Definition Of Treatment Response Research Articles

P1240 Systematic review with meta-analysis: faecal microbiota transplantation as treatment of chronic pouchitis

Abstract Background Pouchitis is inflammation of the ileal pouch-anal anastomosis after proctocolectomy in the surgical treatment of ulcerative colitis. Cohort studies have found evidence that allogenic faecal microbiota transplantation (FMT) can induce short term beneficial effects in patients with chronic pouchitis. Until recently results from randomized controlled trials (RCTs) have been missing. In this systematic review and meta-analysis, we investigated whether FMT treatment was superior to placebo in inducing remission in patients with chronic pouchitis. Methods We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to 15th of November 2023, for RCTs assessing the efficacy of allogenic FMT in the treatment of chronic pouchitis. Autologous FMT or placebo was accepted as control treatment. The primary outcome was the improvement of symptoms as defined by the authors following four weeks. Results The systematic literature search identified a total of three RCTs on the efficacy of FMT in chronic pouchitis comprising 62 patients with 32 patients treated with FMT. Both treatments (FMT and Placebo) and definition of treatment response varied between studies (Table 1). Meta-analysis revealed that FMT was not superior to placebo (risk ratio=0,68;95% CI=(0,47-0,99); p=0.35) in improvement of symptoms four weeks following treatment (Figure 1). Conclusion FMT was not superior to placebo in inducing short-term beneficial effects four weeks after initial treatment in patients with chronic pouchitis. Whether FMT may induce long-term beneficial effects remains to be established.

Treatment response to ursodeoxycholic acid in primary biliary cholangitis: A systematic review and meta-analysis.

Several ursodeoxycholic acid (UDCA) treatment response definitions have been introduced in primary biliary cholangitis (PBC). However, the lack of a gold standard results in heterogeneity in second-line treatment research and clinical practice. This study aimed to explore which UDCA treatment response endpoint serves as the most accurate predictive model of long-term outcome. A systematic review and meta-analysis of UDCA treatment response endpoints (and corresponding validations) were performed. Sixteen individual UDCA treatment response endpoints and 96 external validations were found. Barcelona, Paris-1, Paris-2, Rotterdam, Toronto and GLOBE and UK-PBC Risk Scores are currently most robustly validated in external populations. The results show that the continuous models (GLOBE and UK-PBC Risk Scores) serve as the most accurate predictive models. Besides standard UDCA treatment response endpoints, the alkaline phosphatase and total bilirubin normalization has been suggested as a new therapeutic target. The GLOBE and UK-PBC Risk Scores are the most suitable for the real-world allocation of second-line therapies (obeticholic acid and fibrates). However, in the wake of the recent findings, alkaline phosphatase and total bilirubin normalization should be the primary outcome in trial research in PBC.

70P Invasive lobular breast cancer (ILC), an overlooked subtype in clinical trials

ILC represents ∼15% of all breast cancers (BC). Clinical, histological and molecular differences between ILC and BC of non-special type support the idea of ILC as a separate entity. Unfortunately, evidence on treatment efficacy for ILC is often lacking. We aimed to map out the lack of documentation and representation of patients with ILC in clinical drug trials (CT), trials investigating gene expression profiles (GEPs) and molecular screening programs (MS). Phase III and IV CT for novel BC treatments were identified on clinicaltrials.gov and Pubmed by use of keywords linked to treatment strategies, GEPs and MS and ‘breast cancer’. CT were included if a manuscript was available on 15.01.2023. Inclusion and exclusion criteria were reviewed to see if patients with ILC or non-measurable disease were excluded. Documentation of ILC was assessed and if reported, percentage of ILC, central pathology for ILC and ILC subgroup analyses were evaluated. In total, 80 CT were included of which 14 were neoadjuvant, 11 adjuvant and 55 metastatic. One CT restricted inclusion to patients with NST. Non-measurable disease was an exclusion criterium in 20% of the CT (14.3% neoadjuvant and 25.2% metastatic) and non-measurable disease with the exception of bone-only disease was excluded in 30.9% of the metastatic CT. Inclusion of patients with ILC was documented in 11/80 CT (13.8%: 35.7% neoadjuvant, 9.1% adjuvant, 9.1% metastatic). Inclusion rates varied between 2.0 and 16.3%. Only 2/11 CT had specific sub-analyses on ILC and no CT reported central pathology for ILC. The initial manuscript of 6/7 of the GEPs and 1/3 of the MS was lacking ILC information. Secondary retrospective analyses for ILC are available for 5/6 remaining GEPs. ILC is greatly overlooked in the majority of CT with poor representation, documentation and lack of specific sub-analyses. Eligibility criteria and definitions of treatment response do not reflect the unique biology and clinical course of ILC. Thus, conclusions about efficacy with respect to ILC cannot accurately be drawn. It is critical that these gaps in inclusion and study of ILC are closed. ILC deserves much more attention from both clinical investigators and pharmaceutical industries.

Nonresponder does not mean not better: Improvement in nonsymptom domains in complex depressed patients who are not symptomatic responders to intensive treatment

In treatment studies of depression, response is typically defined as a 50% or greater reduction in symptom severity. However, multiple surveys of depressed patients have found that patients prioritize improved functioning and quality of life objectives over symptom improvement as the most important goal of treatment. The goal of the present study is to widen the lens of assessing outcome by examining response in nonsymptom domains in patients who are, by convention, considered nonresponders to treatment. Eight hundred and forty-four patients with major depressive disorder completed the Remission from Depression Questionnaire (RDQ), a self-report measure that assesses multiple constructs considered by patients to be relevant to assessing treatment outcome. At discharge, the patients made a global rating of the effectiveness of treatment. The 517 patients who were nonresponders on the depression symptom subscale of the RDQ are the focus of this report. The patients showed significant levels of improvement from admission to discharge in all nonsymptom domains, with medium to large effect sizes. Approximately one-third of the patients were responders on at least 1 of the nonsymptom domains. The failure to meet the conventional definition of treatment response based on symptom severity does not preclude significant improvement in nonsymptom domains.

Rifaximin Treatment for Individual and Multiple Symptoms of Irritable Bowel Syndrome With Diarrhea: An Analysis Using New End Points

Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. The current aim was to evaluate rifaximin efficacy on individual and composite IBS-D symptoms using definitions not previously examined. Phase III post hoc analyses of two randomized, double-blind, placebo-controlled trials and the open-label phase of a randomized, double-blind, placebo-controlled trial were conducted. Adults with IBS-D received a 2-week course of rifaximin 550 mg TID. Individual and composite responses for abdominal pain (mean weekly improvements from baseline of ≥30%, ≥40%, or ≥50%), bloating (mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%), stool consistency (mean weekly average stool consistency score <3 or <4), and urgency (improvement from baseline of ≥30% or ≥40% in percentage of days with urgency) for ≥2 of the first 4 weeks after treatment, and weekly for 12 weeks, were assessed. Overall, 1258 patients from the double-blind trials (rifaximin [n = 624]; placebo [n = 634]) and 2438 from an open-label trial were analyzed. The percentage of bloating or urgency responders was significantly greater with double-blind rifaximin versus placebo (P ≤ 0.03). A significantly greater percentage of the double-blind group were composite abdominal pain and bloating responders versus placebo for all thresholds analyzed (P < 0.05). A significantly greater percentage of the double-blind group were tri-symptom composite end point responders (abdominal pain, bloating, and fecal urgency) versus placebo (P = 0.001). A significantly greater percentage of patients achieved response (≥30% composite tri-symptom threshold) with double-blind rifaximin versus placebo as early as 1 week posttreatment, with significance maintained through ≥5 weeks after treatment. Open-label results were consistent with those of the double-blind study. Rifaximin significantly improved multiple, concurrent IBS-D symptoms, using clinically relevant definitions of treatment response. Using a novel tri-symptom composite end point (ie, abdominal pain, bloating, fecal urgency), adults with IBS-D treated with a 2-week course of rifaximin were significantly more likely to be composite end point responders than those receiving placebo (≥30% or ≥40% threshold) for the three symptoms. Thus, rifaximin not only met current standard thresholds used for adjudication of responders in clinical trials but also achieved higher thresholds for many of these symptoms, suggesting potential for even more robust clinical improvements. gov identifiers: NCT00731679, NCT00724126, and NCT01543178.

Defining Treatment Response for Clinical Trials of Pediatric Acute Asthma

An agreed-upon definition of treatment response for clinical trials of pediatric acute asthma does not exist, limiting meaningful comparisons among therapeutic interventions and advances in asthma management. To develop a consensus definition of treatment response for clinical trials of pediatric acute asthma. A multidisciplinary panel of 22 experts participated in a Web-based modified Delphi process to achieve consensus on a definition of treatment response. Round 1 consisted of closed- and open-ended questions in which panelists ranked measures of treatment response developed by literature review, suggested additional measures, and explained their responses. In rounds 2 and 3, panelists reviewed summary statistics of the panel's rating from prior rounds and reconsidered their rankings. In round 3, pairwise ranking was performed to determine the ranked importance of components. Consensus was defined as 70% or greater agreement among panelists choosing Likert-scale values of 1 to 6 (extremely unimportant to extremely important) and an interquartile range less than2. Drawing on results from the expert panel, we developed a definition of treatment response that includes Clinical Severity Score, need for additional therapies, and hospitalization. Clinical Severity Score encompassed most ranked criteria (eg, respiratory distress, wheeze) for a treatment response definition. Panelists recommended that a valid and pragmatic severity score be used consistently across institutions. Panelists also achieved consensus on the top 10 criteria that appropriately classify need for hospitalization. This consensus definition of treatment response can be used in clinical trials of children with acute asthma to standardize outcome measurement and report meaningful outcomes.

The Development of a Comprehensive Clinicopathologic Registry for Glomerular Diseases Using Natural Language Processing.

Glomerulonephritis (GN) represents a common cause of chronic kidney disease, and treatment to slow or prevent progression of GN is associated with significant morbidity. Large patient registries have improved the understanding of risk stratification, treatment selection, and definitions of treatment response in GN, but can be resource-intensive, with incomplete patient capture. To describe the creation of a comprehensive clinicopathologic registry for all patients undergoing kidney biopsy in Manitoba, using natural language processing software for data extraction from pathology reports, as well as to describe cohort characteristics and outcomes. Retrospective population-based cohort study. Tertiary care center in the province of Manitoba. All patients undergoing a kidney biopsy in the province of Manitoba from 2002 to 2019. Descriptive statistics are presented for the most common glomerular diseases, along with outcomes of kidney failure and mortality for the individual diseases. Data from native kidney biopsy reports from January 2002 to December 2019 were extracted into a structured database using a natural language processing algorithm employing regular expressions. The pathology database was then linked with population-level clinical, laboratory, and medication data, creating a comprehensive clinicopathologic registry. Kaplan-Meier curves and Cox models were constructed to assess the relationship between type of GN and outcomes of kidney failure and mortality. Of 2421 available biopsies, 2103 individuals were linked to administrative data, of which 1292 had a common glomerular disease. The incidence of yearly biopsies increased almost 3-fold over the study period. Among common glomerular diseases, immunoglobulin A (IgA) nephropathy was the most common (28.6%), whereas infection-related GN had the highest proportions of kidney failure (70.3%) and all-cause mortality (42.3%). Predictors of kidney failure included urine albumin-to-creatinine ratio at the time of biopsy (adjusted hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.24-1.65), whereas predictors of mortality included age at the time of biopsy (adjusted HR = 1.05, 95% CI = 1.04-1.06) and infection-related GN (adjusted HR = 1.85, 95% CI = 1.14-2.99, compared with the reference category of IgA nephropathy). Retrospective, single-center study with a relatively small number of biopsies. Creation of a comprehensive glomerular diseases registry is feasible and can be facilitated through the use of novel data extraction methods. This registry will facilitate further epidemiological research in GN.

Self-reported improvement in obstructive sleep apnea symptoms compared to treatment response with mandibular advancement device therapy: a retrospective study.

Mandibular advancement device (MAD) is recognized as the treatment option for management of obstructive sleep apnea (OSA) in mild-moderate cases or those unable to tolerate positive airway pressure therapy. Post-treatment sleep study is recommended to establish MAD efficacy when maximal therapeutic benefit is achieved based on OSA symptom improvement or maximum anatomical protrusion. The aim of this study was to investigate the difference between responders and non-responders in OSA symptom improvement and predictors of treatment success. Medical charts of patients referred to the Orofacial Pain Clinic between 2016 and 2021 for management of OSA with MAD were retrospectively evaluated. Participants with post-treatment sleep study with MAD in situ were included. Participants were categorized as responders according to different criteria: 50% reduction in apnea-hypopnea index (AHI) compared to baseline; post-treatment AHI ≤ 10 with ≥ 50% reduction from baseline; AHI ≤ 5 with ≥ 50% reduction. OSA symptoms included snoring, apneas, sleep quality, tiredness upon awakening, daytime sleepiness, and subjective improvement. Differences in pre- and post-treatment variables within/between groups and predictors were analyzed with t test and logistic regression. Among 53 participants (30 females), mean agewas 64.2 ± 10.7 and pre-treatment wasAHI 23.3 ± 17.2. Depending upon the criteria, responders ranged between 26 and 57%. At first follow-up after MAD delivery, non-responders reported less tiredness upon awakening (p = 0.003), better sleep quality (p = 0.005), and greater subjective improvement (p = 0.012) than responders. Among significant OSA symptoms, tiredness upon awakening, poorer sleep quality, and less subjective improvement were consistently found as predictors of treatment response. Subjective improvement, sleep quality, and tiredness upon awakening significantly improved in non-responders at first follow-up compared to responders, according to the strictest definition of treatment response. Therefore, a post-treatment sleep study is crucial to confirm proper management of OSA with MAD.

Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes: Systematic Literature Review

Introduction: Patients with lower-risk myelodysplastic syndromes (LR-MDS) commonly experience chronic progressive anemia, which is initially treated with erythropoiesis-stimulating agents (ESAs). However, many patients do not respond to ESAs, thereby putting them at risk of earlier disease progression, which can require invasive and/or costly treatments, including blood transfusions or hypomethylating agents. A systematic literature review (SLR) was conducted to assess quantitative associations between prognostic factors and response to treatment with ESAs in patients with LR-MDS. Methods: An electronic search for relevant literature was conducted on February 25, 2022, across Embase and MEDLINE via OvidSP. Also, proceedings from the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, Academy of Managed Care Pharmacy, and European Society for Medical Oncology meetings from 2019 to 2022 were searched via OvidSP or manually if not indexed in databases. Articles written in languages other than English were excluded. Adult patients with LR-MDS were included in the analysis. Studies reporting measures of effect between prognostic factors and ESA response were included, as were studies reporting quantitative data pertaining to differences in patient characteristics between ESA responders and non-responders. Studies reporting both univariate and multivariate analyses were included. No geographic or temporal limits were applied to the search strategy, except for congress proceedings, which were limited to 2019 onwards. Results: In total, 38 studies were eligible for inclusion in this SLR, and 8 prognostic factors of interest were most frequently reported: baseline serum erythropoietin (EPO), hemoglobin (Hb), transfusion independence, bone marrow blast count, ferritin levels, International Prognostic Scoring System (IPSS) risk status, age, and karyotype status. Regarding study design, most were retrospective cohort studies (N = 15) or single-arm trials (N = 12), and were conducted in Europe (N = 24). Within the identified publications, ESA response was often assessed using the International Working Group (IWG) MDS 2000 or 2006 criteria in publications after 2000. Studies published prior to 2000 did not use a standardized method of refining response, but still classified patients according to changes in Hb levels or transfusion requirements. The literature available in LR-MDS demonstrated statistically significant relationships suggesting that patients with low serum EPO levels (vs higher EPO levels), high Hb levels (vs lower levels), and transfusion independence (vs transfusion dependent) are more likely to respond to ESA treatment (Table). This relationship was consistent across both univariate and multivariate analyses. The evidence for bone marrow blasts and ferritin levels was inconclusive, but could potentially be influenced in the future by the publication of studies with larger patient populations. There was no published evidence that ESA response was related to IPSS risk status, age, and karyotype status. The associated data for these prognostic factors in responders versus non-responders showed similar patterns. Conclusion: All studies assessing quantitative associations between ESA response and prognostic factors were published after 2000, hence ESA response was assessed according to IWG 2000 or 2006 criteria. The studies demonstrate a clear link between response to ESA treatment and lower serum EPO levels, higher Hb levels, and transfusion independence. The other prognostic factors were either not significant or inconclusive, and more research is needed to clarify whether they have a prognostic impact on ESA response in patients with LR-MDS. Some of the studies comparing prognostic factors for responders versus non-responders to ESA treatment were published before 2000 and did not use standardized methods to describe response. Due to changes in ESA treatment response definitions over time, some patients in the included studies may be classified differently with a more recent version of the IWG MDS criteria. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Operational Definitions of Treatment Response and Remission in Obsessive-Compulsive Disorder Capture Meaningful Improvements in Everyday Life

Introduction: The operational definitions of treatment response, partial response, and remission in obsessive-compulsive disorder (OCD) are widely used in clinical trials and regular practice. However, the clinimetric sensitivity of these definitions, that is, whether they identify patients that experience meaningful changes in their everyday life, remains unexplored. Objective: The objective was to examine the clinimetric sensitivity of the operational definitions of treatment response, partial response, and remission in children and adults with OCD. Methods: Pre- and post-treatment data from five clinical trials and three cohort studies of children and adults with OCD (n = 1,528; 55.3% children, 61.1% female) were pooled. We compared (1) responders, partial responders, and non-responders and (2) remitters and non-remitters on self-reported OCD symptoms, clinician-rated general functioning, and self-reported quality of life. Remission was also evaluated against post-treatment diagnostic interviews. Results: Responders and remitters experienced large improvements across validators. Responders had greater improvements than partial responders and non-responders on self-reported OCD symptoms (Cohen’s d 0.65–1.13), clinician-rated functioning (Cohen’s d 0.53–1.03), and self-reported quality of life (Cohen’s d 0.63–0.73). Few meaningful differences emerged between partial responders and non-responders. Remitters had better outcomes across most validators than non-remitters. Remission criteria corresponded well with absence of post-treatment diagnosis (sensitivity/specificity: 93%/83%). Using both the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Clinical Global Impression Scale yielded more conservative results and more robust changes across validators, compared to only using the Y-BOCS. Conclusions: The current definitions of treatment response and remission capture meaningful improvements in the everyday life of individuals with OCD, whereas the concept of partial response has dubious clinimetric sensitivity.

Tumor necrosis factor (TNF) inhibitors for juvenile idiopathic arthritis-associated uveitis.

Uveitisis the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA) and a potentially sight-threatening condition characterized by intraocular inflammation. Current treatment for JIA-associated uveitis (JIA-U) is largely based on physician experience, observational evidence and consensus guidelines, resulting in considerable variations in practice. OBJECTIVES: To evaluate the effectiveness and safety of tumor necrosis factor (TNF)inhibitors used for treatment of JIA-U. We searched the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We last searched the electronic databases on 3 February 2022. We included randomized controlled trials (RCTs) comparing TNF inhibitors with placebo in participantswith a diagnosis of JIA and uveitis who were aged 2 to 18 years old. We used standard Cochrane methodology and graded the certainty of the body of evidence for seven outcomes using the GRADE classification. We included three RCTs with 134 participants. One study conducted in the USA randomized participants to etanercept or placebo (N = 12). Two studies, one conducted in the UK (N = 90) and one in France (N = 32), randomized participants to adalimumab or placebo. All studies were at low risk of bias.Initial pooled estimates suggested that TNF-inhibitors may result in little to no difference on treatment success defined as 0 to trace cells on Standardization of Uveitis Nomenclature (SUN)-grading; or two-step decrease in activity based on SUN grading (estimated risk ratio (RR) 0.66; 95% confidence interval (CI) 0.21 to 2.10; 2 studies; 43 participants;low-certainty evidence) or treatment failure defined as a two-step increase in activity based on SUN grading (RR 0.31; 95% CI 0.01 to 7.15; 1 study; 31 participants;low-certainty evidence). Further analysis using the individual trial definitions of treatment response and failure suggested a positive treatment effect of TNF inhibitors; a RR of treatment success of 2.60 (95% CI 1.30 to 5.20; 3 studies; 124 participants; low-certainty evidence), and RR of treatment failure of 0.23 (95% CI 0.11 to 0.50; 3 studies; 133 participants). Almost all the evidence was on adalimumab and the evidence on etanercept was very limited. For secondary outcomes, one study suggests that adalimumab may have little to no effect on risk of recurrence after induction of remission at three months (RR 2.50, 95% CI 0.31 to 20.45; 90 participants; very low-certainty evidence) and visual acuity, but the evidence is very uncertain; mean difference in longitudinal logMAR score change over six months was -0.01 (95% CI -0.06 to 0.03) and -0.02 (95% CI -0.07 to 0.03) using the best and worst logMAR measurement, respectively (low-certainty evidence). Low-certainty evidence from one study suggested that adalimumab treatment results in reduction of topical steroid doses at six months (hazard ratio 3.58; 95% CI 1.24 to 10.32; 74 participants who took one or more topical steroid per day at baseline). Adverse events, including injection site reactions and infections, were more common in the TNF inhibitor group. Serious adverse events were uncommon. Adalimumab appears to increase the likelihood of treatment success and decrease the likelihood of treatment failure when compared with placebo. The evidence was less conclusive about a positive treatment effect with etanercept. Adverse events from JIA-U trials are in keeping with the known side effect profile of TNF inhibitors. Standard validated JIA-U outcome measures are required to homogenize assessment and to allow for comparison and analysis of multiple datasets.

Defining response and nonresponse to posttraumatic stress disorder treatments: A systematic review.

There is currently no uniform definition of treatment response for posttraumatic stress disorder (PTSD) to guide researchers and clinicians in the area of posttraumatic mental health. The aim of this systematic review was to explore the operationalization of PTSD treatment response, by reviewing and synthesizing the key criteria used to define treatment response and treatment nonresponse in published trials. Randomized controlled trials (RCTs) assessing the effectiveness of first-line interventions for PTSD were identified for inclusion. Of those, 143 trials provided 226 definitions of treatment response, grouped under five main categories: treatment response (n = 181), remission (n = 23), recovery (n = 5), treatment nonresponse (n = 5), and worsening (n = 12). Overall, the results showed the PTSD field utilizes diverse and interchangeable operational definitions of treatment response and nonresponse, indicating a need for more precise conceptual definitions and operational criteria. A set of operational research definitions are presented in order to advance the PTSD treatment field.

Sensitivity Analysis of Overall Response Rate (ORR) with Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis (HLH)

Background: Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered one of the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation, the only curative therapy. Conventional HLH therapy comprises immunotherapies (namely, dexamethasone and etoposide), which, unfortunately, predispose patients to infections and toxicity. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. Currently, there is no regulatory precedent or validated response criteria for efficacy assessment to guide clinical trials in primary HLH. In the pivotal study of emapalumab in primary HLH, objective response criteria were used to define the primary endpoint of overall response (Locatelli et al NEJM 2020). These response criteria were defined based on the Histiocyte Society HLH diagnostic criteria (Henter et al Pediatr Blood Cancer 2007), clinical considerations from the study's Scientific Steering Committee, and available experience reported with conventional HLH treatments. We now report on findings of a sensitivity analysis of overall response rate (ORR) to emapalumab using various assessment criteria. Methods: The open-label pivotal study included patients aged ≤18 years with a diagnosis of primary HLH and active disease (NCT01818492; Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 10 mg/kg if required, based on predefined laboratory and clinical response parameters, for a treatment duration of 8 weeks. In addition to emapalumab, all patients received dexamethasone, and a protocol amendment allowed for concomitant use of other HLH treatments if deemed appropriate by the investigator. ORR at end of treatment was analyzed as per the protocol definition in the 27 patients previously treated with conventional therapies. In addition, several pre-specified and post hoc sensitivity analyses were performed to pressure test the data; including: (i) a pre-specified analysis using a more conservative approach where any patient who received concomitant HLH therapies during the study was imputed as non-responder; (ii) a pre-specified analysis with physician-reported response rates recorded by the study investigators, based on their clinical judgement and previous experience in treating patients with primary HLH; and (iii) a post hoc sensitivity analysis using a previously published definition of overall response (Henter et al Pediatr Blood Cancer 2007). Results: 63% (95% confidence interval [CI], 0.42, 0.81) of 27 treatment-experienced patients had a response according to the pivotal study protocol definition of ORR (Fig. 1). A pre-specified sensitivity analysis on the primary endpoint where any patient who received concomitant HLH therapy and imputed as non-responders showed a magnitude of response similar to that observed in the protocol-defined primary analysis (59.3%; 95% CI 0.39, 0.78; n=22). Use of the response criteria defined by Marsh et al (Pediatr Blood Cancer 2013) in a retrospective analysis of 27 patients with primary HLH also resulted in a similar ORR to the protocol-defined primary endpoint in treatment-experienced patients (70.4%; 95% CI 0.50, 0.86). When platelet count was added to this analysis, the percentage of responders to emapalumab increased to 74.1% (95% CI 0.54, 0.89). The pre-specified analysis of physician-reported response rates was also in line with the primary analysis, with 70.4% (95% CI 0.50, 0.86) of 27 treatment-experienced patients deemed to have a response to emapalumab. Conclusion: The current analyses using different definitions of treatment response support the primary analysis results by having a numerically comparable point estimate to the primary endpoint, therefore confirming the positive benefit of emapalumab in patient's refractory or intolerant to conventional HLH therapies. Taken together, these findings also suggest that the clinically objective ORR, utilized in the pivotal emapalumab trial, may be used as a primary endpoint in primary HLH. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board; Novartis: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding; Novartis Pharma: Research Funding; Pfizer: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding. Grom:Sobi: Consultancy; Novartis Pharma: Consultancy; AB2Bio: Consultancy. Stoltenberg:Sobi: Current Employment. Vågerö:Sobi: Consultancy. de Min:Sobi: Consultancy.

S0457 Six-Month Efficacy of Polyethylene Glycol (PEG) 3350 in the Treatment of Chronic Idiopathic Constipation: Analysis Using FDA Endpoints

INTRODUCTION: PEG 3350 is an osmotic laxative approved by the FDA for the treatment of constipation in 1999 and available OTC since 2006. Studies establishing the efficacy of PEG 3350 were performed prior to the establishment of standard constipation efficacy endpoints. This post-hoc analysis re-evaluates data from a previously published trial (DiPalma J, et al. Am J Gastroenterol 2007;102:1436-1441; NCT00153153) using the FDA weekly responder definition for chronic idiopathic constipation (CIC). The overall response was analyzed using multiple intervals across 6 months. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy of PEG 3350 vs placebo in patients with CIC (modified ROME criteria). Adults with CIC were randomized (2:1) to receive PEG 3350 17g or placebo once daily for 6 months (24 weeks). This new analysis assesses the FDA CIC endpoint, defined as a weekly CSBM response (i.e., ≥3 complete spontaneous bowel movements (CSBMs) per week and an increase of ≥1 CSBM from baseline) during at least 9 of 12 treatment weeks, including 3 of the last 4 weeks of this period. Similar criteria were used to assess weekly CSBM response for the full duration of the study using an 18/24-week endpoint. Additionally, less stringent weekly CSBM response rate was analyzed using 6/12- and 12/24-week endpoints. All analyses were also completed for weekly spontaneous bowel movement (SBM) response. RESULTS: The intention-to-treat population included 204 PEG 3350–treated and 100 placebo-treated patients. At baseline, mean CSBMs (<1/wk) and mean SBMs (≤4/wk) rates were similar in both treatment arms. Weekly CSBM response for 9/12 weeks (FDA CIC endpoint) was significantly higher in the PEG 3350 group vs placebo (42% vs 13%; P < 0.0001) (Table 1). Response remained consistent for the 18/24-week CSBM analysis (43% vs 11%; P < 0.0001). Similar results were seen across the 9/12-week and 18/24-week SBM endpoints. Response rates for the 6/12-week and 12/24-week endpoints were higher for both CSBM and SBM showing overall consistency in the clinical benefits of PEG 3350 for CIC patients (P < 0.0001; Figure 1). CONCLUSION Using current definitions of treatment response based on the FDA CIC CSBM endpoint and improvements in SBM, once-daily PEG 3350 demonstrated substantial and sustained efficacy in patients with CIC over a period of 6 months.Figure 1.: CSBM and SBM response rates using different time intervalsTable 1.: CSBM and SBM outcomes

Confounding Factors in Renal Denervation Trials: Revisiting Old and Identifying New Challenges in Trial Design of Device Therapies for Hypertension.

Recent randomized sham-controlled trials have demonstrated significant blood pressure reductions following renal denervation (RDN) in patients with hypertension, both in the presence and absence of antihypertensive therapy. These new data encouraged us to revisit previously published insights into potential clinical trial confounding factors that informed the design and conduct of forthcoming trials. Initially identified confounders related to procedural technique, medication variability, and selected patient subgroups have been addressed in contemporary trial design. Regarding procedural method and technology, blood pressure reductions may be improved by ensuring circumferential lesion creation in the distal renal arteries and branch vessels. Safety of the RDN procedure has been demonstrated in multiple independent meta-analyses including thousands of treated patients with low reported rates of renal vessel complications and maintenance of renal function. However, a newer generation of RDN trials has also introduced insights related to medication adherence, patient selection, and the definition of treatment response. Evolving evidence indicates that RDN therapy may be considered in higher risk populations of uncontrolled hypertension regardless of ethnicity and in patients expressing a strong preference for a nondrug therapy option. Despite advances in procedural technique and clinical trial conduct, inconsistent antihypertensive-drug adherence behavior remains perhaps the most critical clinical trial design issue for device-based hypertension therapies. As the balance in clinical equipoise increasingly favors RDN, justification of sham-controlled trial designs will be revisited, and novel study designs may be required to evaluate the safety and efficacy of novel devices and procedures intended to address the escalating prevalence of poorly controlled hypertension.

Pharmacogenetics of Pediatric Asthma: Current Perspectives.

Asthma is a chronic respiratory disease that affects 339 million people worldwide and has a considerable impact on the pediatric population. Asthma symptoms can be controlled by pharmacological treatment. However, some patients do not respond to therapy and continue suffering from symptoms, which impair the quality of life of patients and limit their daily activity. Genetic variation has been shown to have a role in treatment response. The aim of this review is to update the main findings described in pharmacogenetic studies of pediatric asthma published from January 1, 2018 to December 31, 2019. During this period, the response to short-acting beta-agonists and inhaled corticosteroids in childhood asthma has been evaluated by eleven candidate-gene studies, one meta-analysis of a candidate gene, and six pharmacogenomic studies. The findings have allowed validating the association of genes previously related to asthma treatment response (ADRB2, GSDMB, FCER2, VEGFA, SPAT2SL, ASB3, and COL2A1), and identifying novel associations (PRKG1, DNAH5, IL1RL1, CRISPLD2, MMP9, APOBEC3B-APOBEC3C, EDDM3B, and BBS9). However, some results are not consistent across studies, highlighting the need to conduct larger studies in diverse populations with more homogeneous definitions of treatment response. Once stronger evidence was established, genetic variants will have the potential to be applied in clinical practice as biomarkers of treatment response enhancing asthma management and improving the quality of life of asthma patients.

Genetic and epigenetic alteration of the programmed cell death 1 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease where both genetics and epigenetics are contributing factors. In order to discover genetic and epigenetic associations with RA and its phenotypes, we analysed RNA expression, DNA variations and DNA methylation of programmed cell death 1 (PDCD1) in a cohort of RA patients and healthy controls. RA patients (n=206) and healthy controls (n=234) were included for analysis of PDCD1 expression, PDCD1 polymorphisms and PDCD1 methylation. Differences in continuous variables between groups were compared by applying t tests. Associations between phenotypes and genotypes were evaluated with contingency tables. Sensitivity analyses were conducted to confirm the robustness of results, considering potential confounding factors and different treatment response definitions. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Higher expression of PDCD1 was found in RA compared to controls (P<0.001), with similar PDCD1 polymorphisms in RA and controls. rs36084323 decreased inadequate response to conventional synthetic disease-modifying antirheumatic drugs (OR=0.37, 95% CI=0.19-0.72, P=0.003), and rs41386349 increased rheumatoid factor seropositivity (OR=11.89, 95% CI=1.57-89.87, P=0.003). Sensitivity analysis adjusting for further potential confounders and using different treatment response definition indicated similar results. Additionally, DNA methylation change at regulatory region of PDCD1 was detected in RA (P=0.036). Altogether, this was the first study to suggest genetic and epigenetic changes of PDCD1 in RA subsets and RA. Independent prospective cohorts are awaited to address the implications of these genetic and epigenetic changes in disease pathogenesis and phenotypes of RA.

Defining and Predicting Opioid and Cocaine Treatment Response

Background: Treatment with methadone is effective in reducing heroin use, HIV risk, and death; however, not all patients respond to treatment. Better outcomes may emerge with personalized treatment based on factors that influence treatment courses. Objectives: To investigate psychosocial variables contributing to treatment response, using a comprehensive definition of treatment response. Methods: Seventy participants seeking treatment for heroin and cocaine addiction completed up to 40 weeks of daily methadone. At week 22, we administered a semi-structured interview for DSM-IV symptoms. We defined opioid treatment responders as people still enrolled at 22 weeks, not meeting past 30-day criteria for DSM-IV opioid abuse or dependence or DSM-5 opioid use disorder, and providing ≥75% opioid-negative urine samples in the 30 days prior to week 22. The same criteria were applied to assess cocaine treatment response. Results: Sample was 71% male, 41% White, and averaged 39.4 ± 7.9 years old. Opioid treatment response was more likely in participants who had been employed over the past 3 years (OR: 8.1, 95% CI: 1.2–55) and less likely in those who spent more time on hobbies (OR: 0.45, 95% CI: 0.23–0.88). Cocaine treatment response was more likely in participants who had a good relationship with their father (OR: 5.3, 95% CI: 1.2–24) and less likely if positive for hepatitis C (OR: 0.15, 95% CI: 0.03–0.75). Conclusions: Pretreatment characteristics differentially predict treatment response for heroin and cocaine use. Similar research in diverse patient groups may aid in the development of personalized treatment combining biologic treatment with targeted psychosocial interventions.

Tumor regression grade in gastric cancer after preoperative therapy.

168 Background: The AJCC 8th edition updated ypStage TNM grouping for patients with gastric cancer due to the increasing use of preoperative therapy. We previously reported that nodal status after preoperative therapy (ypN) was most predictive for overall survival (OS). We intended to investigate if tumor regression grade (TRG) of the primary tumor scored by pathologists is helpful to predict survival of gastric cancer patients treated with preoperative therapy. Methods: We reviewed an institutional database to identify patients with clinically non-metastatic gastric adenocarcinoma who underwent gastrectomy after preoperative chemo- or chemoradiation therapy. Pathology reports were reviewed, and TRG was classified into following categories: 0 (complete response), 1 (few clusters of viable tumor cells, £1-2%), 2 (significant response, viable cells £ 50%), 3 (minor or no treatment response, viable cells &gt; 50%). Associations between TRG and clinicopathological factors were examined. Univariable and multivariable Cox regressions were performed to determine associations with OS. Results: We identified 356 patients who met study criteria, including 80 (23%) patients with GEJ tumors; 56% were white and 60% were male. Preoperative chemoradiation therapy was given to 268 (75%). Fifty-six (16%) had TRG 0, 57 (16%) had TRG 1, 128 (36%) had TRG 2, and 115 (32%) had TRG 3. There were no associations between TRG and pretreatment factors. TRG 2 or 3 was associated with advanced ypT and ypN categories (both p &lt; 0.001), ypM1 (p = 0.004), and R1 resection (0.052). Of all patients, median OS was 6.6 y, and 5-year OS was 54.1%. TRG 3 was associated with worse OS than other groups ( p = 0.015), while there was no significant OS difference among TRG 0-2 groups ( p = 0.803) in univariate analyses. On multivariable analysis, TRG was not associated with OS after adjustment for ypN status. Conclusions: In patients with gastric cancer who underwent preoperative therapy, TRG 3 was associated with advanced ypStage and R1 resection. Patients with TRG 3 had worse OS, due to associated advanced ypStage, particularly ypN+ status. Further studies are warranted to identify better definitions of treatment response and to identify the optimal modality for obtaining ypN0 status.

Identifying standardized definitions of treatment response in trichotillomania: A meta-analysis

BackgroundSymptom severity in trichotillomania clinical trials is typically rated using the Massachusetts General Hospital Hair Pulling Scale (MGH-HPS) and the National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS). There are no universal definitions of treatment response on these scales. The absence of empirically supported definitions of treatment response hampers advances in trichotillomania treatment. MethodsPubMed and CENTRAL databases were searched for trichotillomania clinical trials. A total of 14 studies were identified and 7 provided adequate data to be included in the meta-analysis (n = 270). Meta-DiSc software was employed. The Youden index and distance to corner were used to determine the optimal cut-point. Response was defined by the Clinical Global Impressions Improvement scale score ≤ 2. ResultsThe optimal cut-points for identifying response on the MGH-HPS was a 35% percent reduction [Youden Index 0.48; distance to corner 0.37] or a seven-point reduction [Youden Index 0.43; distance to corner 0.40]. The optimal cut-points for the NIMH-TSS was a 50% reduction [Youden Index 0.57; distance to corner 0.34] or a six-point reduction [Youden Index 0.53; distance to corner 0.36]. The optimal cut-points were similar when the analysis was confined to only trichotillomania trials involving adult subjects, but the scales appeared to have improved ability to define treatment response when pediatric subjects were excluded. ConclusionThis study provides empirically determined cut-points of treatment response on the MGH-HPS and NIMH-TSS. These data-driven cut-points will benefit future research in trichotillomania by providing definitions of treatment response that can be defined a priori in clinical trials.