Last Observation Carried Forward Research Articles

Comparing Pain Outcomes and Treatment Adherence Between In-Person and Virtual Interdisciplinary Pain Rehabilitation Programs at the San Francisco VA Health Care System.

This study compares clinical pain outcomes between patients in a pain treatment program that was conducted in-person, compared to a virtual program. In-Person (N=127) and Virtual (N=101) pain treatment programs were compared based on patient-reported, practitioner-collected, and medical record data. The patients were measured at baseline and post treatment (week 12 for In-Person and week 8 for Virtual patients). We employed last observation carried forward (LOCF) to handle missing data. Both the In-Person and Virtual groups were similar in regard to all baseline outcomes, except the In-Person group having significantly more co-morbidities at baseline, with particularly more cases of mental, behavioral, or neurodevelopmental diseases. Both groups demonstrated significant improvements in the pain-related measurements of pain interference and pain catastrophizing thoughts, but neither group displayed a change in average pain across treatment. Further, both groups improved significantly on emotional well-being scores, but not on physical functioning scores. No significant differences existed between groups on outcomes, except for pain catastrophizing, which was higher in the Virtual group at both time points. The Virtual group had lower rates of dropouts compared to In-Person, while the In-Person group had a larger proportion reach a clinically meaningful change in pain-related outcomes, defined as a >30% improvement. While some changes were unique to the In-Person program, overall, patients in the Virtual program achieved similar treatment outcomes, suggesting that it can successfully treat Veterans seeking pain management, with less need for in-person facilities for both patients and clinicians.

Incorporating informatively collected laboratory data from EHR in clinical prediction models

BackgroundElectronic Health Records (EHR) are widely used to develop clinical prediction models (CPMs). However, one of the challenges is that there is often a degree of informative missing data. For example, laboratory measures are typically taken when a clinician is concerned that there is a need. When data are the so-called Not Missing at Random (NMAR), analytic strategies based on other missingness mechanisms are inappropriate. In this work, we seek to compare the impact of different strategies for handling missing data on CPMs performance.MethodsWe considered a predictive model for rapid inpatient deterioration as an exemplar implementation. This model incorporated twelve laboratory measures with varying levels of missingness. Five labs had missingness rate levels around 50%, and the other seven had missingness levels around 90%. We included them based on the belief that their missingness status can be highly informational for the prediction. In our study, we explicitly compared the various missing data strategies: mean imputation, normal-value imputation, conditional imputation, categorical encoding, and missingness embeddings. Some of these were also combined with the last observation carried forward (LOCF). We implemented logistic LASSO regression, multilayer perceptron (MLP), and long short-term memory (LSTM) models as the downstream classifiers. We compared the AUROC of testing data and used bootstrapping to construct 95% confidence intervals.ResultsWe had 105,198 inpatient encounters, with 4.7% having experienced the deterioration outcome of interest. LSTM models generally outperformed other cross-sectional models, where embedding approaches and categorical encoding yielded the best results. For the cross-sectional models, normal-value imputation with LOCF generated the best results.ConclusionStrategies that accounted for the possibility of NMAR missing data yielded better model performance than those did not. The embedding method had an advantage as it did not require prior clinical knowledge. Using LOCF could enhance the performance of cross-sectional models but have countereffects in LSTM models.

(125) Efficacy of Hilti Gold vs. Epimedyumlu Macun in Duration of Erection and Its Correlation with Partners ´Sexual Quality of Life

Abstract Introduction In healthy men, the average duration of sexual intercourse ranges from nine to ten minutes. However, duration of erection has been shown to be shorter in men with Erectile Dysfunction (ED) and even shorter for men with ED plus associated underlying conditions. Furthermore, duration of Penis erection is most important for sexual couple. Objective The aim of this study was to assess two herbal supplements: HILTI gold (Hg) vs Epimedyumlu Macun (EM) efficacy in terms of duration of erection and (i) Its correlation with other efficacy end points and male and female sexual quality of life (QoL) and (ii) Its impact on intercourse duration. Methods A double-blind, controlled trial randomized men (18–65 years of age) with ED for more than six months, to receive fixed-dose either Hg, 1 capsule or EM, 1 tea spoon (60 minutes prior intercourse) for 12 weeks in 52 patients with ED, after four-week without medication. Primary efficacy end points were stopwatch-assessed duration of erection (min) at any attempt and when leading to successful intercourse, and the erectile function domain of the International Index of Erectile Function (EF-IIEF) score was assessed at week 12/ last observation carried forward (LOCF). Secondary end points were Sexual Encounter Profile question three (SEP3) response rate and male sexual QoL. End points in participating women were stopwatch-assessed duration of intercourse and sexual QoL. Results 52 men included. 42% had moderate ED. 58% had severe ED at baseline. At week 12 / LOCF, patients taking Hg had longer duration of erections vs EM group (least square mean ± standard error 10.3±0.8 minutes vs. 7.7±0.7 minutes, and 10.3±0.8 vs. 7.8 ±1.0 minutes, respectively), and significant increases in EF-IIEF scores, the SEP3 response, and all sexual QoL items. An increased duration of intercourse was also observed. Female sexual QoL improved significantly. Both duration end points strongly correlated with EF-IIEF scores, and the three end points correlated well with SEP3 response. Correlation was good with sexual QoL scores in men and women and with duration of intercourse, with difference between groups only for duration end points. Safety was better in Hg than in EM group. Conclusions The results indicate that duration of erection represents a novel efficacy measures for evaluating those herbal supplements (HS), and could be used as a predictor or efficacy measure of sexual performance in couples affected by ED. With regard to the method of measuring duration, stopwatch method was shown to be reliable and capable of complementing traditional self-assessment efficacy methods for evaluating the efficacy of HS. Hg is the best to significantly improve: Duration of erection in men with ED and Sexual QoL, in both members of a couple affected by ED than EM Absolutely, Hg and EM: Increase duration of erection; Improve sexual pleasure. And, thereby improving the sexual QoL of the COUPLE. And, most important is that sexual couples don’t risk to be unfaithfulness. Disclosure No.

Norwegian population-based study of effectiveness of vagus nerve stimulation in patients with developmental and epileptic encephalopathies.

Evaluate the long-term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients without intellectual disability (ID). Long-term outcomes from a Norwegian VNS quality registry are reported in 105 patients with DEEs (Lennox-Gastaut syndrome [LGS] n = 62; Dravet n = 16; Rett n = 9; other syndromes n = 18) were compared with 212 epilepsy patients without ID, with median follow-up of 88 and 72 months, respectively. Total seizure reduction was evaluated at 6, 12, 24, 36, and 60 months. Effect on different seizure types was evaluated at baseline and last observation carried forward (LOCF). Median monthly seizure frequency at LOCF was reduced by 42.2% (p < 0.001) in patients with DEE and by 55.8% (p < 0.001) in patients without ID. In DEE patients, ≥50% seizure reduction at 6 and 24 months were 17.1% and 37.1%, respectively, and 33.5% and 48.6% for patients without ID. Seizure reduction ≥75% at 60 months occurred in 14.3% of DEE patients and 23.1% of patients without ID. Highest median reduction was for atonic seizures, most notably 64.6% for LGS patients. A better effect was seen at 2 years among DEE patients with unchanged medication compared with those with changed medication (54.5% vs. 35.6% responders, p = 0.078). More DEE patients were reported to have greater improvement in ictal or postictal severity (43.8% vs. 28.3%, p = 0.006) and alertness (62.9% vs. 31.6%, p < 0.001) than patients without ID. For both groups, use of the magnet reduced seizure severity. Hoarseness was the most common adverse effect in both groups. In addition, DEE patients were frequently reported to have sleep disturbance, general discomfort, or abdominal problems. Our data indicate that VNS is very effective for atonic seizures. Patients without ID had best overall seizure reduction, however, patients with DEE had higher retention rates probably due to other positive effects. DEE refers to a group of patients with severe epilepsy and intellectual disability. Many of these patients have restricted lifestyles with frequent seizures. VNS is a treatment option for patients who do not respond well to medicines, either because of insufficient effect or serious adverse effects. Our study shows that VNS is well tolerated in this patient group and leads to a reduction in all seizure types, most notably for seizures leading to fall. Many patients experience other positive effects like shorter and milder seizures, as well as improvement in alertness.

Efficacy of Prolonged-Release Melatonin Administration in Elderly Patients With Treatment Resistant Insomnia: A Post-Hoc Analysis

Objective: Melatonin, both immediate and prolonged-release formulations, has been explored as an adjunctive treatment for insomnia, with prolonged-release melatonin demonstrating enhanced efficacy compared to its immediate-release counterpart. However, there remains a gap in understanding its effectiveness specifically in individuals with treatment-resistant insomnia, who continue to experience sleep difficulties despite using traditional hypnotic medications.Methods: An 8-week prospective, open-label, observational study was conducted on 115 patients aged 55 years or older with insomnia several years ago. This is a post-hoc analysis, which was performed on 63 out of 115 patients who were already taking hypnotics and still reported symptoms of insomnia. Per protocol (n=40) and last observation carried forward (LOCF) approaches (n=63) were used, assessing changes in sleep indicators after administering 2 mg of prolonged-release melatonin. Psychometric scales including Pittsburgh Sleep Quality Index (PSQI) and WHO-5 Well-Being Index were used for evaluation at baseline, week 4, and week 8.Results: The per protocol and LOCF analysis revealed substantial improvements in sleep latency, total sleep time, sleep efficiency, and total PSQI scores after 8 weeks of prolonged-release melatonin treatment. The LOCF analysis also revealed WHO-5 Well-Being Index significantly increased. Compared to prolonged-release melatonin monotherapy group with combination therapy group (adding prolonged-release melatonin to previous hypnotics) at baseline, 4 weeks, and 8 weeks after treatment, most variables did not differ between two groups in the per protocol and LOCF analysis. However, only WHO-5 Well-Being Index was higher in monotherapy group than in combination group at 4 weeks and 8 weeks after prolonged-release melatonin treatment in the per protocol analysis.Conclusion: Prolonged-release melatonin demonstrated notable efficacy in ameliorating sleep latency, duration, efficiency, and overall quality in treatment-resistant insomnia patients. The study highlights its potential as a treatment avenue for this challenging cohort, prompting further exploration into its benefits, particularly in improving overall well-being, and advocating for expanded research in this domain.

Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial.

Hidradenitis suppurativa (HS) is a disease with an unmet need for treatment. To examine tolerability, safety and efficacy of oral phosphodiesterase-4 (PDE4) inhibitior orismilast 10-40 mg twice daily (BID) in HS. A Phase 2a, single-arm, single-centre, open-label, 16-week trial in HS patients. Adjustments in maximal dose and titration were allowed, to improve tolerability, dividing the study population in two groups who completed and discontinued 16 weeks of treatment. Descriptive statistics were applied to efficacy data from patients who completed treatment and patients who discontinued treatment prematurely. A last-observation-carried-forward (LOCF) approach was used for patients who discontinued treatment. The primary endpoint was percent change in the total number of abscesses and nodules (AN-count) at Week 16, with the HS Clinical Response with a 50% reduction in the AN-count (HiSCR50) as key secondary endpoint. Of the 20 patients included, 9 completed 16 weeks of treatment and 11 discontinued treatment prematurely. The mean AN-count was reduced with 33.1% in patients who completed treatment and with 12.0% in patients who discontinued. HiSCR50 was achieved by 67.0% and 27.0% of patients who completed and discontinued treatment, respectively. Most adverse events were mild to moderate. Oral orismilast demonstrated a dose-dependent tolerability, with mild to moderate adverse effects. Further, the results of this exploratory trial indicate that orismilast may lead to clinical improvements in HS. However, larger trials with tolerable dose ranges are warranted. The Trial is registered at Clinicaltrials.gov (UNI50007201) and EudraCT.ema.europa.eu (2021-000049-42).

Maintenance of Clinical Response With Continued Risankizumab Treatment for Moderate-to-Severe Psoriasis Through 304 Weeks: Interim Analysis of the LIMMitless Open-Label Extension Study

Introduction: Interleukin (IL)-23 is a key regulator of plaque psoriasis pathogenesis. Risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits IL-23 by binding to its p19 subunit, is approved for the treatment of moderate-to-severe plaque psoriasis in adults; however, additional data on long-term maintenance of efficacy with risankizumab treatment are needed. Here we report on the maintenance of clinical response through 304 weeks of continuous risankizumab treatment.&#x0D; Methods: In this interim analysis, we evaluated patients with moderate-to-severe plaque psoriasis who were randomized to receive risankizumab 150 mg at weeks 0, 4, and 16 and every 12 weeks thereafter during 2 double‑blind, phase 3, 52-week base studies (UltIMMa 1 [NCT02684370] and UltIMMa 2 [NCT02684357]) and enrolled in LIMMitless, an ongoing, phase 3, multicenter, single‑arm, open-label extension (OLE) study (NCT03047395) evaluating the long-term safety and efficacy of continuous risankizumab 150 mg treatment every 12 weeks for plaque psoriasis. Safety was assessed through ≤ 324 weeks by monitoring of treatment‑emergent adverse events through the data cutoff date (May 22, 2023). Efficacy was assessed by the proportion of patients who maintained ≥ 90% or 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 90/100) during LIMMitless and mean improvement in PASI from baseline of the UltIMMa-1/2 study through 252 additional weeks in the LIMMitless study (total of 304 weeks). Missing efficacy data were imputed using modified nonresponder imputation (mNRI), last observation carried forward (LOCF), or observed cases (OC) methodology.&#x0D; Results: A total of 525 patients were randomized to receive risankizumab 150 mg treatment for 52 weeks in the UltlMMa‑1/2 studies and continued open-label risankizumab 150 mg treatment in the LIMMitless OLE study. Risankizumab was well tolerated through ≤ 324 weeks; no new safety concerns were reported in patients with moderate-to-severe plaque psoriasis. At OLE entry, most patients (451, 85.9%) achieved PASI 90; of those, 422 (93.6%) maintained PASI 90 through week 304 by mNRI (LOCF, 92.7%; OC, 93.8%). Of 320 patients (61.0%) who achieved PASI 100 at OLE entry, 209 (65.3%) maintained PASI 100 through week 304 by mNRI (LOCF, 80.6%; OC, 79.9%). Mean PASI improvement from baseline was generally consistent from OLE entry (95.6% for both LOCF and OC) through week 304 (LOCF, 95.9%; OC, 96.5%).&#x0D; Conclusion: In this 304-week interim analysis of continuous risankizumab treatment, the safety profile was consistent with previous interim analyses from the LIMMitless study. With continuous risankizumab treatment, most patients maintained PASI 90 or PASI 100 responses from OLE entry through 252 additional weeks in the LIMMitless study.

Efficacy and Safety of Prolonged-Release Melatonin for Primary Insomnia in Elderly Patients

Objective: Insomnia, a prevalent sleep disorder affecting the elderly, necessitates effective and safe treatment options. This study explores the potential of the prolonged-release melatonin (Circadin&lt;sup&gt;®&lt;/sup&gt;) addressing insomnia in elderly patients.Methods: The 8-week prospective observational study involved 115 participants, assessing sleep parameters using the Pittsburgh Sleep Quality Index (PSQI) and WHO-5 Well-being Index. The prolonged-release melatonin (2 mg) was administered nightly, and assessments were conducted at baseline, 4 weeks, and 8 weeks.Results: Both per protocol and last observation carried forward (LOCF) analyses consistently revealed significant improvements in sleep latency, total sleep time, sleep efficiency, and overall well-being. Notably, sleep latency decreased after 4 and 8 weeks, while total sleep time and sleep efficiency increased, reflecting longer and more restful sleep. The WHO-5 Well-being Index exhibited noticeable enhancement. Adverse events, including dizziness and heartburn, were manageable. Despite a high dropout rate, this drug’s potential as an efficacious and safe treatment option for elderly insomnia patients was evident, aligned with prior research.Conclusion: The prolonged-release formulation’s resemblance to the natural circadian rhythm of melatonin release offers advantages over conventional medications. This study contributes to understanding the prolonged-release melatonin’s promise as a valuable therapeutic alternative, encouraging further investigation into its longterm effects and optimal implementation.

Correlation of satellite-based LAI and actual crop yield

The main objective of this article was to investigate the correlation between actual crop yield and Sentinel-2 Leaf Area Index (LAI) for the further possibility of predict model creating. To do so, the following steps have been done. Step 1 – the dataset of actual crop yield was collected for 2364 fields in Ukraine represented with maize, soy, sunflower, winter wheat, winter rapeseed and winter barley. Step 2 – the dataset of Sentinel-2 LAI was collected for 2016-2018 period according to the actual crop yield available. Step 3 – LAI preprocessing (spatial averaging, temporal interpolation/extrapolation to fill the time series gaps, smoothing time series dynamics, temporal averaging). In order to accomplish the process of filling the gaps for the LAI time series, the regular time series dynamics of LAI with a 1-day interval were created using 4 methods: linear interpolation, spline interpolation, LOCF (Last Observation Carried Forward) and ARIMA (AutoRegressive Integrated Moving Average). The time series smoothing process have been accomplish using the local polynomial regression (LOESS) function with different degrees of smoothing. The LAI dynamics preprocessing step did not strongly affect the improvement of the correlation coefficients. Thus, the smoothing process for the time series LAI dynamics at the 0.1 degree of smoothing according to the LOCF and ARIMA gap-filling methods of improved correlation coefficients by 0.01 on average. Step 4 – actual yield values were related to preprocessed satellite-based LAI (correlation of actual yields and LAI). A strong relationship was not indicated (with averaged by vegetation periods correlation coefficient of 0.4 for maize, 0.52 – soy, 0.39 – sunflower, 0.86 – winter barley, 0.54 – winter rapeseed and 0.5 – winter wheat). Since the reliability of obtained correlation coefficients also depends on how many observed data points were in the sample, the hypothesis test of the "significance of the correlation coefficient" has been performed and shows the significance level of p &lt; 0.05 for all crops except winter barley (there is insufficient evidence to conclude that high correlation coefficient of 0.86 for this crop is significant). The average correlation coefficient for all crops is about 0.5 (p &lt; 0.05) which is considered low/moderate. Thus, an attempt to create a linear crop yield prediction model using only Leaf Area Index (LAI) derived from Sentinel-2 will not be effective (based on the cases considered).

Durability of serologic responses to inactivated hepatitis A virus vaccination among people living with HIV following acute hepatitis A outbreak: a 5-year follow-up study

ABSTRACT Serologic responses to hepatitis A virus (HAV) vaccination may wane among immunocompromised populations. To evaluate the long-term seroresponses to 2-dose HAV vaccination, we retrospectively included people living with HIV (PLWH) who had achieved seroconversion within 12 months after vaccination at a university hospital during an outbreak of acute hepatitis A between 2015 and 2017. PLWH included in the study received either Havrix or Vaqta. The seroresponses were evaluated 60 months after the second dose of vaccination and estimated by the intention-to-treat (ITT) with last-observation-carried-forward (LOCF) and per-protocol (PP) analyses. Overall, 986 PLWH (median age, 34 years and CD4 count, 587 cells/µL) were included. The rates of PLWH with persistent seroprotection at month 60 of vaccination were 90.7% (894/986) and 97.4% (748/768) in the ITT with LOCF and PP analyses, respectively. PLWH with persistent seroprotection had achieved higher peak anti-HAV IgG titers after vaccination and had a slower decline in antibody levels compared with those with seroreversion. In the multivariable analysis, seroreversion at month 60 was associated with a higher body-mass index (per 1-kg/m2 increase, AOR, 1.10; 95% CI, 1.04-1.17), lowest-ever CD4 count (per 10-cell/µL increase, AOR 0.98; 95% CI, 0.97-1.00), plasma HIV RNA <200 copies/ml at vaccination (AOR, 0.28; 95% CI, 0.14-0.59), and having received Vaqta as the first dose of HAV vaccination (AOR, 0.44; 95% CI, 0.27-0.70). The seroprotection against HAV remained high in the long-term follow-up among PLWH on antiretroviral therapy after 2-dose HAV vaccination. Regular monitoring of seroresponses and timely administration of HAV vaccines are warranted to maintain seroprotection.

395 Assessing imputation methods with the lebrikizumab clinical trial program

Abstract Missing data occur in clinical trials and have the potential to lead to biased results. Subsequently, the analytical methods for handling the missing data are important to evaluate. In atopic dermatitis (AD) trials, missing data are not handled consistently across studies. Lebrikizumab is a monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. In ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), two randomized, double-blinded, placebo-controlled Phase 3 trials evaluating the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe AD, a combined nonresponder/multiple imputation (NRI/MI) approach, was applied on the primary and key secondary endpoints. This study aims to illustrate the NRI/MI method using individual patient examples and to present Week 16 study results from ADvocate1 and ADvocate2 with NRI/MI and single imputation methods, NRI and last-observation carried forward (LOCF). In the combined NRI/MI method, data from patients after initiating rescue medication or discontinuing treatment due to lack of efficacy were imputed with NRI, and missing data for other reasons were imputed with MI, which uses a statistical model based on all available patient data to impute missing values. The MI method considers each patient’s trajectory and leverages information from other patients within the same treatment arm to impute the missing data. With NRI alone, the cause leading to the missing data is not considered and missing data for any reason are imputed as nonresponse. With LOCF, missing data are replaced with the last available measurement; LOCF assumes that the patient response would be stable over time and does not consider the reason for missing data. We determined the amount of missing data in ADvocate1 and ADvocate2, and we assessed patient-level imputed IGA scores to illustrate NRI/MI, NRI and LOCF. With these missing data handling methods, we evaluated the percentage of patients achieving the co-primary endpoints of ADvocate1 and ADvocate2: an Investigator’s Global Assessment score of 0 or 1 [IGA (0,1); clear or almost clear] with ≥2-point improvement from baseline or 75% improvement in Eczema Area and Severity Index (EASI 75) at Week 16. With the NRI/MI method, most missing data at Week 16 were imputed with NRI (ADvocate1: 73%, ADvocate2: 82%) compared with MI (ADvocate1: 27%, ADvocate2: 18%). Example imputed IGA scores based on patient-level data will be presented to demonstrate the missing data handling methods. For NRI/MI, NRI and LOCF, respectively, the percentage of patients achieving IGA 0,1 were 12.7%, 11.3% and 12.8% for placebo in ADvocate1 and 10.8%, 9.6% and 11.0% for placebo in ADvocate2; 43.1%, 41.0% and 42.4% for lebrikizumab in ADvocate1 and 33.2%, 31.3% and 33.5% for lebrikizumab in ADvocate2. The percentage of patients achieving EASI 75 were 16.2%, 14.2% and 16.3% for placebo in ADvocate1 and 18.1%, 17.1% and 19.2% for placebo in ADvocate2; 58.8%, 56.5% and 60.1% for lebrikizumab in ADvocate1 and 52.1%, 50.2% and 55.5% for lebrikizumab in ADvocate2. When using the NRI/MI method, we determined most missing data in ADvocate1 and ADvocate2 were handled with NRI. This analysis suggests that the NRI/MI method may provide a realistic estimation of response rate in ADvocate1 and ADvocate2.

New approaches to missing biomedical data recovery for machine learning

Missing data is a common problem for medical data sets, especially large ones. This issue is of major importance since it can influence the analysis and further use of the data, e.g., for machine learning purposes. There are various methods for recovering missing data.One such method is to remove observations with missing values, but this is not very usefulgiven the limited amount of data available. Another commonly used approach is the LastObservation Carried Forward (LOCF). But most such methods are not universal and may needadjustments to the data set at hand. This article describes the possibility of solving thisproblem in the case of multimodal time series of biomedical data coming from patients withsepsis. It describes and compares three approaches tailored to a sepsis dataset, which isanalyzed and finally used to build a sepsis prediction system based on clinical data routinelyrecorded in an intensive care unit.

Matching-adjusted indirect comparison (MAIC) of deucravacitinib versus adalimumab for the treatment of patients with moderate to severe plaque psoriasis over 2 years

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, is approved in the US for the treatment of adults with moderate to severe plaque psoriasis (PsO). A previous indirect treatment study showed comparable efficacy between deucravacitinib and first-generation biologics at week 52. The objective of this study was to compare the long-term efficacy of deucravacitinib to that of adalimumab based on long-term extension (LTE) trials, after adjusting for differences in patient characteristics at baseline. &#x0D; Methods: Open-label LTE trials that were feasible for indirect treatment comparison were identified for each treatment (deucravacitinib: POETYK PSO-LTE [NCT04036435]; adalimumab: REVEAL extension [NCT00195676]). Patients who were initially randomized to placebo and switched to continuous active treatment after Week 16 were selected as cohorts due to the comparability of study design and outcomes of interest. Patients with prior adalimumab were excluded from the deucravacitinib cohort. The primary outcome was PASI 75 at Week 112 since randomization and secondary outcomes were PASI 75 at Week 52 and PASI 90 at Weeks 52 and 112; missing PASI data was imputed using the last observation carried forward (LOCF) method. Matching-adjusted indirect comparison was conducted where individual patient-level data from POETYK PSO-LTE were reweighted to achieve balance with the summary baseline characteristics in the REVEAL extension trial: age, sex, race, weight, duration of psoriasis, body surface area affected, prior treatment history, baseline PASI and placebo PASI 75/90 responses at Week 16. Sensitivity analyses explored the effect of adjusting for prior treatment or not as well as history of psoriatic arthritis and patient's overall severity of disease.&#x0D; Results: Patients from POETYK PSO-LTE (N=329) were on average older, with lower weight, but with more prior systemic treatment exposure, higher baseline PASI score and higher placebo PASI 75/90 response at Week 16 than those in REVEAL (N=345). After adjustment, baseline differences between the two trials were mitigated. Results showed adjusted PASI 75 and PASI 90 response rate at Week 112 since randomization was higher for patients who were treated with deucravacitinib compared to those who were treated with adalimumab after 16 weeks of placebo: PASI 75= 67.2% vs 54% (mean difference [95% CI]= 13.2% [4, 22.5]); PASI 90= 41.3% vs 34% (7.3% [-2, 16.7]). Adjusted PASI 75 and PASI 90 at Week 52 were similar between the two cohorts. Results from the sensitivity analyses confirmed the base case findings.&#x0D; Conclusion: This indirect comparison analysis suggests that patients with moderate to severe plaque psoriasis with continuous active treatment on deucravacitinib had better long-term response than adalimumab and highlights the therapeutic role of deucravacitinib.

Switching OnabotulinumtoxinA to Monoclonal Anti-CGRP Antibodies in Drug-Resistant Chronic Migraine.

OnabotulinumtoxinA (BTX-A) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (anti-CGRP mAbs) are approved drugs for chronic migraine (CM), a difficult-to-treat condition. Optimization of CM patient management by choosing the best options and determining appropriate time for switching or adding concomitant treatments are highly needed. Evaluate clinical response to anti-CGRP mAbs in patients who switched from BTX-A due to ineffectiveness defined by different cut-offs and assess the retention rate, effectiveness, and safety of both drugs within the first 9 months of treatment. A monocentric, cohort study, enrolling patients withCM, resistant to several preventive treatments, first treated with BTX-A and then with anti-CGRP mAbs with two observational phases of 9 months preceded by respective baseline. First, the retention rate and effectiveness of both treatments were measured in all patients. A second analysis assessed effectiveness in patients stratified according to <50 or <30% response rate to BTX-A. The absolute change from baseline in monthly headache days (MHDs), response rate, analgesic use, and persistence in medication overuse (MO) at 3, 6, and 9 months of treatment were recorded. Last observation carried forward (LOCF)analyses, including all patients and assuming no further changes after discontinuation, were performed for all outcomes. Of the 78 enrolled patients (80.8% female, and 89.7% with MO at baseline), 32 (41.0%) received erenumab, 32 (41.0%) galcanezumab, and 14 (18.0%) fremanezumab. Retention rate was 62.2 and 91.0% for BTX-A and 76.9 and 96.2%, for anti-CGRP mAbs at 3 and 9 months of treatment, respectively. At 9 months of treatment, 22.4% of BTX-A patients and 65.0% of anti-CGRP mAbs patients achieved a ≥50% response rate. Anti-CGRP mAbs reduced MHDs, AMN, and AMDs, and decreased the number of MO patients at 9 months. In patients stratified according to <50 or <30% response rate to BTX-A, response rate (≥50% response at 9 months) to anti-CGRP was 62.9 and 57.9%, respectively. LOCF analyses confirmed these findings. No serious adverse events (AEs) were recorded and only two patients discontinued treatment due to AEs. Difficult-to-treat CM patients who discontinued BTX-A and received anti-CGRP mAbs showed a substantial clinical improvement in migraine-related outcomes. Switching to an anti-CGRP mAb appears to be a viable option in patients with insufficient response after the first 2 cycles with BTX-A. The appropriate variables, cut-offs, and timing to define ineffectiveness and the best time to switch or combine therapies for difficult-to-treat CM need to be investigated further.

Comparing the performance of eight imputation methods for propensity score matching in missing data problem

Propensity score (PS) is a popular method to control for covariates in observational studies. A challenge in PS analyses is missing values in covariates. This study aims to investigate how different imputation methods of handling missing values of covariates in a PS analysis can affect average treatment on the treated (ATT) estimates. In this study, missing data imputation methods were evaluated using different data sets, whose covariates were low, medium, and high (r=0.10, 0.50, 0.85) correlated with each other, for n=200 units and 1000 times running simulation. Missing data structures were created according to the missing at random (MAR) mechanism and different missing rates. Different datasets were obtained after having imputed the missing values separately by eight imputation methods including mean, median, mode, hot deck, last observation carried forward (LOCF), next observation carried backward (NOCB), regression and predictive mean matching (PMM). Then the PS nearest neighbor matching was implemented and ATT scores were obtained using the imputed data sets. The predictive performance of imputation methods was compared according to ATT scores by hierarchical cluster analysis with Euclidean distance complete linkage. ATT scores of regression and PMM methods were closer to each other and these methods showed the best predictive performance. Additionally, when there were larger amounts of missing data, the PMM was the best method of choice. Ignoring missing values on covariates for PS analyses causes information loss significantly and this information loss becomes greater as the rate of missing data increases. PS analyses might be biased if missing data on covariates are also ignored. To prevent this information loss and bias, PS analyses should be performed after solving the problem of missing data with MAR mechanism on covariates by regression and PMM methods, which showed statistical superiority compared to other methods in this study.

A Pre-Clinical Study of Sub-Anesthetic Ketamine as Remedy in 5-Fluorouracil-Induced Cachexia Model.

Around 0.5-1% of the world population is suffering from cachexia. In particular, cancer patients under cancer radio-chemotherapy have a high prevalence of cachexia, especially during the end stages of therapeutic treatment. Clinically, chemotherapeutic 5-fluorouracil (5-Fu) treatment often leads to the development of adverse effects, such as leukopenia, immune dysfunction, anorexia, muscle wasting, etc., and 5-Fu also tends to exacerbate the occurrence of cancer cachexia. Currently, there are very limited drug choices when seeking to revive cachexia patient's health quality while enduring a full therapeutic regimen as part of advanced cancer therapy. The present study employed chemotherapeutic drug 5-Fu-induced cachexia-like conditions in Balb/c mice. After 8 days of 5-Fu treatment, mice had begun to show cachexia-like symptoms such as weight loss and reduced food intake. After one day of washing out, the cachexia animals received a single dose of either saline solution as a mock dose or a low dose (15 mg/kg BW) or high dose (30 mg/kg BW) of ketamine at day 10. For the following 7 days, food intake, body weight, and mortality were monitored. Data were analyzed with the LOCF (last observation carried forward) method. Improved survival rates were obtained in ketamine groups. Ketamine administration at the high dose of 30 mg/kg BW demonstrated effectively diminished weight loss due to cachexia, and also successfully improved overall survival. The current study demonstrates that a sub-anesthetic level of ketamine administration supports overall beneficial outcomes in 5-Fu-induced cachexia and outlook as a potential clinical remedy.

522. Significant Improvement in Health-Related Quality of Life (HRQL) with RBX2660: Results from a Phase 3 Randomized, Placebo-Controlled Trial in Recurrent Clostridioides Difficile Infection (PUNCH CD3)

Abstract Background Recurrence of Clostridioides difficile infection (rCDI) is common - up to 35% of patients may recur. RBX2660 is a microbiota restoration therapy to reduce rCDI. Here we report 8 weeks HRQL results using the Clostridioides difficile Health-related Quality-of-Life Questionnaire (Cdiff32), a disease-specific instrument, from PUNCH CD3 (a randomized, double-blinded, placebo-controlled RBX2660 Phase 3 trial, NCT03244644). Methods Cdiff32 includes three domains (physical, mental, and social) and a total score (all range from 0 to 100 [100 best possible]). Changes in Cdiff32 from baseline to week 8 were compared between RBX2660 and placebo (PBO) using unadjusted and adjusted analyses controlling for baseline score, demographic and disease characteristics. Per trial protocol, missing data were imputed via last observation carried forward (LOCF); as-observed data were also analyzed. Patients experiencing recurrence after blinded treatment received open-label RBX2660 per physician discretion; these participants were excluded unless, per LOCF, data were available from the blinded period for week 8 use. Results A total of 206 patients (140 RBX2660, 66 PBO) were included, with similar age (mean±SD) 61.1±16.9 yrs (RBX2660) and 57.3±16.4 yrs (PBO) and baseline Cdiff32 scores. More than half of the patients had multiple comorbidities. Cdiff32 scores improved significantly from baseline to weeks 1, 4, and 8 for both arms, with greater improvements for RBX2660 through week 8 (Figs. 1 &amp; 2). At week 8, statistical differences were found for mental domain (unadjusted: 8.01±3.64; adjusted: 7.07, 95% confidence interval: [0.28, 13.86], both P&amp;lt; 0.05) and total score (adjusted: 6.11, [0.14, 12.08], P&amp;lt; 0.05), all favoring RBX2660. Results were similar for the as-observed analyses, with the adjusted physical domain also statistically favoring RBX2660. Conclusion Most patients in this study reported improved HRQL. Improvements were observed in both arms, but RBX2660-treated patients had more robust and sustained improvements with statistically significant differences in Cdiff32 scores. This study suggests that microbiome restoration therapy might positively affect HRQL; future research may link these improvements directly with microbiota changes. Disclosures Paul Feuerstadt, MD, FACG, AGAF, Ferring/Rebiotix Pharmaceuticals: Advisor/Consultant|Ferring/Rebiotix Pharmaceuticals: Grant/Research Support|Merck and Co: Advisor/Consultant|SERES Therapeutics: Advisor/Consultant|SERES Therapeutics: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant Erik R. Dubberke, MD, MSPH, Abbott: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Grant/Research Support|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Seres: Advisor/Consultant|Summit: Advisor/Consultant|Synthetic Biologics: Grant/Research Support Amy Guo, PhD, Ferring Pharmaceuticals: Employee Adam Harvey, PhD, Ferring Pharmaceuticals: Employment Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Viviana García-Horton, PhD, Analysis Group, Inc.: Employee of Analysis Group, Inc., which received consulting fees from Ferring for the conduct of this study. Mirko Fillbrunn, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Glenn S. Tillotson, PhD, Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Spero Pharmaceuticals: Advisor/Consultant|Taro Pharmaceuticals: Advisor/Consultant Lindy Bancke, PharmD, Rebiotix, a Ferring Company: Employee Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support.

Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA).

The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known. In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated. Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose. Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

Safety and Efficacy of Fedratinib in Patients with Primary (P), Post-Polycythemia Vera (Post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) Previously Treated with Ruxolitinib: Primary Analysis of the FREEDOM Trial

Introduction: Fedratinib is an oral selective Janus kinase (JAK) 2 inhibitor approved for treatment (tx) of patients (pts) with MF, including those previously treated with ruxolitinib (RUX). In the single-arm phase 2 JAKARTA2 trial (NCT01523171), fedratinib 400 mg once daily improved spleen volume and MF symptom burden in pts with MF resistant/intolerant to prior RUX (Harrison et al. Am J Hematol 2020). Long-term data are lacking due to early termination. The ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518) further evaluates the safety and efficacy of fedratinib in pts with MF previously treated with RUX and includes proactive strategies to mitigate gastrointestinal (GI) adverse events (AEs), thiamine level decreases, and potential encephalopathy (including Wernicke's encephalopathy [WE]). Methods: Eligible pts aged ≥ 18 years with PMF, post-PV MF, or post-ET MF with ≥ 3 months prior tx with RUX were enrolled in the study. Pts were required to have Dynamic International Prognostic Scoring System (DIPSS) intermediate- or high-risk MF, Eastern Cooperative Oncology Group performance status ≤ 2 and baseline platelet count ≥ 50 x 109/L. Pts were treated with fedratinib 400 mg once daily in continuous 28-day cycles until lack of efficacy, intolerance, or disease progression, and followed for 12 months after end of tx (EOT). AE mitigation strategies included prophylactic use of antiemetics and symptomatic use of antidiarrheals, thiamine supplementation, surveillance for encephalopathy, and adjusting preferred time of day for fedratinib administration. Results: Thirty-eight pts were enrolled and treated. Due to accrual challenges during the COVID-19 pandemic, the study was capped early, and data lost statistical power due to reduced sample size. At the database cutoff (November 29, 2021), median tx duration was 38 weeks, 13 pts had tx ongoing, and 25 pts had discontinued tx. At baseline, median age was 68.5 years, 23 (60.5%) pts had a diagnosis of PMF, 9 (23.7%) post-PV MF, and 6 (15.8%) post-ET MF, with DIPSS assessment of intermediate-1 risk in 13 (34.2%) pts, intermediate-2 risk in 18 (47.4%) pts, and high risk in 7 (18.4%) pts. Baseline median spleen volume was 1831.6 mL. A total of 9/35 (25.7%) evaluable pts met the primary endpoint of ≥ 35% spleen volume reduction (SVR) by magnetic resonance imaging/computed tomography at end of cycle (EOC) 6; 13 (37.1%) pts had ≥ 35% SVR when missing EOC6 assessments were imputed with last observation carried forward (LOCF) method (Table). In addition, 9 (25.7%) pts achieved a ≥ 35% SVR before or after EOC6, for a best overall response of ≥ 35% SVR in 22 (62.9%) pts up to end of tx. With a ≥ 25% SVR threshold, 24 (68.6%) pts had a response with LOCF at EOC6. Of ≥ 35% SVR responders, 19/22 (86.4%) maintained durable response at data cutoff (Figure). In secondary endpoints, 21/36 (58.3%) and 16/36 (44.4%) evaluable pts showed ≥ 50% reduction in total symptom score (TSS) at EOC3 and EOC6, respectively. A total of 34/38 (89.5%) pts had 1 tx-emergent AE related to study medication; 3 (7.9%) were serious AEs. Anemia and thrombocytopenia were reported in 23 (60.5%) and 13 (34.2%) pts, respectively. GI AEs were reported in 34 (89.5%) pts, with nausea, vomiting, and diarrhea reported in 15 (39.5%), 7 (18.4%), and 15 (39.5%) pts, respectively. Most GI AEs were grade 1/2 and occurred during cycle 1, and decreased in the subsequent cycles. Grade 1/2 decreases in thiamine levels were reported in 6 pts after initial tx; all instances were treated and resolved at next assessment. No pts required tx discontinuation due to low thiamine levels. There were no cases of WE reported. There were 2 deaths during tx and 7 during follow-up; none were related to study medication. Conclusions: Clinically relevant and durable spleen and symptom responses were observed in FREEDOM study participants, with a majority of responders showing durable SVR at data cutoff. This supports the use of fedratinib in pts with MF previously treated with RUX. One limitation of the study was small pt sample size. In this first fedratinib study proactively assessing a GI mitigation strategy and thiamine monitoring, results showed GI AEs were easily mitigated and no WE was reported. Study support: This study was supported by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Locf imputation for Astra Agro Lestari Tbk. (Indonesia) and Anadolu Group (Turkey) stock

This study aims to apply time series graphs on stock of Astra Agro Lestari Tbk. and Anadolu Group with last observation carried forward (LOCF) imputation. The imputation was used because the data for the two companies had missing values on several dates. Missing value contained in the company Astra Agro Lestari Tbk. in Indonesia more than Anadolu Group in Turkey because of the difference in the number of holidays. Original data and data with complete dates are combined to form new data where missing values are seen on certain dates. The function used in the R program to form the graph is xts. However, the Date variable has a character class so it needs to be changed to the Date class. The xts function will error if the class is not changed. The modification also causes the horizontal axis of the graph to be replaced by the date. Based on the chart of stock prices and transaction volume of stock of the company Astra Agro Lestari Tbk. and Anadolu Group experienced increases, decreases, and is constant on several dates.&#x0D; Keywords: missing value, R programming, stock prices, transaction volume. MSC2020: 62M10, 91B84, 62-04