Analysis Of Clinical Trial Data Research Articles

A multistate model of health transitions in older people: a secondary analysis of ASPREE clinical trial data

SummaryBackgroundUnderstanding the nature of transitions from a healthy state to chronic diseases and death is important for planning health-care system requirements and interventions. We aimed to quantify the trajectories of disease and disability in a population of healthy older people.MethodsWe conducted a secondary analysis of data from the ASPREE trial, which was done in 50 sites in Australia and the USA and recruited community-dwelling, healthy individuals who were aged 70 years or older (≥65 years for Black and Hispanic people in the USA) between March 10, 2010, and Dec 24, 2014. Participants were followed up with annual face-to-face visits, biennial assessments of cognitive function, and biannual visits for physical function until death or June 12, 2017, whichever occurred first. We used multistate models to examine transitions from a healthy state to first intermediate disease events (ie, cancer events, stroke events, cardiac events, and physical disability or dementia) and, ultimately, to death. We also examined the effects of age and sex on transition rates using Cox proportional hazards regression models.Findings19 114 participants with a median age of 74·0 years (IQR 71·6–77·7) were included in our analyses. During a median follow-up of 4·7 years (IQR 3·6–5·7), 1933 (10·1%) of 19 114 participants had an incident cancer event, 487 (2·5%) had an incident cardiac event, 398 (2·1%) had an incident stroke event, 924 (4·8%) developed persistent physical disability or dementia, and 1052 (5·5%) died. 15 398 (80·6%) individuals did not have any of these events during follow-up. The highest proportion of deaths followed incident cancer (501 [47·6%] of 1052) and 129 (12·3%) participants transitioned from disability or dementia to death. Among 12 postulated transitions, transitions from the intermediate states to death had much higher rates than transitions from a healthy state to death. The progression rates to death were 158 events per 1000 person-years (95% CI 144–172) from cancer, 112 events per 1000 person-years (86–145) from stroke, 88 events per 1000 person-years (68–111) from cardiac disease, 69 events per 1000 person-years (58–82) from disability or dementia, and four events per 1000 person-years (4–5) from a healthy state. Age was significantly associated with an accelerated rate for most transitions. Male sex (vs female sex) was significantly associated with an accelerate rate for five of 12 transitions.InterpretationWe describe a multistate model in a healthy older population in whom the most common transition was from a healthy state to cancer. Our findings provide unique insights into the frequency of events, their transition rates, and the impact of age and sex. These results have implications for preventive health interventions and planning for appropriate levels of residential care in healthy ageing populations.FundingThe National Institutes of Health.

Drug repositioning trends in rare and intractable diseases

Drug repositioning (DR) is an effective way for developing drugs for rare and intractable diseases (RIDs). Preparation of the ontology is essential for drug development in RIDs, in which disease names have been inconsistently used worldwide. Ontology-based analysis of clinical trial data revealed that DR occurs actively in RIDs. Drugs and their target genes are keys to explore repositionable drugs, because shared target genes between diseases indicate a common mechanism of drug action. This approach visualizes a DR landscape that facilitates drug development. Here, we review the current situation of ontology in RIDs, the trends in drug development, and an efficient strategy for DR based on drug target gene information.

OP39 Shorter disease duration is associated with better outcomes in patients with moderately to severely active Crohn’s Disease treated with risankizumab: Results from the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies

BackgroundAn association between shorter disease duration and improved clinical efficacy has been shown in post hoc analyses of clinical trial data with biological therapies in Crohn’s disease (CD). The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy have been recently reported. Here, the efficacy of RZB stratified by baseline CD duration is reported.MethodsIn ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB IV induction were re-randomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, withdrawal). For this post-hoc analysis, patient subgroups were stratified by years of CD duration at baseline (< 2, 2–5, > 5–10, and > 10 years). Induction analyses focused on patients who received RZB 600 mg IV or PBO for 12 weeks. As all patients who entered maintenance responded to RZB IV induction, maintenance analyses were limited to those patients who responded to induction and then received RZB 360 mg SC for 52 weeks. Clinical and endoscopic outcomes were evaluated using nonresponder imputation incorporating multiple imputation to handle missing data due to impact of the COVID-19 pandemic. Safety was assessed throughout the studies.ResultsThe induction and maintenance analyses included 527 patients who received RZB 600 mg IV and 141 patients who received RZB 360 mg SC, respectively. At the end of induction (week 12), patients with CD duration of < 2 years achieved higher rates of endoscopic outcomes with IV RZB induction vs patients with longer durations of disease (Figure 1), and regardless of baseline CD duration, greater proportions of RZB-treated patients achieved clinical remission (defined by stool frequency and abdominal pain), endoscopic response, endoscopic remission, and ulcer-free endoscopy vs PBO (P ≤ .05). Clinical remission rates at week 12 were numerically higher in patients with CD duration of < 5 years vs > 5 years (Figure 1). Similar results for improved clinical and endoscopic outcomes associated with shorter disease duration were observed at week 52 with RZB 360 mg SC maintenance treatment (Figure 2). RZB was well tolerated with lower rates of serious adverse events and serious infections vs PBO in induction, across CD duration subgroups. ConclusionRZB induction and maintenance therapy was effective and well tolerated with a safety profile generally similar across CD duration subgroups. Achievement of clinical and endoscopic endpoints were higher in patients with shorter duration of CD, suggesting that earlier introduction of RZB therapy may lead to improved outcomes.

A Patient-Centered Evaluation of Meaningful Change on the 32-Item Motor Function Measure in Spinal Muscular Atrophy Using Qualitative and Quantitative Data.

The 32-item Motor Function Measure (MFM32) is an assessment of motor function used to evaluate fine and gross motor ability in patients with neuromuscular disorders, including spinal muscular atrophy (SMA). Reliability and validity of the MFM32 have been documented in individuals with SMA. Through semi-structured qualitative interviews (N = 40) and an online survey in eight countries (N = 217) with individuals with Types 2 and 3 SMA aged 2–59 years old and caregivers, the meaning of changes on a patient-friendly version of the MFM32 was explored. In an independent analysis of clinical trial data, anchor- and distribution-based analyses were conducted in a sample of individuals with Type 2 and non-ambulant Type 3 SMA to estimate patient-centered quantitative MFM32 meaningful change thresholds. The results from this study demonstrate that, based on patient and caregiver insights, maintaining functional ability as assessed by a patient-friendly version of the MFM32 is an important outcome. Quantitative analyses using multiple anchors (median age range of 5–8 years old across anchor groups) indicated that an ~3-point improvement in MFM32 total score represents meaningful change at the individual patient level. Overall, the qualitative and quantitative findings from this study support the importance of examining a range of meaningful change thresholds on the MFM32 including ≥0 points change reflecting stabilization or improvement and ≥3 points change reflecting a higher threshold of improvement. Future research is needed to explore quantitative differences in meaningful change on the MFM32 based on age and functional subgroups.

Positioning Infliximab and Vedolizumab in the Treatment of Moderate-to-Severe Ulcerative Colitis

Positioning Infliximab and Vedolizumab in the Treatment of Moderate-to-Severe Ulcerative Colitis

Inference in response-adaptive clinical trials when the enrolled population varies over time.

A common assumption of data analysis in clinical trials is that the patient population, as well as treatment effects, do not vary during the course of the study. However, when trials enroll patients over several years, this hypothesis may be violated. Ignoring variations of the outcome distributions over time, under the control and experimental treatments, can lead to biased treatment effect estimates and poor control of false positive results. We propose and compare two procedures that account for possible variations of the outcome distributions over time, to correct treatment effect estimates, and to control type-I error rates. The first procedure models trends of patient outcomes with splines. The second leverages conditional inference principles, which have been introduced to analyze randomized trials when patient prognostic profiles are unbalanced across arms. These two procedures are applicable in response-adaptive clinical trials. We illustrate the consequences of trends in the outcome distributions in response-adaptive designs and in platform trials, and investigate the proposed methods in the analysis of a glioblastomastudy.

Patterns of Hematologic Function and Cytokine Release Syndrome Severity in ALL Patients Receiving CAR-T and TCR-T Therapies Using Pooled Clinical Trial Data

Background:Despite the potential for durable disease remission seen with Chimeric Antigen Receptor (CAR-T) and T-Cell Receptor (TCR-T) therapies, their use is limited by the potential for acute toxicity from Cytokine-Release Syndrome (CRS).Across all grades, CRS has seen rates as high as 100% in some trials of patients receiving CAR-T, and up to 15% receiving TCR-T. Prior research indicates an association of hematologic abnormalities with CRS. Due to smaller average trial size and limited adoption, to date, of CAR and TCR therapies, there have been no large-scale studies to date exploring these associations with CRS severity in a wide range of patients across treatment types. This study sought to address these evidence gaps using retrospective analysis of pooled clinical trial data in Acute Lymphocytic Leukemia (ALL), using, to our knowledge, the single largest data repository of of CAR-T and TCR-T clinical patient data, with high resolution measurements across a spectrum of clinical domains.Methods:Eligible Phase I, II and III completed clinical trials in Acute Lymphocytic Leukemia (ALL), with patients receiving either CAR-T or TCR-T, were identified from the Medidata Enterprise Data Store, which comprises over 22,000 historical clinical trials, for de-identified retrospective aggregate analyses. Baseline characteristics, including demographics, medical history, prior treatment regimens were assessed and stratified by treatment type. Pre-trial history of hematologic conditions, such as neutropenia and anemia, were also assessed. Using Common Terminology Criteria for Adverse Events (CTCAE) 4.03, patients were assigned to categories of any CRS, mild CRS (grade 1) and moderate-to-severe CRS (2+). Hematologic function was assessed at baseline through first exposure to treatment, including counts of erythrocytes, neutrophils, eosinophils and basophils. Baseline marrow blast cell percentage was assessed as a marker of tumor burden. Univariate analyses of associations between pre-treatment baseline variables and CRS were conducted using Wilcoxon signed rank tests.Results:The pooled CT data contained 1,410 ALL patients, of whom over 60% were 18 year of age or greater. Baseline blood chemistries indicated 21% with anemia, 12% with thrombocytopenia, 6% neutropenic and 5.3% with elevated LDH. Although CAR-T patients accounted for 14.9% of the cohort, 47% of CRS events observed were associated with CAR-T treatment. In line with expectations from prior literature, factors associated with moderate-to-severe CRS included prior history of anemia, reduced platelet levels, low neutrophil counts, and delayed neutrophil recovery. Nearly all cases of moderate-to-severe CRS occurred in subjects exhibiting both low neutrophil and low platelet counts (Figure 1). Similar associations were seen in patients with pretreatment history of anemia (Figure 2). Consistent with literature on tumor burden and CRS, patients without CRS tended to have lower marrow blast percentages. Lymphocyte levels at baseline were far lower in patients receiving CAR-T therapy, with slower recovery than in patients receiving TCR-T. While consistent with CAR-T pre-treatment lymphodepletion, this finding was noteworthy given the association of neutropenia with CRS.Conclusions:Overall findings suggest patterns of routine hematologic function at baseline can potentially be used to assess risk of moderate-to-severe CRS in patients receiving CAR-T and TCR-T agents. The association with these markers could also suggest a mechanism of CRS as a function of tumor cell concentration, modified by the strength and presence of innate immunity mechanisms such as granulocytes, and potentially mediated by intermediates such as macrophages, in line with emerging literature., Further analysis may facilitate development of predictive algorithms to identify patients at greater risk for severe CRS prior to as well as shortly after treatment. This has implications for enhancing supportive care for patients receiving CAR- and TCR therapies. Additionally, a data-driven stratification of patients by risk of CRS will allow improved utilization and management of care resources. [Display omitted] DisclosuresAgarwal: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Socolov: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Buderi: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Rusli: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Bouzit: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Talwai: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Itzkovich: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Galaznik: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment, Current equity holder in publicly-traded company. Aptekar: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment.

Symmetric CTA Collaterals Identify Patients with Slow-progressing Stroke Likely to Benefit from Late Thrombectomy.

Background Understanding ischemic core growth rate (IGR) is key in identifying patients with slow-progressing large vessel occlusion (LVO) stroke who may benefit from delayed endovascular thrombectomy (EVT). Purpose To evaluate whether symmetric collateral pattern at CT angiography (CTA) can help to identify patients with low IGR and small 24-hour diffusion-weighted MRI ischemic core volume in patients with LVO not treated with reperfusion therapies. Materials and Methods In this secondary analysis of clinical trial data from before EVT became standard of care from January 2007 to June 2009, patients with anterior proximal LVO not treated with reperfusion therapies were evaluated. All patients underwent admission CTA and at least three MRI examinations at four time points over 48 hours. Arterial phase CTA collaterals at presentation were categorized as symmetric, malignant, or other. Diffusion-weighted MRI ischemic core volume and IGR at multiple time points were determined. The IGR at presentation was defined as follows: (ischemic core volume in cubic centimeters)/(time since stroke symptom onset in hours). Multivariable analyses and receiver operator characteristic analyses were used. Results This study evaluated 31 patients (median age, 71 years; interquartile range, 61-81 years; 19 men) with median National Institutes of Health Stroke Scale (NIHSS) score of 13. Collaterals were symmetric (45%; 14 of 31), malignant (13%; four of 31), or other (42%; 13 of 31). Median ischemic core volume was different between collateral patterns at all time points. Presentation was as follows: symmetric, 16 cm3; other, 69 cm3; and malignant, 104 cm3 (P < .001). At 24 hours, median ischemic core volumes were as follows: symmetric, 28 cm3; other, 156 cm3; and malignant, 176 cm3 (P < .001). Median IGR was also different, and most pronounced at presentation: symmetric, 4 cm3 per hour; other, 17 cm3 per hour; and malignant, 20 cm3 per hour (P < .001). After multivariable adjustment, independent determinants of higher presentation IGR included only higher NIHSS (parameter estimate [β = 0.20; 95% CI: 0.05, 0.36; P = .008) and worse collaterals (β = -2.90; 95% CI: -4.31, -1.50; P < .001). The only independent determinant of 24-hour IGR was worse collaterals (β = -2.03; 95% CI: -3.28, -0.78; P = .001). Symmetric collaterals had sensitivity of 87% (13 of 15) and specificity of 94% (15 of 16) for 24-hour ischemic core volume less than 50 cm3 (area under the receiver operating characteristic curve, 0.92; 95% CI: 0.81, 1.00; P < .001). Conclusion In patients with large vessel occlusion not treated with reperfusion therapies, symmetric collateral pattern at CT angiography was common and highly specific for low ischemic core growth rate and small 24-hour ischemic core volume as assessed at diffusion-weighted MRI. After further outcome studies, collateral status at presentation may prove useful in triage for endovascular thrombectomy, especially when MRI and CT perfusion are unavailable. Clinical trial registration no. NCT00414726. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Messina in this issue.

Musculoskeletal Features in Adults With X-linked Hypophosphatemia: An Analysis of Clinical Trial and Survey Data.

ContextPatients with X-linked hypophosphatemia (XLH) experience multiple musculoskeletal manifestations throughout adulthood.ObjectiveTo describe the burden of musculoskeletal features and associated surgeries across the lifespan of adults with XLH.MethodsThree groups of adults were analyzed: subjects of a clinical trial, participants in an online survey, and a subgroup of the online survey participants considered comparable to the clinical trial subjects (according to Brief Pain Inventory worst pain scores of ≥ 4). In each group, the adults were categorized by age: 18-29, 30-39, 40-49, 50-59, and ≥ 60 years. Rates of 5 prespecified musculoskeletal features and associated surgeries were investigated across these age bands for the 3 groups.ResultsData from 336 adults were analyzed. In all 3 groups, 43% to 47% had a history of fracture, with the proportions increasing with age. The overall prevalence of osteoarthritis was > 50% in all 3 groups, with a rate of 23% to 37% in the 18- to 29-year-old group, and increasing with age. Similar patterns were observed for osteophytes and enthesopathy. Hip and knee arthroplasty was reported even in adults in their 30s. Spinal stenosis was present at a low prevalence, increasing with age. The proportion of adults with ≥ 2 musculoskeletal features was 59.1%, 55.0%, and 61.3% in the clinical trial group, survey group, and survey pain subgroup, respectively.ConclusionThis analysis confirmed high rates of multiple musculoskeletal features beginning as early as age 20 years among adults with XLH and gradually accumulating with age.

Measuring respiratory symptoms in moderate/severe asthma: evaluation of a respiratory symptom tool, the E-RS\xae: COPD in asthma populations

BackgroundSymptom constructs included in the Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS®: COPD) tool may be relevant to patients with asthma. The purpose of this study was to evaluate content validity and psychometric performance of the E-RS: COPD in moderate/severe asthma patients.MethodsContent validity of the E-RS: COPD was evaluated in patients with moderate/severe asthma using concept elicitation and cognitive debriefing interviews. Secondary analyses using data from two clinical trials in patients with moderate/severe asthma evaluated the factor structure of the E-RS: COPD plus two supplementary items (wheeze; shortness of breath with strenuous physical activity) and assessed psychometric properties of the tool, which will be referred to as E-RS®: Asthma when used in asthma populations.ResultsQualitative interviews (N = 25) achieved concept saturation for asthma respiratory symptoms. Concepts in the E-RS: COPD were relevant to patients and instructions were understood. Most patients (19/25; 76%) reported experiencing all concepts in the E-RS: COPD; no patients indicated missing symptoms. Secondary analyses of clinical trial data supported the original factor structure (RS-Total and three symptom-specific subscales). The two supplemental items did not fit with this factor structure and were not retained. RS-Total and subscale score reliability was high (internal consistency [α] > 0.70). Validity was demonstrated through significant (P < 0.0001) relationships with the St George’s Respiratory Questionnaire (SGRQ) and Asthma Symptom Severity scale. E-RS: Asthma was responsive to change when evaluated using SGRQ, Patient Global Impression of Change and Asthma Quality of Life Questionnaire as anchors (P < 0.0001). Clinically meaningful change thresholds were also identified (RS-Total: − 2.0 units).ConclusionsThe E-RS: Asthma is reliable and responsive for evaluating respiratory symptoms in patients with moderate/severe asthma.

Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials

AbstractObservational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.

Risk of hypertension in erenumab-treated patients with migraine: Analyses of clinical trial and postmarketing data.

ObjectiveTo assess the risk of hypertension in patients with migraine who received erenumab in clinical trials and in the postmarketing setting.BackgroundErenumab is a monoclonal antibody for migraine prevention that targets the calcitonin gene‐related peptide (CGRP) receptor. Hypertension is a theoretical risk for inhibitors of the CGRP pathway. Although no evidence of an association between erenumab treatment and hypertension was observed during the clinical development program, adverse events (AEs) of hypertension have been identified in the postmarketing setting.MethodsSafety data from four phase 2 and phase 3 clinical trials were used to perform a pooled analysis of hypertension AEs in patients with migraine receiving erenumab. Postmarketing AEs of hypertension were identified from the Amgen Global Safety database from May 17, 2018, through January 31, 2020.ResultsIn the pooled analysis of clinical trials, hypertension AEs (placebo, 9/1043 [0.9%]; erenumab 70 mg, 7/893 [0.8%]; erenumab 140 mg, 1/507 [0.2%]) and percentage of patients initiating medication to treat hypertension (12/1043 [1.2%], 7/893 [0.8%], 1/507 [0.2%], respectively) were similar across treatment groups. A total of 362 AEs of hypertension were identified from the postmarketing setting, 26.2% (95/362) of which were serious, >245,000 patient‐years of exposure. The exposure‐adjusted incidence of hypertension was 0.144 per 100 patient‐years.ConclusionsClinical trials did not demonstrate an increased risk of hypertension with erenumab compared with placebo, and AE rates of hypertension reported with erenumab in the postmarketing setting were generally low. Additional data are needed to fully characterize the extent to which hypertension is a risk associated with erenumab.

A Bayesian semiparametric accelerate failure time mixture cure model.

The accelerated failure time mixture cure (AFTMC) model is widely used for survival data when a portion of patients can be cured. In this paper, a Bayesian semiparametric method is proposed to obtain the estimation of parameters and density distribution for both the cure probability and the survival distribution of the uncured patients in the AFTMC model. Specifically, the baseline error distribution of the uncured patients is nonparametrically modeled by a mixture of Dirichlet process. Based on the stick-breaking formulation of the Dirichlet process, the techniques of retrospective and slice sampling, an efficient and easy-to-implement Gibbs sampler is developed for the posterior calculation. The proposed approach can be easily implemented in commonly used statistical softwares, and its performance is comparable to fully parametric method via comprehensive simulation studies. Besides, the proposed approach is adopted to the analysis of a colorectal cancer clinical trial data.

Neonatal Outcomes after Combined Opioid and Nicotine Exposure in Utero: A Scoping Review.

Background: The majority of women who are pregnant with opioid use disorder (OUD) also smoke tobacco but are rarely offered tobacco cessation counseling. While the effects of exposure to opioids and nicotine in utero are well-understood separately, understanding the impact of the combined exposure to these substances on neonatal outcomes is lacking. Methods: A scoping review was conducted using PubMed and Scopus databases for studies addressing the combined exposure to opioids and nicotine during pregnancy published between 1 January 1980 and 9 July 2019. A total of 29 papers met the eligibility criteria for inclusion, with nine being identified as clinical trials (three from the MOTHER study) and two as secondary data analysis of clinical trial data. Results: Neonatal outcomes for infants who had a combined exposure to opioids and nicotine in utero indicated a reduction in birth weight and birth length. Findings in infants exposed to both nicotine and opioids were mixed with regard to the duration of neonatal abstinence syndrome (NAS), the likelihood of treatment for NAS, doses of medicine used to treat NAS, and NAS scores when compared with infants who had opioid exposure without nicotine. Conclusions: The combined exposure to nicotine and opioids during pregnancy may lead to a reduction in neonatal birth weight and birth length and more severe NAS signs, compared with opioid use alone, but more research is necessary to identify the minimum dosage and length of nicotine exposure to accurately predict these outcomes.

Effect of Residual Retinal Fluid on Visual Function in Ranibizumab-Treated Neovascular Age-Related Macular Degeneration

To investigate the relationship between retinal fluid and vision in ranibizumab-treated patients with neovascular age-related macular degeneration (nAMD). Clinical cohort study using post hoc analysis of clinical trial data. We assessed data from HARBOR (NCT00891735), a phase III, randomized, controlled trial. We reviewed 917 patients ≥50 years of age with subfoveal nAMD associated with subretinal (SRF) and/or intraretinal fluid (IRF) at baseline, screening, or week 1. The intervention was intravitreal ranibizumab 0.5 or 2.0 mg (all treatment arms pooled). Outcomes included mean best-corrected visual acuity (BCVA) and BCVA change from baseline at months (M) 12 and 24 evaluated by the presence/absence of SRF and/or IRF. Baseline BCVA was higher with residual vs resolved SRF at M12 (mean [95% confidence interval {CI}] 58.8 letters [57.2-60.4] vs 53.5 [52.4-54.5]) and M24 (59.3 letters [57.8-60.8] vs 53.5 [52.5-54.5]). Mean BCVA change (adjusted for baseline) to M12 was greater with residual vs resolved SRF (mean difference [95% CI], +2.4 letters [+0.1 to +4.7]), but lower with residual vs resolved IRF (-3.5 letters [-5.8 to -1.2]). Eyes with residual SRF (no IRF) exhibited the largest mean BCVA gains (M12, +14.1 letters; M24, +13.2 letters), followed by resolved SRF/IRF (M12, +10.6 letters; M24, +10.0 letters), residual SRF/IRF (M12, +7.2 letters; M24, +8.5 letters), and residual IRF only (M12, +5.5 letters; M24, +3.6 letters). Vision outcomes (adjusted for baseline BCVA) through M24 were better in ranibizumab-treated eyes with residual vs resolved SRF, and worse with residual vs resolved IRF. Presence of residual retinal fluid requires a more complex and nuanced assessment and interpretation in the context of nAMD management.

The Bayesian Multiple Logistic Random Effects Model for Analysis of Clinical Trial Data

A prospective, multi-institutional and randomized surgical trial involving 724 early stage melanoma patients was conducted to determine whether excision margins for intermediate-thickness melanomas (1.0 to 4.0 mm) could be safely reduced from the standard 4-cm radius. Patients with 1- to 4-mm-thick melanomas on the trunk or proximal extremities were randomly assigned to receive either a 2- or 4-cm surgical margin with or without immediate node dissection (i.e. immediate vs. later -within 6 months). The median follow-up time was 6 years. Recurrence rates did not correlate with surgical margins, even among stratified thickness groups. The hospital stay was shortened from 7.0 days for patients receiving 4-cm surgical margins to 5.2 days for those receiving 2-cm margins (p = 0.0001). This reduction was largely due to reduced need for skin grafting in the 2cm group. The overall conclusion was that the narrower margins significantly reduced the need for skin grafting and shortened the hospital stay. Due to the adequacy of subject follow up, recently a statistical focus was on what prognostics factors usually called covariates actually determined recurrence. As was anticipated, the thickness of the lesion (p = 0.0091) and whether or not the lesion was ulcerated (p = 0.0079), were determined to be significantly associated with recurrence events using the logistic regression model. This type of fixed effect analysis is rather a routine. The authors have determined that a Bayesian consideration of the results would afford a more coherent interpretation of the effect of the model assuming a random effect of the covariates of thickness and ulceration. Thus, using a Markov Chain Monte Carlo method of parameter estimation with non informative priors, one is able to obtain the posterior estimates and credible regions of estimates of these effects as well as their interaction on recurrence outcome. Graphical displays of convergence history and posterior densities affirm the stability of the results. We demonstrate how the model performs under relevant clinical conditions. The conditions are all tested using a Bayesian statistical approach allowing for the robust testing of the model parameters under various recursive partitioning conditions of the covariates and hyper parameters which we introduce into the model. The convergence of the parameters to stable values are seen in trace plots which follow the convergence patterns This allows for precise estimation for determining clinical conditions under which the response pattern will change.

61-OR: Glycemic Control and Depressive Symptoms among Minority Women with Type 2 Diabetes Enrolled in the Women In Control (WIC2) Diabetes Medical Group Visit (DMGV) Study

Background: Comorbid depression is associated with poor diabetes control. DMGVs improve glycemic control and depressive symptoms among patients with type 2 diabetes (T2DM). The WIC2 study compared the effectiveness of an eight-week DGMV conducted in a virtual world platform vs. an in-person format to improve diabetes outcomes for 288 minority women with uncontrolled T2DM (HbA1c ≥8.0%). Objective: We conducted a secondary data analysis of the WIC2 clinical trial data to examine the association between improvements in depressive symptom burden (PHQ-8) and improvements in HbA1c among participants enrolled in the WIC2 study. Methods: We measured mean changes in PHQ-8 and HbA1c at baseline, 9-weeks, and 6-months post-enrollment among 288 WIC2 participants. We performed logistic regression to examine the association between a reduction in depressive symptoms per PHQ-8 (-5 points) and reduction in HbA1c (-0.4%) at 9-weeks and 6-months. We used multivariable logistic regression to adjust for potential confounders, including age, education, and study arm. Results: At baseline, nearly half of WIC enrollees reported mild (29.5%), moderate (17.4), or severe (1.7%) depressive symptoms. Their mean PHQ-8 score was 5.5 (SD 5.0) and mean A1c was 9.93% (SD 1.74). From baseline to 6-months, 17.4% (n=41) achieved a 5-point decrease in PHQ-8; among this subset, the mean PHQ-8 score was 10.49 (SD 4.69), indicative of moderate depression at baseline. Of these 41 participants, 68.3% (n=28) also achieved the threshold A1c improvement at 6-months. After controlling for study arm, education, and age, participants with 5-pt or greater reduction in PHQ-8 score from baseline to 6-months had 2.45 times the odds (CI: 1.16, 5.18) of achieving 0.4% or greater reduction in A1c. Conclusion: Improvements in depressive symptom burden correlate with improvements in diabetes management among women with uncontrolled T2DM. Disclosure P. Gardiner: None. B. M. Cruz: None. A. Bragg: None. M. Winter: None. K. Melo: None. J. M. Howard: None. S. Mitchell: Other Relationship; Self; See Yourself Health LLC, Speaker’s Bureau; Self; Merck Sharp &amp; Dohme Corp. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK10653)

P433 Sex-based differences in response to tumor necrosis factor inhibitor induction therapy for ulcerative colitis: a pooled analysis of individual patient-level clinical trials data

Abstract Background There are increasing data on sex-based differences in IBD epidemiology, phenotype and outcomes. The purpose of this study was to characterize sex-based differences in response to tumor necrosis factor inhibitor (TNFi) therapies in patients with ulcerative colitis (UC). Methods We conducted a pooled analysis of individual-level data from randomized clinical trials (RCTs) on induction therapy with infliximab and golimumab, accessed through the Yale University Open Data Access platform. We analyzed patients in the treatment and placebo arms separately. Using multivariable logistic regression modeling, we compared the primary outcome of clinical remission, and secondary outcomes of clinical response and mucosal healing, according to clinical trial definitions, between male and female patients with UC at week 6 (golimumab) or week 8 (infliximab) of induction therapy. Effect estimates were expressed as adjusted odds ratios (aOR) and 95% confidence intervals (CI). Results We included 1639 patients (696, 42.5% were women, Table) from two trials using infliximab (ACT-1 and 2) and one trial using golimumab (PURSUIT). Male patients were older than female patients in the treatment arm of the overall cohort [mean age (standard deviation) 31.31 (16.53) years and 29.34 (15.19) years, respectively). All other baseline characteristics, such as sex, race, Mayo score at screening, and concomitant systemic corticosteroid and immunomodulator use were comparable. Compared to female patients, male patients were significantly less likely to achieve clinical remission in both treatment and placebo arms (aOR 0.55, 95% CI 0.31, 0.97 and 0.34, 95% CI 0.15, 0.82, respectively, Figure). Compared to female patients, male patients were significantly less likely to achieve mucosal healing and clinical response in the treatment arm (aOR 0.47, 95% CI 0.27, 0.83 and 0.51, 95% CI 0.29, 0.90, respectively), but there was no significant difference in these secondary outcomes by sex in the placebo arm. Conclusion Based on this analysis of pooled data from RCTs, we demonstrate that clinical remission, response and mucosal healing with TNFi induction therapies are less likely in male patients compared to female patients with UC. Clinical remission is also less likely in male patients on placebo. These finding may lead to further research on sex-based differences in treatment outcomes, including mechanistic studies.

Galcanezumab Provides Consistent Efficacy Throughout the Dosing Interval Among Patients with Episodic and Chronic Migraine: A Post Hoc Analysis.

IntroductionThe consistency of the treatment effect of galcanezumab throughout the dosing interval is examined in patients with episodic and chronic migraine.MethodsThis study was a post hoc analysis of clinical trial data from episodic (EVOLVE-1; EVOLVE-2; both 6-month duration) and chronic (REGAIN; 3-month duration) migraine double-blind trials evaluating the efficacy of a once-monthly injection of galcanezumab 120 mg relative to placebo. Adults with episodic (placebo, n = 894; galcanezumab, n = 444) or chronic migraine (placebo, n = 558; galcanezumab, n = 278) were included. Mean change from baseline in weekly migraine headache days, averaged across all months for each week of the dosing interval, was compared between groups and within the galcanezumab group during weeks 1 and 4. Additional analyses examined the mean difference from placebo in weekly migraine headache days and a day-by-day analysis.ResultsWeekly migraine headache day reduction was significantly greater with galcanezumab relative to placebo every week (P < 0.001) and did not differ during weeks 1 and 4 for those with episodic (P = 0.740) or chronic migraine (P = 0.231) taking galcanezumab. Estimated probabilities of migraine on day 2 and day 30 did not differ for those with episodic (P = 0.61) or chronic migraine (P = 0.616) taking galcanezumab.ConclusionThis analysis demonstrates once monthly galcanezumab exhibits consistent efficacy throughout the dosing interval among the population of patients with migraine in three clinical trials evaluating the efficacy of galcanezumab. There is no evidence from these trials that the effect of galcanezumab “wears off” at the end of the dosing interval.Trial RegistrationClinicalTrials.gov identifier: EVOLVE-1 (NCT02614183); EVOLVE-2 (NCT02614196); REGAIN (NCT02614261).

Assessing Treatment Effects with Pharmacometric Models: A New Method that Addresses Problems with Standard Assessments

Longitudinal pharmacometric models offer many advantages in the analysis of clinical trial data, but potentially inflated type I error and biased drug effect estimates, as a consequence of model misspecifications and multiple testing, are main drawbacks. In this work, we used real data to compare these aspects for a standard approach (STD) and a new one using mixture models, called individual model averaging (IMA). Placebo arm data sets were obtained from three clinical studies assessing ADAS-Cog scores, Likert pain scores, and seizure frequency. By randomly (1:1) assigning patients in the above data sets to “treatment” or “placebo,” we created data sets where any significant drug effect was known to be a false positive. Repeating the process of random assignment and analysis for significant drug effect many times (N = 1000) for each of the 40 to 66 placebo-drug model combinations, statistics of the type I error and drug effect bias were obtained. Across all models and the three data types, the type I error was (5th, 25th, 50th, 75th, 95th percentiles) 4.1, 11.4, 40.6, 100.0, 100.0 for STD, and 1.6, 3.5, 4.3, 5.0, 6.0 for IMA. IMA showed no bias in the drug effect estimates, whereas in STD bias was frequently present. In conclusion, STD is associated with inflated type I error and risk of biased drug effect estimates. IMA demonstrated controlled type I error and no bias.