Clinical Efficacy Measures Research Articles

The added value of targeting airway hyperresponsiveness by blocking TSLP in the management of severe asthma.

Airways hyperresponsiveness (AHR) is a pathognomonic event of asthma in which the airways are reactive to various bronchoconstrictor stimuli at 'doses' that normally have no bronchoconstrictor effect in non-asthmatics. AHR is an objective measure of clinical efficacy, and the introduction of biologics revived interest as a marker of disease and its pathophysiologic mechanism. This article aims to discuss the mechanisms of AHR, focusing on the role of epithelial damage and TSLP production, and promote its correct assessment for the evaluation of patients with severe asthma, to predict the risk of exacerbations and outcomes, and the eligibility for treatment with an anti-TSLP agent. AHR is a complex trait of asthma, induced by the concurrence of many pathophysiological factors and related to different clinical manifestations. Recent evidence demonstrates the important role of airway epithelial damage and TSLP production in many of these events. A therapeutic response based on AHR control could be considered as a condition of disease remission and seems a promising new goal for the management of patients with severe asthma.

Dose-exposure-efficacy response of intravenous immunoglobulin G 10% in multifocal motor neuropathy.

Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model. The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience.

Construction and efficacy test of a survival prediction model for locally advanced cervical cancer based on anti-angiogenesis

ObjectiveThis study aimed to develop and evaluate an anti-angiogenesis-based model for predicting the survival and the potential benefits of targeted therapy for patients with localized advanced cervical cancer. MethodsWe collected clinical data from 163 patients with cervical cancer who received paclitaxel and cisplatin (TP) or TP plus bevacizumab during or after radiotherapy from June 2017 to February 2023. We analyzed the clinical measures of recent efficacy and overall survival (OS) using univariate and logistic multivariate and Cox regression methods, respectively. We constructed a nomogram model and evaluated its efficacy using the c-index, the area under the curve (AUC), a calibration curve, and the clinical decision curve (DCA). ResultsWe found that targeted agents and hemoglobin were independent determinants of near-term efficacy (P < 0.05), while targeted agents and stage were independent factors of OS (P < 0.05). We developed a predictive model for an OS prognostic nomogram and performed internal validation 1000 times using the Bootstrap re-sampling method. The c-index was 0.81, and the AUC was 0.84 (P < 0.01).The calibration curves showed a good agreement between the projected and actual values. The DCA curve indicated that the model had a high positive predictive accuracy. ConclusionWe developed a novel anti-angiogenesis-based survival prediction model for patients with locally advanced cervical cancer. This model could estimate the benefit of targeted therapy before treatment, and it had good validation.

A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis.

Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humanized monoclonal antibody against TNF-alpha, is approved for the treatment of moderate-to-severe plaque psoriasis. Patients with psoriasis present clinical and molecular variability, affecting response to treatment. Herein, we utilized an in silico approach to model the effects of CZP in a virtual population (vPop) with moderate-to-severe psoriasis. Our proof-of-concept study aims to assess the performance of our model in generating a vPop and defining CZP response variability based on patient profiles. We built a quantitative systems pharmacology (QSP) model of a clinical trial-like vPop with moderate-to-severe psoriasis treated with two dosing schemes of CZP (200 mg and 400 mg, both every two weeks for 16 weeks, starting with a loading dose of CZP 400 mg at weeks 0, 2, and 4). We applied different modelling approaches: (i) an algorithm to generate vPop according to reference population values and comorbidity frequencies in real-world populations; (ii) physiologically based pharmacokinetic (PBPK) models of CZP dosing schemes in each virtual patient; and (iii) systems biology-based models of the mechanism of action (MoA) of the drug. The combination of our different modelling approaches yielded a vPop distribution and a PBPK model that aligned with existing literature. Our systems biology and QSP models reproduced known biological and clinical activity, presenting outcomes correlating with clinical efficacy measures. We identified distinct clusters of virtual patients based on their psoriasis-related protein predicted activity when treated with CZP, which could help unravel differences in drug efficacy in diverse subpopulations. Moreover, our models revealed clusters of MoA solutions irrespective of the dosing regimen employed. Our study provided patient specific QSP models that reproduced clinical and molecular efficacy features, supporting the use of computational methods as modelling strategy to explore drug response variability. This might shed light on the differences in drug efficacy in diverse subpopulations, especially useful in complex diseases such as psoriasis, through the generation of mechanistically based hypotheses.

42999 Rocatinlimab demonstrates a significant reduction in IgE concentrations in addition to clinical efficacy measures in patients with moderate–severe atopic dermatitis (msAD) in a randomised, double-blind, placebo-controlled Phase 2 trial

42999 Rocatinlimab demonstrates a significant reduction in IgE concentrations in addition to clinical efficacy measures in patients with moderate–severe atopic dermatitis (msAD) in a randomised, double-blind, placebo-controlled Phase 2 trial

Cost per responder of adalimumab biosimilars versus methotrexate in patients with psoriasis: a real-life experience

BackgroundPharmacoeconomic studies examining the cost-effectiveness of adalimumab biosimilars versus methotrexate in real-life settings are limited.ObjectivesTo assess the cost per responder from the perspective of the National Health System of adalimumab biosimilars versus methotrexate for psoriasis treatment in a real-life setting.MethodsA cost-per responder analysis comparing adalimumab biosimilars MSB11022 (Idacio®) and ABP 501 (Amgevita) versus subcutaneous methotrexate was performed. The incremental cost per responder was calculated by multiplying the cost of treatment (including the discounts, as published in the framework agreement of the Veneto region) and the number needed to treat each therapy. The clinical efficacy measures were defined as being on treatment (i.e., retention rate) at weeks 24 and 52.ResultsA total of 712 adult patients with moderate-to-severe chronic plaque psoriasis consecutively admitted to the outpatient clinic from January 2021 to December 2022 were included; 160 were treated with ABP 501 (Amgevita), 250 with MSB11022 (Idacio) and 302 with methotrexate. The retention rates of Amgevita, Idacio and methotrexate at week 24 were 86%, 90% and 78%, and 81%, 82% and 63% at week 52, respectively. The cost per responder at week 24 was €674 for Amgevita, €366 for Idacio and €264 for methotrexate, respectively; at week 52, was €1430 for Amgevita® €799 for Idacio® and €652 for methotrexate, respectively.ConclusionsThe real-life cost-effectiveness of biosimilar drugs is largely influenced by discount rates. The week 52 cost-effectiveness of Idacio is comparable to subcutaneous methotrexate. The lowering of the cost of biosimilar drugs makes them a more accessible therapeutic option and they also can be introduced earlier in the treatment of moderate-to-severe psoriasis.

Orbital Dynamics and Efficacy of Retrobulbar Anesthesia With and Without Hyaluronidase in Vitreoretinal Surgery.

Purpose: To compare retrobulbar anesthesia injection (RAI) with hyaluronidase and without hyaluronidase in vitreoretinal surgery using clinical efficacy measures and orbital manometry (OM). Methods: This prospective randomized double-masked study enrolled patients who had surgery using an 8 mL RAI with or without hyaluronidase. Outcome measures were clinical block effectiveness (akinesia, pain scores, need for supplemental anesthetic or sedative medications) and orbital dynamics assessed by OM before and up to 5 minutes after RAI. Results: Twenty-two patients received RAI with hyaluronidase (Group H+), and 25 received RAI without hyaluronidase (Group H-). Baseline characteristics were well matched. No differences in clinical efficacy were found. OM showed no difference in preinjection orbital tension (4 ± 2 mm Hg in both groups) or calculated orbital compliance (0.6 ± 0.3 mL/mm Hg, Group H+; 0.5 ± 0.2 mL/mm Hg, Group H-) (P = .13). After RAI, the peak orbital tension was 23 ± 15 mm Hg in Group H+ and 24 ± 9 mm Hg in Group H- (P = .67); it declined more rapidly in Group H+. Orbital tension at 5 minutes was 6 ± 3 mm Hg in Group H+ and 11 ± 5 mm Hg in Group H- (P = .0008). Conclusions: OM showed faster resolution of post-RAI orbital tension elevation with hyaluronidase; however, there were no clinically evident differences between groups. Thus, 8 mL RAI with or without hyaluronidase is safe and can achieve excellent clinical results. Our data do not support the routine use of hyaluronidase with RAI.

Minimal Residual Disease Data in Hematologic Malignancy Drug Applications and Labeling: An FDA Perspective.

Minimal residual disease (MRD) is increasingly used as a prognostic biomarker, a measure of clinical efficacy, and a guide for treatment decisions in various hematologic malignancies. We sought to characterize MRD data in registrational trials in hematologic malignancies submitted to the U.S. Food and Drug Administration (FDA) with the ultimate goal of expanding the utility of MRD data in future drug applications. We descriptively analyzed MRD data collected in registrational trials, including the type of MRD endpoint, assay, disease compartment(s) assessed, and the acceptance of MRD data in the U.S. prescribing information (USPI). Of 196 drug applications submitted between January 2014 and February 2021, 55 (28%) included MRD data. Of the 55 applications, MRD data was proposed by the Applicant for inclusion in the USPI in 41 (75%) applications but was included in only 24 (59%). Despite an increasing number of applications that proposed to include MRD data in the USPI, the acceptance rate decreased over time. Although MRD data have the potential to expedite drug development, our analysis identified challenges and specific areas for improvement, including assay validation, standardization of collection methods to optimize performance, and considerations in trial design and statistical methodology.

P814 Clinical trial design in Crohn’s disease: interpreting future endpoints based on post hoc analyses of the vedolizumab phase 3 trials GEMINI 2 and VISIBLE 2

Abstract Background Crohn’s disease (CD) is a chronic, relapsing–remitting disease characterized by inflammation of the gastrointestinal tract. Historically, the Crohn’s Disease Activity Index (CDAI) has been used to assess outcomes in clinical trials involving patients with CD. However, in contrast to the alignment of regulatory standards for trials in ulcerative colitis, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) differ regarding the most appropriate endpoint definitions for trials in CD. We examined how clinical remission endpoints in CD trials have evolved and conducted post hoc analyses of two vedolizumab trials, GEMINI 2 and VISIBLE 2, to understand how endpoint definitions influence clinical trial outcome measures of treatment efficacy. Methods Endpoint definitions of clinical remission in completed and ongoing phase 3 trials of advanced therapies in CD were extracted from published literature and ClinicalTrials.gov. Post hoc analyses of data from GEMINI 2 and VISIBLE 2 were conducted by measuring the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 as assessed by six endpoint definitions (A: stool frequency score [SFS] ≤ 2.8 and not worse than baseline score; B: SFS ≤ 3 and not worse than baseline score; C: abdominal pain score (APS) ≤ 1 and not worse than baseline score; D: SFS ≤ 2.8 and APS ≤ 1; E: SFS ≤ 3 and APS ≤ 1; F: CDAI ≤ 150) (Figure 1). Results Most phase 3 trials of advanced therapies in CD included a clinical remission endpoint that was defined by CDAI score: typically, CDAI &amp;lt; 150 or ≤ 150. However, several recent trials have also included a primary or secondary clinical remission endpoint defined using components of the CDAI score such as SFS and APS (Table 1). Post hoc analyses of GEMINI 2 and VISIBLE 2 revealed minimal change in %Δ for each of the new endpoint definitions tested compared with the primary analysis for each trial (Figure 1). Conclusion Objective measures, including patient-reported outcomes and components of the CDAI score such as SFS and APS, have been used to define clinical remission in recent CD trials. Despite differences in regulatory guidance for defining clinical remission, our post hoc analyses of GEMINI 2 and VISIBLE 2 reveal that the efficacy of vedolizumab, measured using a variety of endpoint definitions from recent CD trials, was similar to that previously reported using CDAI ≤ 150.

Cost per responder for vedolizumab and ustekinumab in Crohn’s disease patients after failure of TNF-α inhibitors in Italy

Background: The aim of this economic evaluation was to compare the cost per responder between vedolizumab and ustekinumab in patients with Crohn’s disease (CD) after failure of tumor necrosis factor-α inhibitors in Italy. Methods: Clinical efficacy was assessed using the results of an Italian large multicentre observational retrospective cohort study. The aim of the study was to compare the effectiveness of ustekinumab and vedolizumab as second line therapy in Crohn’s disease patients in which tumour necrosis factor-α inhibitors failed. Clinical efficacy of vedolizumab and ustekinumab was measured by clinical response and clinical remission. Treatment costs were based on the number of administrations at 26 or 52 weeks. Cost per responder, based on clinical efficacy and clinical response, was used as a cost-effectiveness indicator. Results: Regardless of the clinical efficacy measure used and the treatment duration considered, the cost per responder was consistently lower for vedolizumab compared with ustekinumab on all clinical measures. Considering the clinical response, the cost per responder at 26 weeks was € 15,640 for vedolizumab and € 23,667 for ustekinumab and at 52 weeks was € 23,927 for vedolizumab and € 30,820 for ustekinumab. Considering the clinical remission, the cost per responder at 26 weeks was € 22,832 for vedolizumab and € 33,786 for ustekinumab and at 52 weeks was € 29,488 for vedolizumab and € 46,847 for ustekinumab. Sensitivity analysis confirmed the validity of results. Conclusion: These results suggest that vedolizumab is a cost-effective option compared with ustekinumab from the perspective of the Italian health service in patients with CD after failure of TNF-α inhibitors.

Efgartigimod improved health-related quality of life in generalized myasthenia gravis: results from a randomized, double-blind, placebo-controlled, phase 3 study (ADAPT)

There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod—a novel neonatal Fc receptor inhibitor—was well tolerated and that acetylcholine receptor antibody–positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported here, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up–only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG.

Preferences for Biologic Treatment in Patients With Psoriatic Arthritis: A Discrete Choice Experiment.

We aimed to assess patient preferences for the characteristics and outcomes of biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) to manage psoriatic arthritis. We conducted a discrete choice experiment in patients with psoriatic arthritis from 3 rheumatology centers in Sydney, Australia. We assessed preferences for different attributes of biologic medications. The route and frequency of medications had a range of 5 levels, and the following 7 attributes had a range of 3 levels: the ability to attend to normal activities, improvements in joint pain, enthesitis and skin disease, chance of disease remission, risk of infection, and risk of severe adverse events. Multinomial logit models including a latent class model were used to calculate preferences. Of the 150 participants, 58.3% were female, with a median age of 53.5 years. The attributes in order of preference using the β coefficient in absolute values (95% confidence interval [95% CI]) were as follows: oral route compared to subcutaneous and intravenous routes (β coefficient 1.00 [fixed parameter]), avoiding severe side effects (β coefficient 0.72 [95% CI 0.50, 0.95]), increasing ability to attend to normal activities (β coefficient 0.66 [95% CI 0.36, 0.96]), avoiding infections (β coefficient 0.38 [95% CI 0.23, 0.53]), improvement in enthesitis pain (β coefficient 0.28 [95% CI 0.20, 0.36]), improvement in psoriasis (β coefficient 0.28 [95% CI 0.20, 0.36]), increasing chance of remission (β coefficient 0.27 [95% CI 0.19, 0.36]), and improvement in joint pain (β coefficient 0.26 [95% CI 0.00, 0.52]). When choosing biologic medications, patients with psoriatic arthritis preferred oral medications. Patients prioritized avoiding severe complications, maintaining the ability to attend to work and normal activities, and avoiding infection over clinical measures of efficacy.

Health-related quality of life (HRQoL) with enasidenib versus conventional care regimens in older patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML).

7032 Background: Enasidenib (ENA) is an oral inhibitor of mutant-IDH2 (mIDH2) proteins. In the phase 3 IDHENTIFY trial, ENA improved event-free survival (EFS), overall response, and complete remission rate vs conventional care regimens (CCR) ( P &lt; 0.01 for all) in patients (pts) ≥ 60 years of age with m IDH2 R/R AML with 2 or 3 prior treatments (Tx) (DiNardo 2021). Pt-reported HRQoL was a secondary trial endpoint. Methods: IDHENTIFY is an open-label, randomized trial (NCT02577406). Pts were preselected to a CCR (SC azacitidine, intermediate- or low-dose Ara-C, or supportive care) and then randomized 1:1 to ENA 100 mg/d or CCR in 28-d cycles. Key HRQoL endpoints were mean changes from baseline (CFB) overall and by clinical response in the Global Health Status/QoL, Physical Functioning, Role Functioning, Fatigue, and Dyspnea domains of the EORTC QLQ-C30 questionnaire, and in EQ-5D-5L utility index (UI) and visual analogue scale scores. The QLQ-C30 and EQ-5D-5L were assessed on D1 of each Tx cycle (C) and at end of Tx. Minimally important differences (MIDs) in CFB scores within or between Tx arms were based on accepted thresholds. Sensitivity analysis using imputed data on CFB was conducted using pattern mixture modeling. Results: HRQoL-evaluable cohorts included 118/158 (74.7%) pts in the ENA arm and 80/161 (49.7%) in the CCR arm; 40 ENA pts and 81 CCR pts were not evaluable due to missing data at baseline (BL; 22 ENA and 51 CCR) and/or at ≥1 post-BL visit (26 ENA and 69 CCR). Pts ineligible for HRQoL analyses had lower response rates and worse EFS and overall survival than HRQoL-evaluable pts. Overall QLQ-C30 completion rates in the ENA and CCR arms were 79% and 65%, respectively ( P &lt; 0.001). While there was no meaningful improvement or worsening from BL (ie, exceeding MID) within either Tx arm in the key QLQ-C30 domains, scores worsened during initial Tx cycles and then improved with continued Tx. Mean EQ-5D-5L scores also worsened during early cycles in both Tx arms, with meaningful UI deterioration in the ENA arm from C2 through C7. However, between-group comparisons showed no consistent differences between ENA and CCR in mean CFB. Sensitivity analysis with imputation of missing CFB data showed worsened HRQoL compared with non-imputed data in the CCR arm but not with ENA. In the ENA arm, clinical responders reported relatively stable mean HRQoL scores over time, and non-responders showed no meaningful differences in CFB vs the CCR arm. Conclusions: HRQoL measures tended to worsen during early cycles in both Tx arms and gradually improved with continued Tx. Data should be interpreted with caution as only approximately one-half of pts in the CCR arm were HRQoL-evaluable. ENA improved clinical efficacy measures vs CCR without compromising HRQoL in older pts with R/R AML. Clinical trial information: NCT02577406.

Validating an SVM-based neonatal seizure detection algorithm for generalizability, non-inferiority and clinical efficacy

Neonatal seizure detection algorithms (SDA) are approaching the benchmark of human expert annotation. Measures of algorithm generalizability and non-inferiority as well as measures of clinical efficacy are needed to assess the full scope of neonatal SDA performance. We validated our neonatal SDA on an independent data set of 28 neonates. Generalizability was tested by comparing the performance of the original training set (cross-validation) to its performance on the validation set. Non-inferiority was tested by assessing inter-observer agreement between combinations of SDA and two human expert annotations. Clinical efficacy was tested by comparing how the SDA and human experts quantified seizure burden and identified clinically significant periods of seizure activity in the EEG. Algorithm performance was consistent between training and validation sets with no significant worsening in AUC (p > 0.05, n = 28). SDA output was inferior to the annotation of the human expert, however, re-training with an increased diversity of data resulted in non-inferior performance (Δκ = 0.077, 95% CI: −0.002-0.232, n = 18). The SDA assessment of seizure burden had an accuracy ranging from 89 to 93%, and 87% for identifying periods of clinical interest. The proposed SDA is approaching human equivalence and provides a clinically relevant interpretation of the EEG.

Therapeutic efficacy and safety of Yinzhihuang granules with phototherapy in neonatal pathologic jaundice: An updated systematic review and meta-analysis

BackgroundYinzhihuang granule, consisting of extracts of Artemisia capillaris Thunb., Gardenia jasminoides Ellis, Lonicera japonica Thunb., and Scutellaria baicalensis Georgi is a well-known traditional Chinese patent medicine for patients with liver injury in China. However, the effects and safety of its use for pathologic jaundice in newborns require further systematic evaluation. PurposeTo systematically evaluate the efficacy and safety of Yinzhihuang granules for the treatment of neonatal pathologic jaundice and to provide clinical evidence. MethodsChinese databases (China Network Knowledge Infrastructure, Wan Fang Database, and VIP Database) and English databases (PubMed, EmBase, and the Cochrane Library) were thoroughly investigated through screening randomized controlled trials on Yinzhihuang granules for neonatal pathologic jaundice from the establishment of all databases to November 18, 2021. A meta-analysis was performed for selected data using STATA software. TSA software was used for trial sequential analyses of the total effective rate and adverse reactions. ResultsA total of 19 trials and 2,221 newborns with pathologic jaundice were included in this study. Outcome measures of clinical efficacy in the experimental group were higher than in controls, including total bilirubin (WMD = -30.34, 95% CI = -35.44 to -25.23, p < 0.001), direct bilirubin (WMD = -15.03, 95% CI = -23.54 to -6.52, p < 0.001), indirect bilirubin (WMD = -11.22, 95% CI = -17.50 to -4.95, p < 0.001), recovery time (WMD = -2.96, 95% CI = -3.92 to -2.00, p < 0.001), hospitalization time (WMD = -3.83, 95% CI = -4.89 to -2.76, p < 0.001), and liver function indices. There were statistically significant differences between the two groups. Likewise, the incidence of adverse reactions, including diarrhea, erythra, and fever decreased remarkably in the trial group (RR = 0.44, 95% CI = 0.33 to 0.59, p < 0.001). Publication bias did not exist. We verified the efficacy and safety of Yinzhihuang granules with phototherapy for pathologic jaundice in newborns according using TSA analysis. ConclusionYinzhihuang granules with phototherapy for neonatal pathologic jaundice are more effective than phototherapy alone. The incidence of ADRs does not increase with the application of Yinzhihuang granules. Due to the heterogeneity across the included studies, additional multicenter clinical trials with follow-ups are needed to confirm our findings

Abstract WMP5: Non-invasive Vagus Nerve Stimulation For The Acute Treatment Of Ischemic Or Hemorrhagic Stroke

Background: This first-in-human randomized, blinded, sham-controlled, multicenter study assessed the safety and feasibility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of ischemic and hemorrhagic stroke. Potential efficacy was also assessed. Methods: Eligible participants admitted to nine clinical sites received standard care for acute stroke and were randomly assigned to low-dose nVNS, sham (2-minute stimulation applied to the skin overlying the vagus nerve every 10 minutes for an hour; 7 stimulations) or high-dose nVNS (2-minute stimulation every 10 minutes during hour 1 and hour 5; 14 stimulations) within 6 hours of stroke onset. Safety endpoints included severe bradycardia (≤50 beats/min) or significant hypotension (≥20-mm Hg reduction in arterial blood pressure) evaluated at 2 and 5 minutes after each stimulation and 30 minutes after the final stimulation. Feasibility was measured as the proportion of eligible patients in whom nVNS could be initiated within 6 hours of stroke onset and the ability to deliver scheduled stimulations per protocol. Efficacy measurements included absolute and relative infarct growth 24 hours poststroke compared to baseline and the proportion of patients with an NIH Stroke Scale (NIHSS) score of ≤4 or a ≥8-point improvement at 24 hours. Results: Sixty-eight patients with ischemic (n=60) or hemorrhagic (n=8) stroke completed the study. Baseline characteristics did not differ between sham (n=24) and nVNS (n=44). No significant bradycardia (2.9% of sham vs 3.1% of nVNS; p =0.965) or hypotension (1.1% of sham vs 2.5% of nVNS; p =0.145) occurred with nVNS. No deaths, acute coronary syndrome, symptomatic intracerebral hemorrhage, or stimulation site reactions were noted. All patients received 100% of intended stimulations per protocol. Clinical efficacy measures were similar between sham and total nVNS. Relative infarct growth, measured by diffusion weighted imaging, in the high dose nVNS group (63.3%) was lower than in the sham group (185.8%; p =0.05). Conclusions: This study suggests that nVNS is safe and feasible for the acute treatment for ischemic and hemorrhagic stroke. Possible efficacy is suggested by a decrease in relative infarct growth.

P612 Mirikizumab Pharmacokinetics and Exposure - Efficacy Relationships in Patients with Ulcerative Colitis

Abstract Background Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy in a Phase 2 trial in patients with moderately-to-severely active ulcerative colitis (UC)1 (NCT02589665). Analyses of the pharmacokinetics (PK) of miri and the relationships between exposure and efficacy at Week 12 are reported. Methods Patients were randomised to receive IV placebo, miri 50 mg or 200 mg with possibility of exposure-based dose increases, or miri 600 mg every 4 weeks, with efficacy assessment at Week 12. Serum concentrations of miri were analyzed using population PK methods. Population models were also used to evaluate the relationships between various clinical efficacy measures at Week 12 and miri exposure. The effects of patient factors on both PK and exposure-efficacy relationships were evaluated. Model-based and graphical methods were also used to understand the potential for confounded relationships between miri exposure and efficacy. Results A systemic clearance of 0.023 L/hr was estimated for miri, similar to estimates in healthy subjects and patients with psoriasis. Miri exposure increased in a linear manner. Patients with lower serum albumin concentration or lower body weight tended to have significantly higher clearance or lower volume of distribution, respectively (p&amp;lt;0.01); however, the magnitude of the impact was small and contributed less than 15% to random variability. The model-based exposure-response analyses generally showed that patient factors had a stronger impact on efficacy at Week 12 than miri exposure. Prior biologic experience and baseline rectal bleeding (RB) score had significant impacts (p&amp;lt;0.01) on the estimated placebo effect and maximal miri treatment effect (Emax), respectively. In the clinical response model, the estimated placebo response rate was 20 percentage points higher in biologic naïve vs experienced patients. The estimated response rate at a miri dose of 600mg was 28% higher in patients with a baseline RB≥2. Inclusion of these factors in the exposure-efficacy models caused the estimated EC50 to drop substantially, suggesting that the post-hoc exposure-efficacy relationships are likely confounded based on these patient factors. Graphical evaluations also suggested the presence of confounding factors. Conclusion Miri PK in UC patients was consistent with PK observed in healthy subjects and psoriasis patients. Evaluation of the relationships between miri exposure and efficacy in UC patients accounted for the potential impact of patient factors. Confounding patient factors may distort the true cause-effect relationship between exposure and efficacy and were carefully considered in support of optimal selection of doses for miri Phase 3 studies. Reference 1. Gastroenterology. 2020;158(3):537–549.

Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease.

Mannitol, a natural alcoholic-sugar, was recently suggested as a potential disease-modifying agent in Parkinson's disease. In animal models of the disease, mannitol interferes with the formation of α-synuclein fibrils, inhibits the formation of α-synuclein oligomers and leads to phenotypic recovery of impaired motor functions. Parkinson's patients who consume mannitol report improvements of both motor and non-motor symptoms. Safety of long-term use of oral mannitol, tolerable dose and possible benefit, however, were never clinically studied. We studied the safety of oral mannitol in Parkinson's disease and assessed the maximal tolerable oral dose by conducting a phase IIa, randomized, double-blind, placebo-controlled, single-center, dose-escalating study (ClinicalTrials.gov Identifier: NCT03823638). The study lasted 36 weeks and included four dose escalations of oral mannitol or dextrose to a maximal dose of 18 g per day. The primary outcome was the safety of oral mannitol, as assessed by the number of adverse events and abnormal laboratory results. Clinical and biochemical efficacy measures were collected but were not statistically-powered. Fourteen patients receiving mannitol completed the trial (in addition to eight patients on placebo). Mannitol-related severe adverse events were not observed. Gastrointestinal symptoms limited dose escalation in 6/14 participants on mannitol. None of the clinical or biochemical efficacy secondary outcome measures significantly differed between groups. We concluded that long-term use of 18 g per day of oral mannitol is safe in Parkinson's disease patients but only two third of patients tolerate this maximal dose. These findings should be considered in the design of future efficacy trials.

Association between low hemoglobin, clinical measures, and patient-reported outcomes in patients with rheumatoid arthritis: results from post hoc analyses of three phase III trials of sarilumab

BackgroundAnemia is common in patients with rheumatoid arthritis (RA). Higher hemoglobin (Hb) levels may be associated with better clinical outcomes and patient-reported outcomes (PROs). To assess this hypothesis, we conducted two post hoc analyses in three sarilumab phase III studies: TARGET, MOBILITY, and MONARCH.MethodsPooled data from combination therapy from placebo-controlled MOBILITY (sarilumab + methotrexate) and TARGET (sarilumab + conventional synthetic disease-modifying antirheumatic drugs [csDMARDs]) and monotherapy data from active-controlled MONARCH (sarilumab vs. adalimumab) studies were included. Associations between Hb levels and clinical measures and PROs were assessed over 24 weeks. The mean changes from baseline in clinical outcomes and PROs (to week 24) and radiographic outcomes (to week 52) were evaluated between low and normal Hb levels (based on the World Health Organization [WHO] criteria).ResultsFrom TARGET, MOBILITY, and MONARCH, 546, 1197, and 369 patients, respectively, were stratified according to Hb levels (low vs. normal). Over 24 weeks, higher Hb levels were found to be consistently associated with better clinical outcomes and PROs in combination therapy and monotherapy groups and were more pronounced among the patients treated with sarilumab than those treated with placebo and adalimumab. The mean change from baseline to week 24 in clinical efficacy measures and PROs was similar in patients with low vs. normal Hb at baseline. Differences between sarilumab and/or adalimumab, for all outcomes, were larger for low Hb subgroups. In MOBILITY, by week 52, the inhibition of progression of structural damage (assessed via Modified Total Sharp Score [mTSS]) was 84% (sarilumab 200 mg) and 68% (sarilumab 150 mg) vs. placebo in patients with low Hb and 97% (sarilumab 200 mg) and 68% (sarilumab 150 mg) vs. placebo in patients with normal Hb. Similar results were observed for other radiographic outcomes.ConclusionsIn these post hoc analyses, a consistent relationship was observed between higher Hb levels and better clinical outcomes and PROs in patients with RA. Irrespective of the baseline Hb levels, sarilumab treatment was associated with improvements in clinical measures and PROs over 24 weeks (improvements were more pronounced than those with adalimumab treatment) and mitigation of joint damage progression over 52 weeks.Trial registrationClinTrials.gov NCT01061736, NCT01709578, and NCT02332590

A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Mitapivat in Patients with Sickle Cell Disease

A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Mitapivat in Patients with Sickle Cell Disease