Pooled Clinical Trial Research Articles

Racial Differences in Multiple Myeloma Survival and Treatment Using Pooled Clinical Trial and Real-World Electronic Medical Record Data

Background: Past studies have indicated a potential racial disparity in Multiple Myeloma (MM) survival between black and white patients (Costa et al., 2017; Marinac et al., 2020), an issue compounded by minority underrepresentation in clinical trials (Ailawadhi et al., 2018). To better understand how racial disparities affect both MM survival and access to treatment, we performed an analysis of pooled clinical trial (CT) and Real-World EMR Data (RWD). Methods: Eligible Phase II and III open-label MM clinical trials were identified from the Medidata Enterprise Data Store, which comprises over 22,000 historical clinical trials, for de-identified aggregate analyses. De-identified Oncology RWD was sourced from the Guardian Research Network of integrated delivery systems from 2016 to 2020. Baseline characteristics were analyzed in both cohorts. Race was categorized as black, white, or other. Overall Survival (OS) was assessed using Kaplan-Meier analysis. In the RWD, therapy utilization was assessed by race. Results: The RWD contained 5871 patients, with 17.5% black, 78.3% white, and 4.2% other race. Median age in years at diagnosis was 69 for blacks, 72 for whites, and 70 for other races. The gender breakdown was 54.2% female in blacks, 46.0% in whites, 45.9% in those of other races respectively. Median number of prior regimens was 2, with no differences between racial groups. The CT data contained 851 patients, with 1.4% black, 93.5% white, and 5.1% other race. Median age in years at diagnosis was 62 for blacks, 58 for whites, and 55 for other races. The gender breakdown was 33.3% female in blacks, 43.5% in whites, and 46.7% in those of other races respectively. Median number of prior regimens was 5, with no differences between racial groups. There was no statistically significant difference in OS between racial groups in either dataset. In the CT data with median follow-up of 7.8 years, survival from date of diagnosis to last visit or date of death was 25% for blacks and 18% for whites. Currently, in the RWD, 3-year survival comparing blacks to whites is 85% to 83%. The proportion of treated RWD patients appears to be similar between black and white patient groups, with 56% of white and 53% of black patients receiving 1st line therapy, and 33% and 31% receiving 2nd line therapy, respectively. Among newer therapy modalities, white patients had a higher utilization of targeted antibody agent daratumumab (8.7% utilization among whites, 5.2% in blacks, p<0.001), and although not statistically different, proteasome inhibitor carfilzomib use was also higher among whites compared to blacks (6.5% versus 5.5%). Mono daratumumab and ixazomib were used as 1st-line therapy in white patients, while these agents were administered in combination with other treatments in black patients. Adjusting for age and novel therapy use, there was also a suggestion that treatment initiation after diagnosis occurred earlier in whites than blacks (median 1.1 years vs. 1.6 years, p=0.3). Conclusions: Though there were no demonstrated differences in survival between racial groups in either dataset, the RWD suggested differences in treatment utilization, with underutilization of novel therapies like proteasome inhibitors and targeted antibody therapy and later treatment initiation in blacks. Previous studies (Fiala et al., 2017) have noted similar trends, which suggest that therapeutic advances may not be equitably available to all racial groups. This observation could not be replicated in CT data, but merits further exploration. Despite black patients making up 17.5% of patients in the RWD, a racial distribution consistent with published literature (Rosenberg et al., 2015), black patients made up only 1.3% of patients in the CT data. Furthermore, in the CT data, the median age of black patients was older than that of the white and other race groups (62 years compared to 58 and 55, respectively). This observation is magnified by evidence in both the RWD and other datasets (Fillmore et al., 2019) that shows a younger age of onset in black MM patients. Given the strong correlation between age and poorer outcomes in MM (Ludwig et al.,2008), it is possible that these clinical trials are not capturing a representative black patient population, and results may not be generalizable to other groups. Recruitment of black patients should remain a priority in clinical studies in order to effectively assess racial disparities in MM treatment access and survival. Disclosures Rusli: Acorn AI by Medidata, a Dassault Systemes Company: Current Employment, Current equity holder in publicly-traded company. Diao:Acorn AI by Medidata, a Dassault Systemes Company: Current Employment. Liu:Acorn AI by Medidata, a Dassault Systemes Company: Current Employment. Kelkar:Acorn AI by Medidata, a Dassault Systemes Company: Current Employment. Ensign:Acorn AI by Medidata, a Dassault Systemes Company: Current Employment, Current equity holder in publicly-traded company. Watson:Guardian Research Network, Inc.: Current Employment. Galaznik:Acorn AI by Medidata, a Dassault Systemes Company: Current Employment, Current equity holder in publicly-traded company.

FRI0087 DURABILITY OF CERTOLIZUMAB PEGOL IN PATIENTS WITH RHEUMATOID ARTHRITIS OR PSORIASIS OVER THREE YEARS: AN ANALYSIS OF POOLED CLINICAL TRIAL DATA

Background:Durability over time varies according to the safety, tolerability and efficacy of a drug.1However, durability may vary between patient (pt) subgroups,1,2and physicians should consider pt characteristics when making treatment decisions. Certolizumab pegol (CZP) is an anti-tumour necrosis factor (anti-TNF) agent approved for the treatment of chronic inflammatory diseases, including rheumatoid arthritis (RA) and plaque psoriasis (PSO).3However, little is known about the impact of pt baseline characteristics on long-term CZP durability.Objectives:To investigate the durability of CZP and reasons for discontinuation over 3 years (yrs) in subgroups of pts with RA or PSO using pooled clinical trial data.Methods:27 RA and 3 PSO clinical trials were pooled for indication-specific analyses. Kaplan-Meier curves were calculated to estimate CZP durability for pt subgroups by age, gender, disease duration, prior anti-TNF use and geographic region. Reasons for CZP discontinuation were investigated.Results:6927 RA and 1112 PSO pts were included; mean ages were 53.0 yrs (standard deviation [SD]: 12.2 yrs) and 45.4 (13.0) yrs, respectively. 79.3% RA pts were female (of all patients, 19.4% were women of childbearing age [18–<45 yrs; WoCBA]) compared with 33.5% (15.2% WoCBA) in PSO. Mean disease durations were 6.4 (6.9) yrs for RA and 18.4 (12.3) yrs for PSO. 18.5% RA and 13.3% PSO pts had prior anti-TNF use. Maximum CZP exposure was ~8 yrs for RA and ~3 yrs for PSO. At 1 yr, 63.4% of RA pts remained on CZP vs 80.3% PSO pts, decreasing to 49.2% RA pts and 70.1% PSO pts at 3 yrs (Table 1). Reasons for discontinuation, at any time during the trials, included lack of efficacy (RA 13.5%; PSO 1.8%), adverse events (RA 11.9%; PSO 8.1%), consent withdrawn (RA 6.7%; PSO 6.7%), lost to follow-up (RA 1.8%; PSO 4.3%), protocol violation (RA 1.7%; PSO 0.3%) and other (RA 9.2%; PSO 8.7%). In RA pts, CZP durability was lower in the elderly and in pts with disease duration <1 yr. In PSO, durability was lower in pts with disease duration <1 yr or prior anti-TNF use. Durability was lower in WoCBA pts than male pts aged 18–<45 yrs for both indications. CZP durability was lower in Western Europe and North America compared to other regions.Table 1.CZP durability at 3 years,[a] by patient subgroup% patientsRAPSOAll49.270.1Age, yrs 18–<4552.166.3 45–<6549.468.3 ≥6543.369.4Gender Female49.364.1 Male48.269.2 WoCBA51.162.0 Male aged 18–<45 yrs56.568.3Prior anti-TNF use Yes49.360.1 No49.668.5Disease duration, yrs <143.239.6 1–<552.663.6 5–<1051.464.4 ≥1048.769.7Region Asia-Pacific58.5 Central Europe61.578.8 Eastern Europe54.2 Latin America57.1 N America36.653.9 W Europe33.867.7 Rest of the world66.3[a] For PSO, the 3 year analysis was calculated with Week 144 data. CZP: certolizumab pegol; N: North; PSO: psoriasis; RA: rheumatoid arthritis; TNF: tumour necrosis factor; W: Western; yrs: years.Conclusion:Overall, CZP durability was similar to that reported for other anti-TNFs with some differences between indication and subgroups.1Factors influencing durability included age, disease duration and geographic region. Gender differences were observed in the 18–45 yrs age group, however, both male and female CZP durability was higher than in older RA pts.

Assessing the relationship in relapsed-refractory multiple myeloma between response, progression, and survival between pooled clinical trial subjects and a real-world electronic medical record data source.

e20525 Background: Despite new treatments, Relapsed-Refractory Multiple Myeloma (RRMM) remains an incurable disease1. In a recent study by Moreau et al, there was a demonstrated survival benefit to treatment with pomalidomide in RRMM patients2. To better understand how the relationships between initial depth of response and long-term prognosis can inform clinical decision making and guide new compound development, we performed an analysis of standardized clinical trial patient pool data compared with Real-World Data (RWD), across multiple studies. Methods: Pooled clinical trial data was obtained from a Study Data Tabulation Model (SDTM) dataset (n=1,815) from the Medidata Enterprise Data Store. De-identified Oncology EMR data was sourced from the Guardian Research Network™ (GRN)5 of integrated delivery systems from 2010-2018, with robust clinical endpoint extraction and curation to enable outcomes comparisons (n=962). Subject selection was refined based on the inclusion/exclusion criteria from the NIMBUS trial2. Response, Progression-free survival (PFS), and Overall Survival (OS) were extracted. Patients were stratified by age, gender, and prior regimens. Log-rank tests were conducted to compare PFS and OS in patient sub-populations at 90, 180, and 240 days from most recent treatment start. Cox proportional hazard models assessed predictors of survival. Rates were estimated for common adverse events, including leukopenia, neutropenia, and thrombocytopenia. Factors associated with neutropenia were assessed using logistic regression. Results: Within pooled trial and RWD patients, the majority were on regimens with proteasome inhibitors, followed by immunomodulators, and approximately one third on monoclonal antibodies. Within the pooled trial analysis, survival rates were consistent with published literature rates, at ~4 months and ~12 months, respectively. EMR data analysis showed overall longer times to progression with an increased depth of response, with similar associations. Frequency-Factored Time-to-Progression also decreased. Conclusions: The use of SDTM for pooled clinical trial analyses, together with real-world data, can overcome individual trial sample size limitations and biases. Together this approach can expand the range of populations, relative treatment comparisons, and clinical events that can be studied to more comprehensively understand the complexity of the oncology treatment landscape.

Evaluating progression-free survival in black and white women with triple-negative breast cancer in pooled clinical trials from a synthetic control database (SCD) and real-world electronic medical records (EMR).

e13102 Background: Previous studies have shown a lower survival rate in Black women with breast cancer compared with other ethnic groups, largely explained by the increased incidence of triple negative breast cancer (TNBC). In this study we further explore relative survival by race within a TNBC population. By using pooled clinical trial data, we seek to control for variation in patient assessment on outcomes. We further use a real-world electronic medical records (EMR) data source to compare the representativeness of pooled trial findings to patients receiving care not on trial. Methods: Phase II and III open-label breast cancer studies having completed their primary analysis were selected from the Medidata Enterprise Data Store (MEDS), comprised of over 19,000 historical clinical trials, for de-identified aggregate analyses. The Synthetic Control Database (SCD) for this study contains 749 patients with TNBC enrolled in second line and higher treatment trials between 2010 and 2017. De-identified Oncology EMR data was sourced from the Guardian Research Network (GRN) of integrated delivery systems from 2010 to 2018, and contained 1877 patients. Baseline characteristics were assessed between pooled trial and real-world data cohorts. Patients were stratified by race. Progression-free survival (PFS) was assessed using a Kaplan-Meier analysis. We conducted further analysis to assess the impact of additional factors that may influence the aggressive progression of TNBC response in Black women and TNBC disparity. Factors included, but were not limited to: age, stage at diagnosis, baseline benign neutropenia, Body Mass Index (BMI) and genetic factors (BRCA). Results: The TNBC SCD population was 73.0% White, 6.8% Black, and 20.2% Non-White Non-Black (NWNB). The real-world distribution, by contrast was 79%, 10%, and 11%, respectively, with patients predominantly stage 2 at diagnosis. Median BMI at diagnosis was 28.6, 32.6 and 27.1. Unadjusted progression-free survival (PFS) was directionally lower in Black patients in a Kaplan-Meier assessment with a Median PFS of 105 days vs 144 days for all others. Conclusions: A representative pool of cross trial TNBC patients demonstrated lower PFS in Black patients compared to their non-Black counterparts. Based on these findings, further investigation to explore potential biological and treatment factors associated with racial disparity in TNBC is warranted.

Outcomes in patients with advanced non-small cell lung cancer (aNSCLC) and high PD-L1 expression treated with immune checkpoint inhibitor monotherapy: An FDA-pooled analysis.

9606 Background: Higher PD-L1 score ≥ 50% predicts for greater benefit to immune checkpoint inhibitor (ICI) therapy in first line (1L) treatment of aNSCLC. It has recently been reported that PD-L1 score ≥ 90% predicts for even greater benefit to 1L ICI monotherapy (Aguilar et al., 2019). We examined pooled clinical trial databases to examine the relationship between high PD-L1 expression across multiple ICI monotherapies in 1L and second line (2L) treatment of aNSCLC. Methods: Data was pooled from trials (five 1L and five 2L) of ICI for the treatment of patients with aNSCLC. We defined PD-L1 score as the proportion of tumor cell stained by the assay (total of four assays identified) and included patients in the analysis with PD-L1 score ≥ 50%. Tumor-infiltrating immune cell staining was not considered. Progression-free survival (PFS) and overall survival (OS) by line of therapy for patients with PD-L1 score ≥ 90% and patients with PD-L1 score 50-89% was analyzed. Results: A total of 1320 patients treated with ICI monotherapy were identified, 873 in 1L and 447 in 2L. Median follow-up was 9.6 months in 2L patients and 13.3 months in 1L patients. Patients receiving 2L ICI therapy with PD-L1 score ≥ 90% (N = 208) had longer PFS and OS compared to patients with PD-L1 score 50-89% (N = 239), with mPFS 7.1 vs. 4.2 months (HR = 0.66 [95% CI: 0.52-0.83]) and mOS NR vs. 15.8 months (HR = 0.66 [95% CI: 0.49-0.89]). 1L ICI therapy analysis revealed similar trends, as patients with PD-L1 score ≥ 90% (N = 405) had longer PFS and OS compared to patients with a PD-L1 score 50-89% (N = 468), with mPFS 8.3 vs. 5.4 months (HR = 0.78 [95% CI: 0.66-0.92]) and mOS 22.9 vs. 16.4 months (HR = 0.74 [95% CI: 0.61-0.90]). Conclusions: This analysis showed the potential of an enhanced clinical benefit in patients with aNSCLC and PD-L1 score ≥90% across ICI monotherapies in both the 1L and 2L treatment setting. These data will be further analyzed in real world populations.

Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada

Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment. To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness. A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017. Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients. Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care. The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain. To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.

Estimating Relationships between Response, Progression, and Survival in Relapsed-Refractory Multiple Myeloma in Pooled Clinical Trials Database

BACKGROUND: Despite an increasing number of treatment options available and in development, Relapsed-Refractory Multiple Myeloma (RRMM) remains an incurable disease with survival less than 12 months (Kumar SK et al., 2012). In a recent study by Moreau, et al. (2016), a relationship between response and survival was demonstrated in RRMM patients treated with pomalidomide. Understanding the relationships between initial response and long-term prognosis can potentially inform patient treatment changes or guide development of new therapeutic compounds. In a prior presentation by Berry, et al. (2017) clinical trial Study Data Tabulation Data Model (STDM) standards were used to effectively pool clinical trial data in Acute Myeloid Leukemia (AML) to show correlations between response and survival. OBJECTIVES: In this study, we expand upon the analysis of Moreau, et al. (2016) in a pooled clinical trial dataset of RRMM patients. Within this expanded, standardized patient pool, we assess the relationship between response, progression and survival both overall and within patient sub-populations based on patient profiles and prior treatment regimens. METHODS: A retrospective pooled analysis was conducted in a dataset from the Medidata Enterprise Data Store. Subjects were selected based on the inclusion/exclusion criteria from the NIMBUS trial (Moreau et al., 2016). Descriptive statistics were calculated to characterize differences between the overall pooled population and the study group. Response, Progression-free survival (PFS), and Overall Survival (OS) were extracted. Patients were stratified by several covariates including age, gender, number of prior regimens, and prior treatments received. Log-rank tests were conducted to compare PFS and OS in patient sub-populations. Both survival measures were assessed at 90, 180, and 240 days after first day of patient's most recent regimen. Cox proportional hazard models were developed to assess predictors of PFS and OS. Safety was characterized for common potentially treatment-limiting adverse events, such as leukopenia, neutropenia, and thrombocytopenia. Factors associated with development of neutropenia were assessed using logistic regression. Covariates included patient demographics, comorbidities, and treatment regimens (current and prior). RESULTS: Within the pooled analysis, PFS and OS rates were consistent with published literature rates, at ~4 months and ~12 months, respectively. Pooled analysis demonstrated a significant association between response, PFS, and OS. Results were consistent with findings of Moreau, et al. (2016), showing little difference between patients with Stable Disease and Partial Response, and lower overall survival in patients with Progressive Disease versus Stable Disease. Neutropenia was seen in approximately one-fourth of overall patients, and was associated with male patients, older age, and treatment regimen. CONCLUSIONS: The use of SDTM for pooled clinical trial analyses represents an effective way to overcome individual trial sample size limitations, expanding the range of populations, relative treatment outcomes, and safety event rates that can be studied. By working directly with individual patient-level data, there is also a potential for greater matching between trials than with meta-analysis approaches using aggregated data. Disclosures Galaznik: Medidata Solutions: Employment. Rusli:Medidata Solutions: Employment. Davi:Medidata Solutions: Employment.

The Use of CEP (Lomustine, Etoposide and Prednisone), an All-Oral Palliative Chemotherapy Regimen, in Aggressive Lymphomas

The Use of CEP (Lomustine, Etoposide and Prednisone), an All-Oral Palliative Chemotherapy Regimen, in Aggressive Lymphomas

Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data.

ObjectiveWe report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery.MethodsStandardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form–36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness.ResultsThe performance measures had excellent test–retest reliability and showed expected differences between subgroups based on disease duration and EDSS level. Progression rates in detecting time to 3-month confirmed worsening were lower for T25FW and 9HPT compared to EDSS, while progression rates for LCLA and SDMT were similar to EDSS. When the 4 measures were analyzed as a multidimensional measure rather than as individual measures, progression on any one performance measure was more sensitive than the EDSS. Worsening on the performance measures analyzed individually or as a multidimensional test battery was associated with clinically meaningful SF-36 PCS score worsening, supporting clinical meaningfulness of designated performance test score worsening.ConclusionThese results support the use of the 4 proposed performance measures, individually or combined into a multidimensional test battery as study outcome measures.

Malignancy rates in patients with moderate to severe psoriasis during treatment with risankizumab: Analysis of pooled clinical trial data

Malignancy rates in patients with moderate to severe psoriasis during treatment with risankizumab: Analysis of pooled clinical trial data

Long-term safety of risankizumab in patients with moderate to severe psoriasis: Analysis of pooled clinical trial data

Long-term safety of risankizumab in patients with moderate to severe psoriasis: Analysis of pooled clinical trial data

Risankizumab treatment is associated with low and consistent infection rates over time in patients with moderate to severe psoriasis: Analysis of pooled clinical trial data

Risankizumab treatment is associated with low and consistent infection rates over time in patients with moderate to severe psoriasis: Analysis of pooled clinical trial data

Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data

BackgroundSecukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS).MethodsThe integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab.ResultsA total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs.ConclusionsSecukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

The efficacy of pregabalin for the treatment of neuropathic pain in Japanese subjects with moderate or severe baseline pain.

PurposeAlthough analyses of pooled clinical trial data have reported how international populations respond to pregabalin by baseline neuropathic pain (NeP) severity, no studies have evaluated this specifically in patients from Japan. Thus, this post hoc pooled analysis evaluated the efficacy of pregabalin in Japanese subjects for treating moderate or severe baseline NeP.Patients and methodsData were pooled from three placebo-controlled trials enrolling Japanese subjects with postherpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and spinal cord injury (SCI). The efficacy of pregabalin was evaluated by baseline pain severity (moderate or severe NeP). The trials on PHN and DPN included a 1-week titration of pregabalin from 150 mg/day to 300 or 600 mg/day; the SCI trial included a 4-week dose optimization phase (150 mg/day, titrated up to 600 mg/day). Treatment durations were 13–16 weeks (excluding 1-week taper periods), and pregabalin was administered in two divided doses per day.ResultsMean baseline pain scores and demographic characteristics were comparable between treatment cohorts. Pregabalin treatment significantly reduced pain scores from baseline to endpoint compared with placebo in subjects with both moderate (P<0.001) and severe (P<0.05) baseline pain. Significant improvements in mean sleep scores from baseline to endpoint were associated with pregabalin compared with placebo in subjects with both moderate and severe baseline pain (both P<0.0001). A greater proportion of subjects in both pain cohorts achieved a ≥30% reduction in pain from baseline with pregabalin vs placebo (P<0.05). Higher proportions of pregabalin-treated vs placebo-treated subjects shifted to a less severe pain category at endpoint. Consistent with the known safety profile of pregabalin, common adverse events included dizziness, somnolence, weight gain, and peripheral edema.ConclusionPregabalin demonstrated efficacy for pain relief and sleep improvement with a consistent safety profile in Japanese subjects with either moderate or severe baseline pain severity.ClinicalTrials.gov identifiersNCT0039490130, NCT0055347522, NCT0040774524

Dose tailoring of human cell line-derived recombinant factor VIII simoctocog alfa: Using a limited sampling strategy in patients with severe haemophilia A.

The use of factor VIII (FVIII) prophylaxis in haemophilia A is considered the standard of care, particularly in children. Despite adjustment of doses for body weight and/or age, a large pharmacokinetic (PK) variability between patients has been observed. PK-tailored prophylaxis may help clinicians adjust coagulation factor FVIII activity (FVIII:C) to the desired level, which may differ in individual patients. The objective was to develop a population PK model for simoctocog alfa based on pooled clinical trial data and to develop a Bayesian estimator to allow PK parameters in individual patients to be estimated using a reduced number of blood samples. PK data from 86 adults and 29 children/adolescents with severe haemophilia A were analysed. The FVIII data measured using 2 different assays (chromogenic and the 1-stage clotting assay) were fit to separate develop population PK models using nonlinear mixed-effect models. A Bayesian estimator was then developed to estimate the time above the threshold of 1%. The PK data for chromogenic and the 1-stage clotting assays were both best described by a 2-compartment models. Simulations demonstrated good predictive capacity. The limited sampling strategy using blood sample at 3 and 24hours allowed an accurate estimation of the time above the threshold of 1% FVIII:C (mean bias 0.01 and 0.11, mean precision 0.18 and 0.45 for 2 assay methods). In this study, we demonstrated that a Bayesian approach can help to reduce the number of samples required to estimate the time above the threshold of 1% FVIII:C with good accuracy.

Geographic modeling of best transport options for treatment of acute ischemic stroke patients applied to policy decision making in the USA and Northern Ireland

Ischemic stroke is a treatable disease with alteplase, a clot-busting medical treatment, and endovascular therapy (EVT), mechanical removal of the clot through a minimally invasive procedure. The effectiveness of both treatments is time dependent, and they are usually given together. Alteplase is less effective than EVT, but is widely available at community hospitals; EVT is highly effective, but it is only available at large urban tertiary hospitals. There is uncertainty if it is better to receive alteplase early and delay EVT or vice versa. We developed a conditional probability model based on decay curves that were generated from pooled clinical trials, and then created a software solution using C# that interfaced with ArcGIS’s Software Development Kit and Google’s Distance Matrix API. The maps were developed based on pre-specified time interval variables to determine the best transportation for multiple US states (Colorado, Arizona, Tennessee, and Massachusetts/Rhode Island) and Northern Ireland. The overall objective of this work was to determine if these maps could be used to influence health policy decision making for acute stroke patients.

Post prostatectomy outcomes of patients with high-risk prostate cancer treated with neoadjuvant androgen blockade.

Patients with high-risk prostate cancer have an increased likelihood of experiencing a relapse following radical prostatectomy (RP). We previously conducted three neoadjuvant androgen-deprivation therapy (ADT) trials prior to RP in unfavorable intermediate and high-risk disease. In this analysis, we report on the post-RP outcomes of a subset of patients enrolled on these studies. We conducted a pooled analysis of patients with available follow-up data treated on three neoadjuvant trials at three institutions. All patients received intense ADT prior to RP. The primary endpoint was time to biochemical recurrence (BCR). BCR was defined as a PSA ≥ 0.2 ng/mL or treatment with radiation or androgen-deprivation therapy for a rising PSA < 0.2 ng/mL. Overall, 72 patients were included of whom the majority had a Gleason score ≥ 8 (n = 46, 63.9%). Following neoadjuvant therapy, 55.7% of patients (n = 39/70) had pT3 disease, 40% (n = 28) had seminal vesicle invasion, 12.9% (n = 9) had positive margins, and 11.4% (n = 8) had lymph node involvement. Overall, 11 (15.7%) had tumor measuring ≤ 0.5 cm, which included four patients (5.7%) with a pathologic complete response and seven (10.0%) with residual tumor measuring 0.1-0.5 cm. Compared to pretreatment clinical staging, 10 patients (14.3%) had pathologic T downstaging at RP. The median follow-up was 3.4 years. Overall, the 3-year BCR-free rate was 70% (95% CI 57%, 90%). Of the 15 patients with either residual tumor ≤ 0.5 cm or pathologic T downstaging, no patient experienced a recurrence. In this exploratory pooled clinical trials analysis, we highlight that neoadjuvant therapy prior to RP in unfavorable intermediate and high-risk patients may potentially have a positive impact on recurrence rates. Larger studies with longer follow-up periods are warranted to evaluate the impact of neoadjuvant hormone therapy on pathologic and long-term outcomes.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability

Background: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. Objectives: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. Methods: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. Conclusion: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS (http://www.cdisc.org/therapeutic#MS) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

Impact of geographic region on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.

4583 Background: Health determinants vary according to the geographic region and may impact the outcomes of mRCC patients treated on clinical trials of targeted therapy. We investigate the OS by geographic region of mRCC patients treated in the targeted therapy era. Methods: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Clinical characteristics and survival data were collected. Statistical analyses were performed using the Kaplan-Meier method and log-rank test in univariate analysis. Results: Overall, 4736 patients were included in the analysis. Patient characteristics differed according to geographic region (table). No statistically significant differences in OS were observed when comparing US/Canada (USC, reference) to other regions: Latin America (LA), Asia/Oceania/Africa (AOA), and Eastern Europe (EE). OS differed among patients enrolled on trials in the USC compared to Western Europe (WE) (20.3 vs.17.4 months, respectively; HR: 1.15; 95%CI 1.03-1.3 p = 0.015). All grade treatment-related adverse events (AE) were reported more frequently in USC. There were no significant differences in grade 3-5 AEs between groups. Conclusions: We highlight that despite differing baseline characteristics, OS was similar among most geographic regions. Factors such as disease biology, access to care, AE reporting, and quality of care that may contribute to potential differences in outcomes among regions need to be further characterized. [Table: see text]

Effect of empagliflozin on diabetic ketoacidosis in patients with type 2 diabetes: pooled clinical trial data

Effect of empagliflozin on diabetic ketoacidosis in patients with type 2 diabetes: pooled clinical trial data