Placebo Treatment Arms Research Articles

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis

BackgroundPositive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. Study design and settingsA randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. ResultsMean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline. Conclusions and relevanceIn this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. Trial registrationStudy preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Nocebo expectations rather than placebo expectations affect topical pain relief: A randomized clinical trial

Patients' expectations and beliefs regarding the potential benefits and harms of medical interventions may induce placebo and nocebo effects, and affect the response to pain therapies. In a randomized clinical trial, we examined the effect of placebo and nocebo expectations on pain relief and adverse events (AEs) in association with a topical treatment among 65 cancer survivors experiencing chronic musculoskeletal pain. Participants received either a 1% camphor-based topical pain patch or a placebo treatment for 14 days. We measured pain severity with the worst pain item of the Brief Pain Inventory (BPI) at baseline and 14 days and treatment expectations at baseline with validated expectation questionnaires. We found that high vs. low nocebo expectations decreased pain severity improvements by 2.5 points (95% confidence interval [CI] −3.8 to −1.2; p<0.001) on a 0–10 numeric rating scale of the BPI and pain response rate by 42.7% (95% CI 0.2–0.6; p<0.001) at day 14, irrespective of placebo expectation status or treatment arms. Patients with high vs. low nocebo expectations in the true arm reported 22.4% more unwanted AEs. High nocebo expectations were associated with increased AEs by 39.5% (odds ratio: 12.0, 95% CI 1.2, 145.5; p=0.029) and decreased pain response in the true arm vs. placebo. Our study demonstrated that nocebo expectations, rather than placebo expectations, elevate the risk of AEs and compromise the effect of topical pain interventions. The findings raise the possibility that nocebo expectations may worsen somatic symptoms through heightening central pain amplification and should be further investigated.

Financial Incentives for COVID-19 Vaccines Help

Cash incentives for COVID-19 vaccination involve offering individuals a financial reward as an encouragement to get vaccinated against the coronavirus. This strategy has been implemented by various governments, organizations, and businesses as part of their efforts to increase vaccination rates. Duch and colleagues randomly assigned about 700 residents of several villages in Ghana to four groups in a cluster-controlled trial. The results show that participants assigned to the cash incentive treatments had an average rate of 81% (1,733 of 2,168) compared to 71% (1,895 of 2,669) for those in the placebo treatment arm. For self-reported vaccinations, the average rate for participants in the cash treatment was 3.5% higher than for participants in the placebo treatment (95% confidence interval (CI): 0.001, 6.9; P = 0.045): 40% (602 of 1,486) versus 36.3% (672 of 1,850). These results suggest that cash incentives help in vaccination uptake but paradoxically, low cash incentives resulted in higher vaccine uptake compared to high cash incentives. We found that cash incentives motivate individuals who may be hesitant or reluctant to receive the COVID-19 vaccine. Financial rewards can serve as an additional motivator for those who may be on the fence about getting vaccinated. Trial identifier: AEARCTR-0008775. Nat Med. 2023 Nov 27. doi: 10.1038/s41591-023-02670-4.

Financial incentives for COVID-19 vaccines in a rural low-resource setting: a cluster-randomized trial

We implemented a clustered randomized controlled trial with 6,963 residents in six rural Ghana districts to estimate the causal impact of financial incentives on coronavirus disease 2019 (COVID-19) vaccination uptake. Villages randomly received one of four video treatment arms: a placebo, a standard health message, a high cash incentive (60 Ghana cedis) and a low cash incentive (20 Ghana cedis). For the first co-primary outcome—COVID-19 vaccination intentions—non-vaccinated participants assigned to the cash incentive treatments had an average rate of 81% (1,733 of 2,168) compared to 71% (1,895 of 2,669) for those in the placebo treatment arm. For the other co-primary outcome of self-reported vaccinations 2 months after the initial intervention, the average rate for participants in the cash treatment was 3.5% higher than for participants in the placebo treatment (95% confidence interval (CI): 0.001, 6.9; P = 0.045): 40% (602 of 1,486) versus 36.3% (672 of 1,850). We also verified vaccination status of participants: in the cash treatment arm, 36.6% (355 of 1,058) of verified participants had at least one dose of the COVID-19 vaccine compared to 30.3% (439 of 1,544) for those in the placebo—a difference of 6.3% (95% CI: 2.4, 10.2; P = 0.001). For the intention and the vaccination outcomes, the low cash incentive (20 Ghana cedis) had a larger positive effect on COVID-19 vaccine uptake than the high cash incentive (60 Ghana cedis). Trial identifier: AEARCTR-0008775.

Real-World Evidence to Supplement Randomized Clinical Trials: Tocilizumab for Severe COVID-19 Pneumonia vs. a Cohort Receiving Standard of Care.

Randomized controlled trials (RCTs) remain the gold standard for evaluating treatment efficacy, but real-world evidence can supplement RCT results. Tocilizumab was not found to reduce 28-day mortality in a phase III, double-blind, placebo-controlled trial (COVACTA) among hospitalized patients with severe coronavirus disease 2019 (COVID-19) pneumonia. We created a real-world external comparator arm mirroring the COVACTA trial to confirm findings and assess the feasibility of using an external comparator arm to supplement an RCT. Eligible COVACTA participants in both the tocilizumab treatment and placebo arms were matched 1:1 using propensity score matching to persons without tocilizumab exposure in an external comparator arm. Adjusted Cox proportional hazard models estimated differences in 28-day mortality comparing COVACTA participants to matched external comparator arm participants. Patients in the COVACTA tocilizumab treatment arm had a similar risk of death compared with patients in the external comparator arm (hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.64-1.84) with similar estimated 28-day mortality in the COVACTA tocilizumab treatment arm compared with the external comparator arm (18%, 95% CI: 13-24 vs. 19%, 95% CI: 13-24, P > 0.9). COVACTA placebo treatment arm participants had a similar risk of mortality (adjusted HR: 0.69, 95% CI: 0.32-1.46) compared with the external comparator arm. Using an external comparator arm has the potential to supplement RCT data and support results of primary RCT analyses.

The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment.

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.

Combinatorial immune biomarkers of efficacy on buparlisib and paclitaxel in patients with SCCHN: BERIL-1 sub-analysis.

e18030 Background: Previous analysis of the BERIL-1 Phase 2 clinical trial (Soulieres et al, CCR, 2018), evaluating the efficacy of Buparlisib + Paclitaxel, was one of the largest genomic landscape analyses to date in metastatic SCCHN. With the recent approval of PD-1 in this indication, we sought to expand the analysis, focusing on combinatorial biomarkers of immune infiltration in addition to specific genomic alterations. The goal is to evaluate hierarchically prognostic and predictive biomarkers to select predefined analysis in the current Phase 3 clinical trial, BURAN (NCT04338399) post immune modulatory therapy. Methods: The results of this analysis focused on combination of genomic alterations in both tumor and plasma samples. Alterations found in tumor versus plasma revealed over 50 differentially altered genes. Combination of these sample types is more comprehensive of the patients’ true mutational and copy number status; no significant differences in alteration frequency between treatment and placebo treatment arms were identified. We evaluated correlations between select biomarkers and improvement in efficacy end points of Progression Free Survival (PFS) and Overall Survival (OS) between the treatment and control arms and within the treatment arm. Results: The most frequently altered genes were, TP53 (49%), NOTCH1 (21%), PIK3CA (19%), FAT1 (15%), and CDKN2A (13%). Previous analysis demonstrated that TP53 mutations as well as high immune infiltration (&gt; 10% intratumoral or stromal TILs) showed improvement in PFS &amp; OS. Further improvement to OS was observed in subjects with high immune infiltration and TP53 (p = .031, HR = 0.52), PIK3CA (p = .005, HR = 0.34), NOTCH1(p = .046, HR = 0.13) or FAT1(p = .007; HR = 0.28) alterations when compared to non-altered subjects in the treatment arm. Further improvement to PFS was observed in subjects with high immune infiltration and TP53(p = .031, HR = 0.52) or FAT1(p = .006, HR = 0.23) alterations when compared to non-altered subjects in the treatment arm; NOTCH1 alterations showed strong trends in improved PFS. Additionally, high tumor mutational burden (TMB) combined with alterations in the TP53 pathway showed significant OS improvement (p = .052, HR = 0.44) compared with the placebo arm. Conclusions: This analysis highlights unique insights into the mechanism of Buparlisib and Paclitaxel in of metastatic SCCHN patients; a significant improvement in efficacy observed when specific alterations are considered in the context of immune infiltration. These observations will be further explored in the ongoing Phase 3 clinical trial, BURAN. Additional analysis to be presented at the meeting include prognostic and predictive value of each biomarker and combination, differences between tumor and plasma samples, and comparison with end of treatment samples.

P393 Effect of filgotinib on anaemia in patients with Ulcerative Colitis in SELECTION

Abstract Background Patients with ulcerative colitis (UC) often have anaemia owing to inflammation and/or blood loss.1 Filgotinib (FIL) is a once-daily, oral, Janus kinase (JAK) 1 preferential inhibitor approved for the treatment of UC, which may be associated with fewer haematological events than pan-JAK inhibitors. In the phase 2b/3 SELECTION trial (NCT02914522),2 FIL 200 mg (FIL200) was well tolerated and effective vs placebo (PBO) in patients with UC. This post hoc analysis of SELECTION data compared haematological events across the FIL and PBO treatment arms. Methods In SELECTION, adults with moderately to severely active UC were randomized 2:2:1 to receive FIL200, or FIL 100 mg, or PBO once daily for 11 weeks during induction. FIL responders (clinical remission or a Mayo Clinic Score response at week 10 [W10]) were rerandomized to continue their induction FIL dose or PBO in the 47-week Maintenance (MNT) Study. PBO responders continued PBO during MNT. This analysis evaluated the proportions of patients with haematological events (anaemia, leukopenia, lymphopenia, neutropenia and thrombocytopenia) at baseline (BL), W10 and W58. Haematological events were defined based on the relevant laboratory parameters being below the lower limit of normal. For anaemia at W10 and W58, patients were further stratified by rectal bleeding (RB) status (no: RB subscore=0; yes: RB subscore ≥1) at W10 and W58, respectively. Results At BL, ~50% of patients had anaemia in all treatment arms. Among these patients, the proportion without anaemia at W10 was similar across the FIL and PBO arms (25.0–30.7%; Table 1). Among patients without BL anaemia, the proportion with anaemia at W10 was also similar across all arms (12.1–17.3%). Among patients without RB at W10, the proportion of patients with a change in anaemia status from BL to W10 was also similar across arms. At W58, the proportion of patients with anaemia was similar across all arms, although ~40% of patients overall had missing data (Table 2). At BL, &amp;lt;5% of patients had leukopenia across all treatment arms (Tables 3 and 4). Lymphopenia, neutropenia and thrombocytopenia were also uncommon at BL (&amp;lt;10%, &amp;lt;4%, and &amp;lt;1% of patients, respectively). Among patients without these four haematological events at BL, &amp;lt;5%, &amp;lt;6%, 4% and ~1%, respectively, had them at W10. Conclusion Treatment with JAK1-preferential FIL up to W58, was not associated with anaemia, thought to occur via JAK2 inhibition, in patients overall and in those without RB at W10, compared with PBO. The small numbers of patients with haematological events excluding anaemia at BL limit rigorous inter-arm comparison. 1. Malesza IJ et al. Nutrients 2022;14:3478. 2. Feagan BG et al. Lancet 2021;397:2372–84.

Periarticular multimodal analgesia in decreasing perioperative pain in tibial plateau fractures: A double blind randomized controlled pilot study

IntroductionThe use of periarticular multimodal analgesia injections is increasing and has become commonplace in some surgeries. However, there is no data on the effectiveness of local periarticular multimodal analgesia for tibial plateau fractures. We hypothesized that closed tibial plateau fracture patients receiving the local multimodal analgesic medications would experience a decrease in VAS pain scores. MethodsPatients aged between 18 and 79 with an isolated closed tibial plateau fracture (AO 41-B and C) were prospectively enrolled and randomized in a 1:1 double blinded fashion to either a placebo or active medication treatment arm. After ORIF, gel-foam sponges soaked in either multimodal analgesic solution or normal saline. Patients were followed for 24 h post-operatively with Visual Analog pain Scores (VAS). Patients were monitored post-operatively for complications including compartment syndrome, infection, and non-union. ResultsThe planned study was terminated prior to completion due to higher than anticipated rates of infection (18%), distributed equally among active (3) and placebo (2) groups, raising concerns that this may have been due to the presence of the delivery device. Twenty-eight patients were enrolled, 15 in the active group and 13 in the placebo group. Patients in the active medication group had significantly decreased pain scores at hours 4 (p = 0.005, 4.2 vs 6.9), 8 (p = 0.05, 5 vs 7), and 12 (p = 0.02, 3.8 vs 6.2). Pain scores at hours 16 (p = 0.10, 4.5 vs 6.5), 20 (p = 0.08, 4.6 vs 6.4), and 24 (p = 0.10, 4.8 vs 6.5) were also decreased but did not reach significance. DiscussionThe use of local multimodal periarticular analgesic for closed tibial plateau fractures appears to be beneficial for short-term pain control post-operatively. Concerns regarding an implantable delivery vehicle leading to infection has warranted a change in method of drug administration. Completion of the full study will permit us to validate or refute these findings. Level of EvidenceTherapeutic Level 1

Placebo effect on progression and regression in NASH: Evidence from a meta-analysis.

The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH. A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients. Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.

Disease-modifying treatments for multiple sclerosis have not affected the incidence of neoplasms in clinical trials over 3 decades: a meta-analysis with meta-regression.

Our study aimed to estimate the incidence of neoplasms in clinical trials of DMTs for MS and to test the hypothesis that DMTs increase the risk of neoplasms in the duration of MS randomized controlled trials (RCTs). Data were extracted from 42 RCTs of DMTs published between 1991 and 2020. The incidence rate (IR) of neoplasms was estimated by pooling the neoplasms in the active and placebo-treatment arm per patient-year. The neoplasm incidence rate ratio (IRR) of active over placebo-treatment arms was used as measure of the effect of DMTs on the risk of developing neoplasms. The meta-analysis included 10,638 placebo and 16,360 active-treatment arm patients. A non-significant pooled neoplasm incidence rate ratio (IRR: 1.0797; 95% CI: 0.8281 to 1.4077; P = 0.5711) with no heterogeneity (I2 = 0%) was observed in active over placebo-treatment groups from 1991 to 2020. We found a significant association between the incidence of neoplasms and the year of publication in both active and placebo arms of RCTs. Trials of sequestrating and depletive DMTs were associated with significantly higher incidence of neoplasms in both active and placebo-treated arms compared to immunomodulatory treatment trials. Our study indicates that treatment with DMTs has not modified the risk of neoplasms in MS clinical trials from 1991 to 2020, which may reflect a low carcinogenic potential of DMTs and/or that the neoplasia latencies far exceed the typical MS trial observation periods.

The Effect of Low-Dose Aspirin on Frailty in Older Adults in the Aspirin in Reducing Events in the Elderly Study

There are no widely accepted pharmacologic treatments for frailty prevention. Since frailty is associated with inflammation, aspirin has the potential to reduce frailty. We investigated whether low-dose aspirin reduces incident frailty in participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. In the U.S and Australia, 19,114 healthy community-dwelling individuals aged ≥70 years (U.S. minorities ≥65 years) were enrolled in ASPREE, a double-blind, placebo-controlled trial of 100mg daily low-dose aspirin vs. placebo. Frailty was defined according to a modified Fried frailty definition, and a frailty index which used a deficit accumulation model. Competing risk Cox proportional hazards models were used to compare time to incident frailty for aspirin vs. placebo. At baseline, 2.2% and 8.1% met criteria for frailty by Fried and frailty index criteria, respectively. Over a median of 4.7 years of follow-up, 2252 participants developed incident frailty according to Fried classification, and 4376 according to the frailty deficit accumulation index. There was no difference in the risk of incident frailty between individuals randomized to aspirin versus placebo according to either criteria (Fried frailty HR: 1.03, 95% CI 0.97-1.09, p=0.41; frailty index HR: 1.03, 95% CI 0.97-1.10, p=0.29). Change in frailty over time was not different between the aspirin and placebo treatment arms. The results were consistent across a series of sub-groups, including baseline frailty status. Based on these results, aspirin use in healthy older adults does not reduce incident frailty.

Analysis of a precision medicine approach to treating Parkinson's disease: Analysis of the DATATOP study

IntroductionThe aim of this study was to examine the potential application of a targeted proteomic predictive biomarker comprised predominantly of inflammatory proteins in distinguishing those who responded to a previously conducted clinical trial for Parkinson's disease (PD). MethodsPlasma samples obtained from a biorepository were assayed from a total of n = 520 DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) clinical trial participants across treatment arms. Support vector machine analyses were conducted to distinguish responder status on primary (need for Levodopa) and secondary trial endpoints (UPDRS Motor and Total Scores). ResultsFor the α-tocopherol and deprenyl placebo treatment arm (TOC), the targeted proteomic biomarker was able to distinguish responder status with an accuracy (area under the curve [AUC]) of 91% for the primary endpoint while it was 100% across secondary endpoints. For the deprenyl and α-tocopherol placebo treatment arm (DEP), the AUC was 93% for the primary endpoint and 99–100% for the secondary endpoints. For the combined treatment arm, AUC was 87% for the primary and 94–96% for the secondary endpoints. DiscussionThe targeted proteomic predictive biomarker was highly accurate in distinguishing responder status across treatment arms thereby supporting the application of a precision medicine approach to treating PD.

Trial in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase IIa CROSSWALK-c Trial Evaluating the Efficacy of Crovalimab As Adjunct Treatment in the Prevention of Vaso-Occlusive Episodes (VOEs) in Patients with Sickle Cell Disease (SCD)

BackgroundSCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β- globin gene, with either homozygous inheritance, or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. This point mutation results in the production of hemoglobin S, which polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. In addition to VOEs, patients with SCD may experience severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. The current treatment strategy for patients with SCD includes hydroxyurea, along with newer treatments such as L-glutamine, crizanlizumab, and voxelotor. However, despite the availability of these treatments, considerable morbidity and mortality among patients with SCD represents a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crisis, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. Crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety in a Phase I/II study (Röth et al. Blood 2020), in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder.Study Design and MethodsCROSSWALK-c (NCT number pending) is a placebo-controlled, randomized, double-blind, Phase IIa study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0), and presenting with ≥ 2 to ≤ 10 VOEs are eligible for this study. Patients on concurrent SCD-directed therapies are also eligible. Vaccination against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumonia are required for enrollment. Patients with a history of hematopoietic stem cell transplant are excluded from the study. Eligible patients will be randomized 1:1 to the crovalimab or placebo treatment arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be administered on Day 1 Week 1, followed by four weekly SC doses on Day 2 Week 1, and then on Weeks 2-4. Maintenance dosing will be administered from Week 5, followed by once every 4 weeks thereafter, for 48 weeks. All patients will receive study treatment according to a weight-based tiered dosing schedule. The primary objective is to evaluate the efficacy of crovalimab compared with placebo, based on the annualized rate of medical facility VOEs. Secondary efficacy objectives include the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin-creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetics, immunogenicity, and exploratory biomarker objectives will also be evaluated. [Display omitted] DisclosuresCallaghan: Agios Pharmaceuticals: Current Employment; Roche/Genentech: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy, Speakers Bureau; Forma: Consultancy; Hema Biologics: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; BioMarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Chiesi: Consultancy; Kedrion: Consultancy; Pfizer: Consultancy. Ataga: Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: CSL Behring: Other: Endpoint adjudicator ; Forma: Consultancy; Novo Nordisk: Consultancy; Chiesi: Consultancy; Bluebird Bio: Other: Endpoint adjudicator ; Novartis: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy. Balachandran: F. Hoffmann-La Roche Ltd: Current Employment. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Perretti: F. Hoffmann-La Roche Ltd: Current Employment. Ramos: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Bartolucci: Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; INNOVHEM: Other: Co-founder; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Hemanext: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy.

A Systematic Review of Flurbiprofen 8.75mg Dose and Risk of Haemorrhagic Events.

Oral non-steroidal anti-inflammatory drugs (NSAIDs) are known to be associated with an increased risk of bleeding. The NSAID, flurbiprofen, in the form of 8.75 mg lozenge or oromucosal spray is indicated for the symptomatic relief of sore throat. Despite the low dose as compared to alternative flurbiprofen preparations, concerns have been raised regarding its safety in terms of haemorrhagic events. This systematic review was conducted to identify existing evidence on the risk of haemorrhagic events with flurbiprofen 8.75 mg dose (any formulation), particularly where this may be due to potential interactions with other medicinal products. The systematic review examined studies reporting haemorrhagic events in patients receiving flurbiprofen 8.75 mg dose. Six individual electronic databases were searched up to 28th April 2020. Records were initially screened for relevance followed by further review of potentially eligible studies. Data extraction was performed for eligible studies and risk of bias in studies was assessed. The search strategy identified 1093 individual records. Of these, 1038 records were excluded after initial review; the majority of these records related to flurbiprofen in alternative formulations with alternative doses (e.g., eye drops, skin patches, oral tablets) thus were not considered relevant for further review. The 55 remaining records related to flurbiprofen 8.75 mg dose (any formulation) or flurbiprofen lozenge/oromucosal spray where the dose was not specified. After further review, 52 of these records were not considered eligible. Thus, only three records were included in this systematic review. The three studies reported a total of five haemorrhagic events in patients taking flurbiprofen 8.75 mg lozenge; the corresponding risk in each of the studies was 8.33, 1.98 and 1.96%. Where possible, comparison of flurbiprofen 8.75 mg lozenge to placebo produced risk ratios of 0.96 (95% CI 0.07, 13.25) and 2.00 (95% CI 0.10, 118.0). This systematic review found limited evidence on the risk of haemorrhagic events with flurbiprofen when used at a dose of 8.75 mg. Counts were low across all studies and results comparing flurbiprofen and placebo treatment arms were non-significant. However, scarcity of studies and low certainty of evidence for the outcome of haemorrhagic events limits the conclusions of this systematic review.

Effect of immunotherapy on survival outcomes in prostate cancer: Systematic review and meta-analysis.

e17030 Background: Prostate cancer is one of the leading cancers in men with an estimated 191,930 new cases in 2020 in the USA alone. Treatment options for metastatic castration resistant prostate cancer (mCRPC) have evolved in recent years. Immunotherapy involving vaccines like sipuleucel-T, PROSTVAC and immune checkpoint inhibitors have been evaluated in these patients. We present a systematic review and meta-analysis of the randomized controlled trials (RCTs) testing the effect of immunotherapy in mCRPC. Methods: A systematic search was performed using PubMed, Embase and the Cochrane library without language limitations from inception to January 3, 2021. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), prostate specific antigen (PSA) reduction ≥ 50% and incidence of grade 3-4 adverse events. The analysis of OS, PFS was done using random effects hazard ratio (HR) by generic inverse variance method and analysis of PSA reduction ≥ 50% and grade 3-4 adverse events was done using random effects risk ratio (RR) by the Mantel-Haenszel method. Results: 12 RCTs comprising 4109 patients were included in the analysis. There was a statistically significant improvement in OS (HR 0.89; 95% CI (0.81, 0.97)) and PFS (HR 0.83; 95% CI (0.76, 0.92)) in the immunotherapy arm compared to placebo or standard treatment arms with moderate quality of evidence. Patients in the immunotherapy group had significant reduction in PSA ≥ 50% (RR 1.71; 95% CI (1.09, 2.68)) but also had statistically significant increased risk of grade 3-4 adverse events (RR (1.25; 95% CI (1.02, 1.54)) when compared to placebo and the standard treatment group. Subgroup analysis showed that the use of vaccine therapy in prostate cancer leads to significant improvement in OS (HR 0.83; 95% CI (0.74, 0.93)) and PFS (HR 0.80; 95% CI (0.67, 0.95)) compared to placebo and standard treatment. The use of immune checkpoint inhibitors was not associated with statistically significant improvement in OS (HR 0.98; 95% CI (0.88, 1.09)) but is associated with improvement in PFS (HR 0.87; 95%CI (0.81, 0.94)). Conclusions: This meta-analysis showed that immunotherapy led to significant improvement in OS, PFS and PSA reduction of ≥ 50%. However, there is an increased incidence of grade 3-4 adverse events with the use of immunotherapy when compared to other standard therapies and placebo. The improvement in overall survival is limited to the use of vaccine therapy and not to immune checkpoint inhibitors. Careful use of selective forms of immunotherapy in mCRPC can lead to greater improvement in survival.

Effect of intranasal corticosteroid treatment on allergen-induced changes in group 2 innate lymphoid cells in allergic rhinitis with mild asthma.

Allergic rhinitis is characterized by rhinorrhea, nasal congestion, sneezing and nasal pruritus. Group 2 innate lymphoid cells (ILC2s), CD4+ T cells and eosinophils in nasal mucosa are increased significantly after nasal allergen challenge (NAC). Effects of intranasal corticosteroids (INCS) on ILC2s remain to be investigated. Subjects (n=10) with allergic rhinitis and mild asthma were enrolled in a single-blind, placebo-controlled, sequential treatment study and treated twice daily with intranasal triamcinolone acetonide (220µg) or placebo for 14days, separated by a 7-day washout period. Following treatment, subjects underwent NAC and upper airway function was assessed. Cells from the nasal mucosa and blood, sampled 24h post-NAC, underwent flow cytometric enumeration for ILC2s, CD4+ T and eosinophil progenitor (EoPs) levels. Cell differentials and cytokine levels were assessed in nasal lavage. Treatment with INCS significantly attenuated ILC2s, IL-5+ /IL-13+ ILC2s, HLA-DR+ ILC2s and CD4+ T cells in the nasal mucosa, 24h post-NAC. EoP in nasal mucosa was significantly increased, while mature eosinophils were significantly decreased, 24h post-NAC in INCS versus placebo treatment arm. Following INCS treatment, IL-2, IL-4, IL-5 and IL-13 were significantly attenuated 24h post-NAC accompanied by significant improvement in upper airway function. Pre-treatment with INCS attenuates allergen-induced increases in ILC2s, CD4+ T cells and terminal differentiation of EoPs in the nasal mucosa of allergic rhinitis patients with mild asthma, with little systemic effect. Attenuation of HLA-DR expression by ILC2s may be an additional mechanism by which steroids modulate adaptive immune responses in the upper airways.

P174 Upadacitinib response rates in patients with psoriatic arthritis enrolled in the SELECT-PsA-1 and SELECT-PsA-2 trials assessed according to modified PsARC

P174 Upadacitinib response rates in patients with psoriatic arthritis enrolled in the SELECT-PsA-1 and SELECT-PsA-2 trials assessed according to modified PsARC

Evaluation of MADRS Severity Thresholds in Patients With Bipolar Depression

AbstractIntroductionThe Montgomery-Åsberg Depression Rating Scale (MADRS) is commonly used for the assessment of depressive symptom changes in patients with major depressive disorder (MDD) or bipolar depression. Categories of depression severity that correspond to ranges of MADRS total score have been previously reported in patients with MDD, but it appears that MADRS severity ranges have not been reported for patients with bipolar I disorder. The objective of this study was to evaluate MADRS total score ranges that correspond with different grades of depression severity in patients with bipolar I depression.MethodsData were pooled from 3 randomized, double-blind, placebo-controlled, 6- or 8-week trials of cariprazine in patients with bipolar I depression. MADRS severity ranges were evaluated using an anchor-based approach with the clinician-rated, 7-category Clinical Global Impression-Severity (CGI-S) scale. CGI-S has previously been used to determine severity thresholds in MDD. Correlations between MADRS total score and CGI-S score were assessed in the pooled dataset at week 6; placebo and active treatment arms were pooled together. Youden index from receiver operating characteristic (ROC) curves was used to determine the optimal threshold for MADRS total score corresponding to each CGI-S severity level.ResultsThe pooled dataset included 1523 patients with bipolar depression. Mean CGI-S scores were highly correlated with mean MADRS total scores at week 6 (r=.87; P&lt;.0001), with MADRS total scores increasing with CGI-S severity. Using the ROC curves, MADRS total score ranges corresponding to each CGI-S severity category were estimated as follows: score of 0-6 for “normal, not at all ill”, 7-12 for “borderline mentally ill”, 13-18 for “mildly ill”, 19-23 for “moderately ill”, 24-36 for “markedly ill”, 37-39 for “severely ill”, and 40 or greater for “extremely ill”. Area under the curve (AUC) values for these cutoffs ranged from 0.930 to 0.997, representing outstanding sensitivity and specificity.ConclusionsUtilizing data from 3 recent clinical trials of subjects with bipolar depression, we were able to identify MADRS severity thresholds. These empirical findings may help clinicians to understand and contextualize MADRS results from bipolar clinical research and apply to their patients in practice.FundingAbbVie Inc.

A randomized trial comparing prescribed light exercise to standard management for emergency department patients with acute mild traumatic brain injury.

Persistent post-concussion symptoms (PCS) after a mild traumatic brain injury (mTBI) or concussion do not occur in the majority of patients sustaining such injuries, but when they do occur, they have significant functional consequences for patients. Delays in return to school, work, recreational, and social activities can deeply impact quality of life and have major long-term negative life consequences that are anything but mild, despite the classification of the initial injury. Predictive abilities to determine which patients will suffer PCS are currently poor, although certain presentation characteristics may be associated, such as age at injury, the occurrence and timing of prior concussions, the mechanism of injury, and others. Research into utilization of various biomarkers as predictive tools is underway but clear answers are still forthcoming.