anemia affects 46% of pregnancies in Africa. WHO estimates 50% of anaemia in pregnancy (44% in Africa) is responsive to iron; other causes of anaemia in Africa include infection (e.g. P. falciparum). Antenatal oral iron supplementation improves maternal anaemia and birthweight, but adherence may be suboptimal. Ferric carboxymaltose (FCM) is a modern intravenous iron formulation which enables provision of 1000mg (or 20mg/kg) in one 15 minute infusion. We reasoned FCM is an option to treat antenatal anaemia in low income primary-care settings, but the feasibility, efficacy and safety of this approach is unproven. Methods REVAMP was an open label, individually randomised controlled trial set in Malawi, sub-Saharan Africa, a low income setting where anaemia, malaria and other infections (including HIV) are common. Women were screened at antenatal clinics and were eligible if they met criteria including capillary haemoglobin (Hb) <10.0g/dL, negative Plasmodium rapid diagnostic test, and ultrasound-confirmed singleton pregnancy of 13 to 26 weeks gestation. HIV positivity was not an exclusion. Women were randomly assigned 1:1 to the intervention arm (FCM 20mg/kg, up to 1000mg, once at enrolment) or standard of care (SOC, 60mg elemental iron b.d for 90 days, in alignment with local practice). All women received IPTp with Suphadoxine-Pyrimethamine at enrolment and 28 days. The primary maternal outcome was anaemia at 36 weeks gestation. Secondary maternal outcomes included anaemia at other timepoints (28 days post infusion, during delivery and 28 days post-partum), and Hb, iron deficiency (ID) and iron deficiency anaemia (IDA) at each timepoint. The primary neonatal outcome was birthweight. Subgroup analyses (e.g. by baseline anaemia severity, ID, IDA, HIV status) were prespecified. Safety outcomes included incidence of adverse events (AEs) during infusion, and all AEs from randomisation to 4 weeks postpartum, including serious AEs (SAEs): unplanned hospitalisation or death including pregnancy loss and neonatal death. Results We screened 21258 women and randomised 862. Baseline characteristics, including anaemia severity and prevalence of iron deficiency, inflammation, and HIV were similar between arms. Compared with SOC, FCM reduced the prevalence of anaemia at 28 days post infusion (PR 0.91 95% CI 0.85 to 0.97, P=0.007) but did not statistically significantly decrease anaemia prevalence at the primary timepoint of 36 weeks gestation (52.5% vs 56.8%, prevalence ratio (PR) 0.92, 95% CI 0.81 to 1.06, P=0.27), or at delivery or 28 days postpartum (Table 1). Hb concentrations increased from baseline to 28 days post partum in both arms and were greater in women randomised to FCM 28 days post infusion (1.3 vs 1.1 g/dL, difference 0.19 [0.06-0.33]) and at 28 days postpartum (3.1 vs 2.9 g/dL, difference 0.25 [0.06-0.45]). IDA prevalence was reduced at each timepoint, including at 36 weeks gestation (PR 0.29 [0.20 to 0.43], P<0.001). ID prevalence was also reduced at all timepoints. Birthweight did not differ between FCM and SOC. Adverse reactions during FCM administration were reported by 26/430 (6.0%) women; there were no infusion-related SAEs. There was no clinically relevant difference in AEs by any systemic organ class, including infection (including malaria), and SAEs in women and neonates (Table 2). Hypophosphataemia (PO4<0.080mmol/L) at 28 days post infusion was seen in 22/403 (5.5%) women randomised to FCM compared to 8/382 (2.0%) with SOC. There was no difference in pregnancy loss or stillbirth between arms. Conclusions In this low-income, malaria endemic setting, treatment of anaemic pregnant women in the second trimester with FCM worked faster than SOC to resolve anaemia but benefit was not evident by 36 weeks. However FCM reduced ID and IDA at every timepoint. Administration of FCM was feasible and safe. Extended follow-up of mothers and babies is underway. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

QOL-16. SYMON-SAYS (SYMPTOM MONITORING &amp; SYSTEMATIC ASSESSMENT AND REPORTING SYSTEM IN YOUNG SURVIVORS) PROGRAM HAS THE POTENTIAL TO DECREASE SYMPTOM BURDEN ON CHILDREN WITH CANCER

Abstract AIMS The unrelieved symptoms and side effects of often-aggressive cancer treatments can lead to poor outcomes. SyMon-SAYS was developed to minimize symptom management barriers and symptom burdens by routinely collecting and interpreting patient-reported outcomes in pediatric oncology ambulatory settings. This paper reports the preliminary results of the 16-week SyMon-SAYS trial. METHODS Children (ages 8-17) with cancer (on-therapy or within 6-M post-treatment) were randomly assigned to either intervention (IG; weeks 1-16 intervention) or waitlist (WG; weeks 1-8 waitlist, weeks 9-16 intervention) group. Children in the intervention phase reported on 9 symptoms (fatigue, sadness, itch, pain, worry, appetite, nausea, sleep, headache) weekly via an electronic medical record patient portal. Scores exceeding a pre-defined threshold triggered an alert to the treatment team. Parents completed a symptom management barriers questionnaire (SMBQ) at baseline, weeks 8 (primary time-point and analyzed in this paper) and 16. Mixed-effects models were used to evaluate symptom burden over time. RESULTS Data from 75 children (37 IG, 38 WG) were analyzed (mean age=13.3 years, 58.8% male, 74.7% white). Of them, 43.9% had leukemia, and 17.5% brain tumor. On average, the IG completed 11 (possible min=0 max=16) and the WG completed 5 (possible min=0 max=8) symptom checklists; of them, 60% triggered symptom alerts. Results of the mixed-effects models showed significantly (p&amp;lt; 0.05) improvement in fatigue, sadness, worry, appetite and headache. No significant changes were found on others. For SMBQ, IG parents reported significantly in favor of “enough time with my child's doctors/nurses to talk about symptoms” than WG parents from baseline to week 8. No significant differences between IG and WG over time on other SMBQ items. CONCLUSIONS Our preliminary findings showed SyMon-SAYS alleviated emotional related symptoms over time. Physical symptoms might be related more to disease severity and treatment intensity, which we plan to investigate when more data is available.

Telehealth-delivered group-based education and exercise-therapy for knee osteoarthritis: A randomised clinical trial interrupted by the COVID-19 pandemic

Introduction: Guidelines recommend education and exercise-therapy as first-line treatments for knee osteoarthritis. The Good Life with osteoArthritis from Denmark (GLA:D®) program provides physiotherapist-led group-based education and exercise-therapy at >500 sites in Australia. It is associated with clinically meaningful improvements in pain and quality of life (QoL). However, inability to attend in-person sessions due to geography, transportation requirements, or other commitments limits access. Telehealth (videoconferencing) may improve the equity of access to GLA:D®. One-on-one telehealth services for knee musculoskeletal pain conditions including osteoarthritis are reported to be non-inferior to in-person care, but there is a lack of research evaluating group-based telehealth services. This randomised clinical trial (RCT) aimed to determine if GLAD® delivered via telehealth was non-inferior to in-person delivery for knee-related burden at 3- (primary timepoint) and 12-months. Methods: This pre-registered (ACTRN12619000235101) two-arm (telehealth, in-person), non-inferiority RCT commenced in April 2019. Knee osteoarthritis clinical diagnosis was based on NICE guidelines. Difference between groups for change in knee-related burden (primary outcome) was evaluated by averaging four Knee injury and Osteoarthritis Outcome Score subscales (KOOS4: pain, symptoms, function in daily living, QoL), measured at 3- and 12-months follow-up. The KOOS-QoL subscale was evaluated to relate findings to GLA:D® Australia registry data. Planned sample size (n=88) was powered at 90% to detect a minimal important difference between groups of 10 (SD=16) points for KOOS4. Results: Forty-four participants enrolled at baseline (22 per group), with no difference between telehealth and in-person groups for sex distribution (female/male: 14/8 v 12:10), age (years: 62±8 v 64±10), or body mass index (kg/m2: 29.8±5.3 v 31.1±5.2). Recruitment ceased in March 2020 due to COVID-19 restrictions on in-person healthcare. Forty-three (98%) and 40 (91%) participants provided 3- and 12-month follow-up data respectively. Primary outcome: There were no between group differences for changes in KOOS4, with outcomes favouring telehealth at 3-months (mean difference, 95%CI = 6, -2 to 15), and neither group at 12-months (0, -9 to 9). The lower limit of the 95%CI was within the non-inferiority margin (i.e. -10 points) at both time points. Secondary outcome: Changes in KOOS-QoL at 3- and 12-months for telehealth (18 and 14 points) and in-person (10 and 15) were comparable to published GLA:D® registry data (13 and 16). Discussion: This RCT was underpowered due to COVID-19 pandemic restrictions causing early cessation, but findings do indicate telehealth-delivered GLA:D® is unlikely to be inferior to in-person delivery for knee-related burden at 3- and 12-months. This finding builds on recently published qualitative findings indicating patient acceptability of telehealth-delivered GLA:D® and positive telehealth outcomes from the GLA:D® registry during the pandemic (submitted to SMA 2022: Ezzat et al). Further supporting implementation, findings are also consistent with published non-inferiority trials of one-on-one telehealth services for knee osteoarthritis and other musculoskeletal pain conditions, and KOOS-QoL outcomes in both groups were consistent with published GLA:D® registry data. Implications and application to the field•Telehealth-delivered group-based education and exercise-therapy for knee osteoarthritis appears unlikely to be inferior to in-person delivery.•Physiotherapists should be supported to implement telehealth-delivered GLA:D® in Australia. Conflict of interest: A/Profs Barton and Kemp lead the ‘not-for-profit’ implementation initiative, GLA:D® Australia, which trains Australian physiotherapists to implement guideline-recommended education and exercise-therapy.

Effectiveness of an Unsupervised Online Yoga Program on Pain and Function in People With Knee Osteoarthritis : A Randomized Clinical Trial.

Yoga is a mind-body exercise typically done in groups in person, but this delivery method can be inconvenient, inaccessible, and costly. Effective online programs may increase access to exercise for knee osteoarthritis. To evaluate the effectiveness of an unsupervised 12-week online yoga program. Two-group superiority randomized trial. (Australian New Zealand Clinical Trials Registry: ACTRN12620000012976). Community. 212 adults with symptomatic knee osteoarthritis. Both groups received online osteoarthritis information (control). The yoga group also received access to an unsupervised online yoga program delivered via prerecorded videos over 12 weeks (1 video per week, with each session to be performed 3 times per week), with optional continuation thereafter. Primary outcomes were changes in knee pain during walking (0 to 10 on a numerical rating scale) and physical function (0 to 68 on the Western Ontario and McMaster Universities Osteoarthritis Index) at 12 weeks (primary time point) and 24 weeks, analyzed using mixed-effects linear regression models. Secondary outcomes were self-reported overall knee pain, stiffness, depression, anxiety, stress, global change, quality of life, self-efficacy, fear of movement, and balance confidence. Adverse events were also collected. A total of 195 (92%) and 189 (89%) participants provided 12- and 24-week primary outcomes, respectively. Compared with control at 12 weeks, yoga improved function (between-group mean difference in change, -4.0 [95% CI, -6.8 to -1.3]) but not knee pain during walking (between-group mean difference in change, -0.6 [CI, -1.2 to 0.1]), with more yoga participants than control participants achieving the minimal clinically important difference (MCID) for both outcomes. At 12 weeks, knee stiffness, quality of life, and arthritis self-efficacy improved more with yoga than the control intervention. Benefits were not maintained at 24 weeks. Adverse events were minor. Participants were unblinded. Compared with online education, an unsupervised online yoga program improved physical function but not knee pain at 12 weeks in people with knee osteoarthritis, although the improvement did not reach the MCID and was not sustained at 24 weeks. National Health and Medical Research Council and Centres of Research Excellence.

Rehabilitation to Improve Gaze and Postural Stability in People With Multiple Sclerosis: A Randomized Clinical Trial

Background People with multiple sclerosis (PwMS) frequently experience dizziness and imbalance that may be caused by central vestibular system dysfunction. Vestibular rehabilitation may offer an approach for improving dysfunction in these people. Objective To test the efficacy of a gaze and postural stability (GPS) retraining intervention compared to a strength and endurance (SAE) intervention in PwMS. Methods About 41 PwMS, with complaints of dizziness or history of falls, were randomized to either the GPS or SAE groups. Following randomization participants completed 6-weeks of 3×/week progressive training, delivered one-on-one by a provider. Following intervention, testing was performed at the primary (6-weeks) and secondary time point (10-weeks). A restricted maximum likelihood estimation mixed effects model was used to examine changes in the primary outcome of the Dizziness Handicap Inventory (DHI) between the 2 groups at the primary and secondary time point. Similar models were used to explore secondary outcomes between groups at both timepoints. Results Thirty-five people completed the study (17 GPS; 18 SAE). The change in the DHI at the primary time point was not statistically different between the GPS and SAE groups (mean difference = 2.33 [95% CI −9.18, 12.85]). However, both groups demonstrated significant improvement from baseline to 6-weeks (GPS −8.73; SAE −7.31). Similar results were observed for secondary outcomes and at the secondary timepoint. Conclusions In this sample of PwMS with complaints of dizziness or imbalance, 6-weeks of GPS training did not result in significantly greater improvements in dizziness handicap or balance compared to 6-weeks of SAE training.

Estimating Risk of Chronic Pain and Disability Following Musculoskeletal Trauma in the United Kingdom

Serious traumatic injury is a leading cause of death and disability globally, with most survivors known to develop chronic pain. To describe early variables associated with poor long-term outcome for posttrauma pain and create a clinical screening tool for this purpose. This was a prospective cohort study at a major trauma center hospital in England. Recruitment commenced in December 2018 and ceased in March 2020. Participants were followed up for 12 months. Patients aged 16 years or older who were hospitalized because of acute musculoskeletal trauma within the preceding 14 days were included. Data were analyzed from March to December 2021. Acute musculoskeletal trauma requiring admittance to a major trauma center hospital. A poor outcome was defined as Chronic Pain Grade II or higher and measured at both 6 months (primary time point) and 12 months. A broad range of candidate variables potentially associated with outcomes were used, including surrogates for pain mechanisms, quantitative sensory testing, and psychosocial factors. Univariable models were used to identify the variables most likely to be associated with poor outcome, which were entered into multivariable models. A clinical screening tool (nomogram) was derived from 6-month results. In total, 1590 consecutive patients were assessed for eligibility, of whom 772 were deemed eligible and 124 (80 male [64.5%]; mean [SD] age, 48.9 [18.8] years) were recruited. At 6 months, 19 of 82 respondents (23.2%) reported a good outcome, whereas at 12 months 27 of 44 respondents (61.4%) reported a good outcome. At 6 months on univariable analysis, an increase in total posttraumatic stress symptoms (odds ratio [OR], 2.09; 95% CI, 1.33-3.28), pain intensity average (OR, 2.87; 95% CI, 1.37-6.00), number of fractures (OR, 2.79; 95% CI, 1.02-7.64), and pain extent (OR, 4.67; 95% CI, 1.57-13.87) were associated with worse outcomes. A multivariable model including those variables had a sensitivity of 0.93, a specificity of 0.54, and C-index of 0.92. A poor long-term pain outcome from musculoskeletal traumatic injuries may be estimated by measures recorded within days of injury. These findings suggest that posttraumatic stress symptoms, pain spatial distribution, perceived average pain intensity, and number of fractures are good candidates for a sensitive multivariable model and derived clinical screening tool.

Effectiveness of a brief group behavioural intervention on psychological distress in young adolescent Syrian refugees: A randomised controlled trial.

BackgroundMillions of young adolescents in low- and middle-income countries (LMICs) affected by humanitarian crises experience elevated rates of poor mental health. There is a need for scalable programs that can improve the mental health of young adolescents. This study evaluated the effectiveness of a nonspecialist delivered group-based intervention (Early Adolescent Skills for Emotions (EASE)) to improve young adolescents’ mental health.Methods and findingsIn this single-blind, parallel, controlled trial, Syrian refugees aged 10 to 14 years in Jordan were identified through screening of psychological distress as defined by scores ≥15 on the Paediatric Symptom Scale. Participants were randomised to either EASE or enhanced usual care (EUC) involving referral to local psychosocial services (on a 1:1.6 ratio). Participants were aware of treatment allocation but assessors were blinded. Primary outcomes were scores on the Paediatric Symptom Checklist (PSC; internalising, externalising, and attentional difficulty scales) assessed at week 0, 9 weeks, and 3 months after treatment (primary outcome time point). It was hypothesised that EASE would result in greater reductions on internalising symptoms than EUC. Secondary outcomes were depression, posttraumatic stress, well-being, functioning, school belongingness, and caregivers’ parenting and mental health. Between June 2019 and January 2020, 1,842 young adolescent refugees were screened for eligibility on the basis of psychological distress. There were 520 adolescents (28.2%) who screened positive, of whom 471 (90.6%) agreed to enter the trial. Overall, 185 were assigned to EASE and 286 to EUC, and 169 and 254 were retained at 3 months for EASE and EUC, respectively. Intent-to-treat analyses indicated that at 3 months, EASE resulted in greater reduction on the PSC-internalising scale than EUC (estimated mean difference 0.69, 95% CI 0.19 to 1.19; p = 0.007; effect size, 0.38) but there were no differences for PSC-externalising (estimated mean difference 0.24, 95% CI −0.43 to 0.91; p = 0.49; effect size, −0.10), PSC-attentional problem (estimated mean difference −0.01, 95% CI −0.51 to 0.54; p = 0.97; effect size, −0.01) scores, or on depression, posttraumatic stress, well-being, functioning, or school belongingness. Relative to EUC, caregivers in EASE had less psychological distress (estimated mean difference 1.95, 95% CI 0.71 to 3.19; p = 0.002) and inconsistent disciplinary parenting (mean difference 1.54, 95% CI 1.03 to 2.05; p < 0.001). Secondary analyses that (a) focused on adolescents with probable internalising disorders; (b) completed the 3-month assessment; and (c) controlled for trauma exposure did not alter the primary results. Mediation analysis indicated that for caregivers in the EASE condition, reduction in inconsistent disciplinary parenting was associated with reduced attentional (β = 0.11, SE 0.07; 95% CI 0.003, 0.274) and internalising (β = 0.11, SE 0.07; 95% CI 0.003, 0.274) problems in their children. No adverse events were attributable to the intervention. A limitation was that EUC was not matched to EASE in terms of facilitator attention or group involvement.ConclusionsEASE led to reduced internalising problems in young refugee adolescents and was associated with reduced distress and less inconsistent disciplinary parenting in caregivers. This intervention has the potential as a scalable intervention to mitigate young adolescents’ emotional difficulties in LMIC.Trial registrationProspectively registered at Australian and New Zealand Clinical Trials Registry: ACTRN12619000341123.

Abstract 3815: Investigating the role of bone marrow microenvironment dysregulation at remission in disease outlook of multiple myeloma

Abstract Multiple myeloma (MM) is a cancer characterized by the unchecked proliferation of antibody-secreting plasma cells (PCs), which to date remains incurable despite therapeutic advancements. The idea that deeper tumor clearance leads to better outcomes is widely accepted in MM treatment: minimal residual disease (MRD) testing, whereby ultra-sensitive sequencing or fluorescence-based cytometric detection of the clonal immunoglobulin secreted by tumor PCs, has been found to be the strongest independent prognostic factor when predicting survival. However, MRD status remains an imperfect predictor. As PCs have a well-defined physiological niche within the bone marrow (BM), and patients often exhibit immunosuppressive BM dysregulation, we investigate the presence of BM microenvironment signatures present at remission that may influence clinical outcomes insufficiently explained by tumor risk strata or MRD status. We conducted 3’ single-cell RNA sequencing of 36 remission, 8 primary diagnosis, and 3 relapse whole BM aspirates taken from 35 patients enrolled in an ongoing clinical trial evaluating a treatment regimen consisting of ixazomib, lenalidomide, and dexamethasone (IRD). 19 of 35 patients were MRD+ at remission; among these, 6 have been reported as having poor outcome (PO; progression-free survival &amp;lt;2.5yrs post sample collection), 12 have had average outcomes (AO; PFS &amp;gt;2.5yrs), and 1 is awaiting assessment. The remaining 16 patients were MRD- at remission, 6 of whom had poor outcome, 7 average, and 3 awaiting assessment. Preliminary analysis of 43 samples have yielded an average capture of 8,620 cells per sample with 1,247 median genes per cell. In comparing 3 PO to 8 AO MRD- remission samples, we see clear polarity between PO and AO cells in every major immune lineage, with a majority of clusters being predominantly (&amp;gt;80%) made of either PO or AO cells. Surprisingly, T, NK, and B cells from AO samples exhibit FOS/JUN upregulation relative to those from PO samples, indicative of AP-1 transcription factor activity that is typically associated with cell proliferation. PO samples also exhibited signs of active cytotoxicity, including upregulated granzymes H and B and IL7R in T and NK cells. Sizeable PC populations were detected in several MRD- remission samples with subpopulation heterogeneity in the expression of MM marker genes; comparison against PCs isolated from healthy donor BM suggests possible persistence of disease phenotypes not captured by MRD testing. We further investigate BM microenvironment evolution between primary diagnosis, remission, and relapse timepoints to elucidate changes in response to tumor clearance. Overall, this study enhances our understanding of how immune surveillance and interaction may influence treatment response in MM. Citation Format: Julia T. Wang, Mark Fiala, Julie Fortier, Ruiyang Liu, Reyka Jayasinghe, Ravi Vij, Li Ding. Investigating the role of bone marrow microenvironment dysregulation at remission in disease outlook of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3815.

GCT-20. Multi-Institutional Analysis of Pediatric Relapsed/Refractory Central Nervous System Germ Cell Tumors

Central nervous system (CNS) germ cell tumors (GCTs) constitute ~ 4% of primary pediatric brain tumors in the United States. While multimodality therapy approaches have ensured >80% survival benefit, these patients still experience relapses, with no established standard of care. Their rarity limits knowledge of their outcomes and associations with location, metastatic status, impact of surgery, serum, and cerebrospinal fluid (CSF) biomarkers, to only a few smaller trials and case series.This international multi-institutional retrospective study for relapsed/refractory germinomas and NGGCTs, will evaluate the association between different treatment modalities and 5-year OS and EFS; patterns of relapse, including along biopsy tracts; and potentially identify predictors of recurrence. De-identified patient data at primary and relapse time points will be collected focusing on treatment approaches such as surgery, conventional/high dose chemotherapy, photon/proton radiation therapy; timing and site of relapse; imaging characteristics and serum/CSF biomarkers (BHCG/AFP). Our collaborators include multiple sites across North America, Australia, Europe, Africa, South America, the Middle east, India, Singapore, and Malaysia. 6 recurrent intracranial germinomas on the CBTN (Children’s Brain Tumor Consortium) database were assessed, demonstrating a male gender preponderance (4) and recurring in the suprasellar region (3), frontal lobe (2) and spinal cord (1). 2 underwent gross total resection while 1 had biopsy only. Conventional or high-dose chemotherapy was administered in 5, while 2 received craniospinal and 1 proton radiation. 4 patients are alive. Median OS was 738 days and EFS 1093 days. However, biomarker (AFP/BHCG) data was unavailable. Updated results will be presented at the conference. With global partnership and contribution, we anticipate this study to help bridge existing gaps in our knowledge of this rare patient cohort and establish a consensus standard of care, through prospective clinical trials in the future. We acknowledge the CBTN for kindly providing data access.

Impact of Using A Mixed Data Collection Modality on Statistical Inferences in Decentralized Clinical Trials.

BackgroundDecentralized clinical trials offer the promise of reduced patient burden, faster and more diverse recruitment, and have received regulatory support during the COVID-19 pandemic. However, lack of data accuracy or data validation poses a challenge for fully decentralized trials. A mixed data collection modality where onsite measurements are collected at key time points and decentralized measurements are taken at intermediate time points is attractive operationally. To date, the impact of decentralized measurements (which could presumably be less accurate) taken at intermediate time points on statistical inference on the primary or other key time points has not been evaluated.MethodsIn this article we evaluate the estimation and statistical inference for three scenarios: (1) all onsite measurements, (2) a mixture of onsite and decentralized measurements, and (3) all decentralized measurements, in the setting of a chronic weight management trial. We consider scenarios where decentralized measurements have additional within- and between-subject variabilities and/or bias.ResultsIn the mixed modality setting, simulation studies showed that the estimation and inference for the key time points with onsite measurements have good properties and are not impacted by the additional variability and bias from intermediate decentralized measurements. However, estimates for intermediate decentralized time points for the mixed modality and estimates for the all decentralized modality measurements have increased variability and bias.ConclusionMixed modality trials can help achieve the benefits of decentralized clinical trials by reducing the number of onsite visits with little impact on statistical inferences for various estimands, compared to traditional (all onsite) clinical trials.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43441-022-00416-x.

OP0023 A RANDOMIZED, DOUBLE-BLIND TRIAL COMPARING SECUKINUMAB 300 MG AND 150 MG AT WEEK 52 IN PATIENTS WITH ANKYLOSING SPONDYLITIS WHO DID NOT ACHIEVE INACTIVE DISEASE DURING AN INITIAL 16 WEEKS OF OPEN-LABEL TREATMENT WITH SECUKINUMAB 150 MG

OP0023 A RANDOMIZED, DOUBLE-BLIND TRIAL COMPARING SECUKINUMAB 300 MG AND 150 MG AT WEEK 52 IN PATIENTS WITH ANKYLOSING SPONDYLITIS WHO DID NOT ACHIEVE INACTIVE DISEASE DURING AN INITIAL 16 WEEKS OF OPEN-LABEL TREATMENT WITH SECUKINUMAB 150 MG

Reducing Morbidity in High Panel Reactive Antibody Heart Transplant Recipients Through Human Leukocyte Antigen Matching

<h3>Purpose</h3> A high PRA prior to heart transplantation places recipients at risk for rejection and mortality. The purpose of this study was to assess the impact donor-recipient HLA matching has on post-transplant survival and morbidity. <h3>Methods</h3> A retrospective review of heart transplant recipients in the UNOS database was performed from 2000-2021. Patients were stratified by normal (<25%) and high (≥25%) PRA reactivity. Recipients HLA matched to their donors at ≥ 3 alleles in the high PRA subgroup were identified. Primary outcome was Kaplan-Meier survival estimates at 1, 3 and 5 years post-transplant. Multivariable regression was also performed on high PRA-HLA matched recipients to determine if matching reduced the odds of rejection or infection. <h3>Results</h3> A high PRA was identified in 4,214 heart transplant recipients of which 678 (16%) were HLA matched (Table 1a). Survival estimates were significantly different between normal and high PRA recipients at all primary time points. High PRA-HLA matched patients did not have a significantly different survival than high PRA-HLA mismatched recipients at any time point (Figure 1). On multivariable analysis (Table 1b), HLA matching significantly reduced the odds of graft rejection (OR 0.62) and infection (OR 0.73) <h3>Conclusion</h3> A high PRA places recipients at an increased risk for post-transplant mortality. HLA matching does not improve survival but does significantly reduce the odds of rejection and infection. HLA matching donors to high PRA recipients should be considered to reduce future morbidity, lost time hospitalized and financial burden for these patients.

Interventions for Altering Blood Pressure in People With Acute Subarachnoid Hemorrhage

Interventions for Altering Blood Pressure in People With Acute Subarachnoid Hemorrhage

Effectiveness of a brief group behavioral intervention for common mental disorders in Syrian refugees in Jordan: A randomized controlled trial.

BackgroundCommon mental disorders are frequently experienced by refugees. This study evaluates the impact of a brief, lay provider delivered group-based psychological intervention [Group Problem Management Plus (gPM+)] on the mental health of refugees in a camp, as well as on parenting behavior and children’s mental health.Methods and findingsIn this single-blind, parallel, randomized controlled trial, 410 adult Syrian refugees (300 females, 110 males) in Azraq Refugee Camp (Jordan) were identified through screening of psychological distress (≥16 on the Kessler Psychological Distress Scale) and impaired functioning (≥17 on the WHO Disability Assessment Schedule). Participants were randomly allocated to gPM+ or enhanced usual care (EUC) involving referral information for psychosocial services on a 1:1 ratio. Participants were aware of treatment allocation, but assessors were blinded to treatment condition. Primary outcomes were scores on the Hopkins Symptom Checklist-25 (HSCL; depression and anxiety scales) assessed at baseline, 6 weeks, and 3 months follow-up as the primary outcome time point. It was hypothesized that gPM+ would result in greater reductions of scores on the HSCL than EUC. Secondary outcomes were disability, posttraumatic stress, personally identified problems, prolonged grief, prodromal psychotic symptoms, parenting behavior, and children’s mental health. Between October 15, 2019 and March 2, 2020, 624 refugees were screened for eligibility, 462 (74.0%) screened positive, of whom 204 were assigned to gPM+ and 206 to EUC. There were 168 (82.4%) participants in gPM+ and 189 (91.7%) in EUC assessed at follow-up. Intent-to-treat analyses indicated that at follow-up, participants in gPM+ showed greater reduction on HSCL depression scale than those receiving EUC (mean difference, 3.69 [95% CI 1.90 to 5.48], p = .001; effect size, 0.40). There was no difference between conditions in anxiety (mean difference −0.56, 95% CI −2.09 to 0.96; p = .47; effect size, −0.03). Relative to EUC, participants in gPM+ had greater reductions in severity of personally identified problems (mean difference 0.88, 95% CI 0.07 to 1.69; p = .03), and inconsistent disciplinary parenting (mean difference 1.54, 95% CI 1.03 to 2.05; p < .001). There were no significant differences between conditions for changes in PTSD, disability, grief, prodromal symptoms, or childhood mental health outcomes. Mediation analysis indicated the change in inconsistent disciplinary parenting was associated with reduced attentional (β = 0.11, SE .07; 95% CI .003 to .274) and internalizing (β = 0.08, SE .05; 95% CI .003 to 0.19) problems in children. No adverse events were attributable to the interventions or the trial. Major limitations included only one-quarter of participants being male, and measures of personally identified problems, grief, prodromal psychotic symptoms, inconsistent parenting behavior, and children’s mental health have not been validated with Syrians.ConclusionsIn camp-based Syrian refugees, a brief group behavioral intervention led to reduced depressive symptoms, personally identified problems, and disciplinary parenting compared to usual care, and this may have indirect benefits for refugees’ children. The limited capacity of the intervention to reduce PTSD, disability, or children’s psychological problems points to the need for development of more effective treatments for refugees in camp settings.Trial registrationProspectively registered at Australian and New Zealand Clinical Trials Registry: ACTRN12619001386123.

OPAL: a randomised, placebo-controlled trial of opioid analgesia for the reduction of pain severity in people with acute spinal pain—a statistical analysis plan

BackgroundLow back and neck pain are a leading cause of disease burden globally. Opioids are recommended in guidelines for acute low back and neck pain; however, there is a lack of compelling efficacy data to support this.MethodsThe OPAL trial is a prospectively registered, triple-blinded, randomised, placebo-controlled trial. Patients with acute (≤12 weeks duration) back and/or neck pain receive guideline care plus either an opioid (oxycodone + naloxone, up to 20 mg per day) or a placebo for up to 6 weeks or earlier, if pain is resolved. The primary outcome is pain measured using the Pain Severity Score of the Brief Pain Inventory with the primary time point being 6 weeks. Secondary outcomes include physical function, time to recovery, quality of life, adverse events and risk of opioid misuse. Outcomes are collected at weeks 2, 4, 6, 12, 26 and 52. Analysis will be done on an intention-to-treat principle. p values of < 0.05 will be considered significant and 95% confidence intervals will be reported. Repeated-measures linear mixed models will be used to assess the effect of the treatment group on the primary outcome and continuous secondary outcomes. Adverse events will be compared between groups using Fisher’s exact test. Cost-effectiveness analyses will be conducted if a treatment effect on pain is seen at week 6. Subgroup analyses will be performed to assess whether pain duration and pain location are treatment effect modifiers.DiscussionThe OPAL trial will provide important evidence about whether a short course of opioids is effective in the treatment of acute non-specific low back and/or neck pain. This pre-specified statistical analysis plan details the methodology for the analysis of the OPAL trial results.Trial registrationACTRN12615000775516. The trial has completed recruitment. Follow-up on the last patient will be completed in March 2022.

Associations between Gut Microbiota and Intestinal Inflammation, Permeability and Damage in Young Malawian Children

BackgroundEnvironmental enteric dysfunction (EED) is common in low- and middle-income countries and associated with childhood undernutrition. The composition of gut microbiota has been implicated in the pathogenesis of EED. Our aim was to assess the associations between gut microbiota and EED biomarkers in rural Malawian children. We hypothesized that there would be an inverse association between microbiota maturity and diversity and fecal concentrations of EED biomarkers.MethodsWe used data from fecal samples collected at 6, 18 and 30 months from 611 children who were followed up during a nutrition intervention trial. The primary time point for analysis was 18 months. Microbiota data were obtained through 16S rRNA sequencing and variables included microbiota maturity and diversity, phylogenetic dissimilarity and relative abundances of individual taxa. EED biomarkers included calprotectin (marker of inflammation), alpha-1 antitrypsin (intestinal permeability) and REG1B (intestinal damage).ResultsThere was an inverse association between microbiota maturity and diversity and fecal concentrations of all 3 EED biomarkers at 18 months (p≤0.001). The results were similar at 30 months, while at 6 months inverse associations were found only with calprotectin and alpha-1 antitrypsin concentrations. At 18 months, EED biomarkers were not associated with phylogenetic dissimilarity, but at 6 and 30 months several associations were observed. Individual taxa predicting EED biomarker concentrations at 18 months included several Bifidobacterium and Enterobacteriaceae taxa as well as potentially displaced oral taxa.ConclusionsOur findings support the hypothesis of an inverse association between microbiota maturity and diversity and EED in rural Malawian children.

The association between socioeconomic status and the 30- and 90-day risk of infection after total hip arthroplasty : a registry-based cohort study of 103,901 patients with osteoarthritis.

The aim of this study was to examine whether socioeconomic status (SES) is associated with a higher risk of infections following total hip arthroplasty (THA) at 30 and 90 days. We obtained individual-based information on SES markers (cohabitation, education, income, and savings) on 103,901 THA patients from Danish health registries between 1 January 1995 and 31 December 2017. The primary outcome measure was any hospital-treated infection (i.e. all infections). The secondary outcomes were further specified to specific hospital-treated infections (pneumonia, urinary tract infection, and periprosthetic joint infection). The primary timepoint was within 90 days. In addition, the outcomes were further evaluated within 30 days. We calculated the cumulative incidence, and used the pseudo-observation method and generalized linear regression to estimate adjusted risk ratios (RRs) with 95% confidence intervals (CIs) for each marker. The cumulative incidence of any infection at 90 days was highest in patients who lived alone (1.5% (95% CI 1.3 to 1.6)) versus cohabitant (0.7% (95% CI 0.7 to 0.8)), had the lowest educational achievement (1.1% (95% CI 1.0 to 1.2)) versus highest (0.7% (95% CI 0.5 to 0.8)), had the lowest income (1.6% (95% CI 1.5 to 1.70)) versus highest (0.4% (95% CI 0.3 to 0.5)), or had lowest savings (1.3% (95% CI 1.2 to 1.4)) versus highest (0.7% (95% CI 0.6 to 0.8)). Within 90 days, the RRs for any infection were 1.3 (95% CI 1.2 to 1.4) for patients living alone versus cohabiting, 1.2 (95% CI 1.0 to 1.3) for low education achievement versus high, 1.7 (95% CI 1.4 to 2.1) for low income versus high income, and 1.5 (95% CI 1.4 to 1.8) for low savings versus high savings. The same trends were also seen for any infections within the first 30 days. Our study provides evidence that socioeconomic inequality adversely influences the risk of infection after THA, thus contributing to healthcare disparities and inequalities. We found that living alone, low educational achievement, low income, or low savings were associated with higher risks of infections within the first 30 and 90 days after THA. Therefore, the development of targeted intervention strategies with the aim of increasing awareness of patients identified as being at greatest risk is needed to mitigate the impact of SES on the risk of infections following THA. Cite this article: Bone Joint J2022;104-B(2):221-226.

Family interventions for relapse prevention in schizophrenia: a systematic review and network meta-analysis

Family interventions are efficacious for relapse prevention in schizophrenia. Multiple different models have been developed. We aimed to compare the efficacy, acceptability, and tolerability of family interventions for relapse prevention in schizophrenia. In this systematic review and network meta-analysis, we searched for randomised controlled trials that investigated family intervention models aimed at preventing relapse in patients with schizophrenia. We searched EMBASE, MEDLINE, PsycINFO, BIOSIS, CENTRAL, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform up to Jan 20, 2020 and PubMed up to July 15, 2021. We included blinded and open-label randomised controlled trials in which at least 80% of patients had schizophrenia spectrum disorders. We excluded studies in which all patients were acutely ill, had a concurrent medical or psychiatric disorder, or were prodromal or "at risk of psychosis". Study selection and data extraction were done by two independent reviewers. Data were extracted about overall, positive, negative, and depressive symptoms of schizophrenia, quality of life, adherence, overall functioning, family burden, expressed emotion, and discontinuations due to inefficacy. The primary outcome was relapse, measured with operationalised criteria, psychiatric hospital admissions, or clinical judgement. We did a frequentist, random-effects, network meta-analysis to calculate odds ratios ([ORs]; dichotomous outcomes) or standardised mean differences (continuous outcomes) with 95% CIs. The study protocol was registered with PROSPERO, CRD42020169951. We identified 28 395 studies through the database search and 334 from references of previous studies. We compared 11 family intervention models tested on a total of 90 randomised controlled trials with 10 340 participants (3579 females and 5632 males with sex indicated; median age 31 years [range 14-65]) in the network meta-analysis. Ethnicity data were not available. All interventions, with the exception of crisis-oriented interventions and family psychoeducation with two sessions or fewer, reduced the relapse rate significantly when compared with treatment as usual at the primary timepoint of 12 months. ORs compared with treatment as usual ranged from 0·18 (95% CI 0·12-0·27) for family psychoeducation alone to 0·63 (0·42-0·94) for community-based interventions involving family members. The results were robust in various sensitivity and subgroup analyses. The confidence in the estimates ranged from moderate to very low for different comparisons. Almost all family intervention models were efficacious in preventing relapse in schizophrenia. Family psychoeducation alone, without behavioural or skills training, was superior to the more complex models. Our results suggest that in contexts where there are financial constraints, family psychoeducation alone should be implemented. German Ministry for Education and Research.

Social Equity in the Efficacy of Computer-Based and In-Person Brief Alcohol Interventions Among General Hospital Patients With At-Risk Alcohol Use: A Randomized Controlled Trial

BackgroundSocial equity in the efficacy of behavior change intervention is much needed. While the efficacy of brief alcohol interventions (BAIs), including digital interventions, is well established, particularly in health care, the social equity of interventions has been sparsely investigated.ObjectiveWe aim to investigate whether the efficacy of computer-based versus in-person delivered BAIs is moderated by the participants’ socioeconomic status (ie, to identify whether general hospital patients with low-level education and unemployed patients may benefit more or less from one or the other way of delivery compared to patients with higher levels of education and those that are employed).MethodsPatients with nondependent at-risk alcohol use were identified through systematic offline screening conducted on 13 general hospital wards. Patients were approached face-to-face and asked to respond to an app for self-assessment provided by a mobile device. In total, 961 (81% of eligible participants) were randomized and received their allocated intervention: computer-generated and individually tailored feedback letters (CO), in-person counseling by research staff trained in motivational interviewing (PE), or assessment only (AO). CO and PE were delivered on the ward and 1 and 3 months later, were based on the transtheoretical model of intentional behavior change and required the assessment of intervention data prior to each intervention. In CO, the generation of computer-based feedback was created automatically. The assessment of data and sending out feedback letters were assisted by the research staff. Of the CO and PE participants, 89% (345/387) and 83% (292/354) received at least two doses of intervention, and 72% (280/387) and 54% (191/354) received all three doses of intervention, respectively. The outcome was change in grams of pure alcohol per day after 6, 12, 18, and 24 months, with the latter being the primary time-point of interest. Follow-up interviewers were blinded. Study group interactions with education and employment status were tested as predictors of change in alcohol use using latent growth modeling.ResultsThe efficacy of CO and PE did not differ by level of education (P=.98). Employment status did not moderate CO efficacy (Ps≥.66). Up to month 12 and compared to employed participants, unemployed participants reported significantly greater drinking reductions following PE versus AO (incidence rate ratio 0.44, 95% CI 0.21-0.94; P=.03) and following PE versus CO (incidence rate ratio 0.48, 95% CI 0.24–0.96; P=.04). After 24 months, these differences were statistically nonsignificant (Ps≥.31).ConclusionsComputer-based and in-person BAI worked equally well independent of the patient’s level of education. Although findings indicate that in the short-term, unemployed persons may benefit more from BAI when delivered in-person rather than computer-based, the findings suggest that both BAIs have the potential to work well among participants with low socioeconomic status.Trial RegistrationClinicalTrials.gov NCT01291693; https://clinicaltrials.gov/ct2/show/NCT01291693

Effectiveness of a Videoconferencing-Delivered Psychological Intervention for Mental Health Problems during COVID-19: A Proof-of-Concept Randomized Clinical Trial

Introduction: Anxiety and depression have increased markedly during the COVID-19 pandemic. There is a lack of evidence-based strategies to address these mental health needs during the pandemic. Objective: We aim to conduct a proof-of-concept trial of the efficacy of a brief group-based psychological intervention delivered via videoconferencing for adults in Australia distressed by the pandemic. Methods: In this single-blind, parallel, randomised controlled trial, adults who screened positive for COVID-related psychological distress across Australia were randomly allocated to either a 6-session group-based program based on behavioural principles (n = 120) or enhanced usual care (EUC, n = 120). Primary outcome was total score on the Hospital Anxiety and Depression (HADS) anxiety and depression subscales assessed at baseline, 1 week posttreatment, 2 months (primary outcome time point), and 6 months after treatment, as well as secondary outcome measures of worry, sleep impairment, anhedonia, mood, and COVID-19-related stress. Results: Between May 20, 2020, and October 20, 2020, 240 patients were enrolled into the trial. Relative to EUC, at 2 months participants receiving intervention showed greater reduction on anxiety (mean difference, 1.4 [95% CI, 0.3 to 2.6], p = 0.01; effect size, 0.4 [95% CI, 0.1 to 0.7]) and depression (mean difference, 1.6 [95% CI, 0.4 to 2.8], p = 0.009; effect size, 0.4 [95% CI, 0.2 to 0.7]) scales. These effects were maintained at 6 months. There were also greater reductions of worry, anhedonia, COVID-19-related fears, and contamination fears. Conclusions: This trial provides initial evidence that brief group-based behavioural intervention delivered via videoconferencing results in moderate reductions in common psychological problems arising during the COVID-19 pandemic. This program may offer a viable and scalable means to mitigate the rising mental health problems during the pandemic.