Strategic Trial Designs To Avoid Pitfalls, Interpreting and Reducing High Placebo Rates, Era of More Stringent Trial Endpoints (e.g.: HiSCR 50 → HiSCR75/90/100, NRS 0/1)

AB0412 Exploratory Results from The Bliss and Illuminate Trials Support The Design of The CHABLIS-SC1 Trial, A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study To Evaluate The Efficacy and Safety of...

BackgroundRisankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks.AimsFORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZBMethodsWeek 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time.ResultsRates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P<0.01); RZB 180mg was superior to PBO for clinical remission per CDAI and endoscopic response ( P<0.01). Endoscopic remission and deep remission rates increased over time with 360mg, remained steady with 180mg, and decreased with PBO. Mean fecal calprotectin (FCP) and C-reactive protein (CRP) levels decreased with SC RZB, but increased with PBO, over 52wks. Exposure-adjusted event rates (per 100 pts-years) of serious adverse event (AE) were generally similar among groups (360mg, 21.0 E/100PY and 180mg, 19.5 E/100PY vs PBO, 19.3 E/100PY), as were AEs leading to drug discontinuation (4.8 E/100PY and 2.4 E/100PY vs 3.7 E/100PY), and serious infections (6.0 E/100PY and 3.0 E/100PY vs 5.0 E/100PY).ConclusionsIn pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated.Funding AgenciesAbbVie

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

To review progress in the field of clinical trials for SLE. Treatment development for SLE has been marked by failures of many later phase studies, representing billions of dollars of lost research and development funding. Recently, more successful Phase II trials have tested reductions in background medications, novel stringent endpoints, and identification of informative immunologic subsets to achieve greater treatment effects. A large number of agents with promising novel biologic mechanisms have continued to enter clinical development, and momentum is building to capitalize on newer strategies for trial designs. Widespread SLE drug development is proceeding despite setbacks and controversies. Approaches focusing on patients with high disease activity, reduction of background polypharmacy, or increased endpoint stringency provide strategies that might improve interpretation of trial results. Pharmacodynamics of immune-modulation is a field in its infancy, but ripe for development.

Background:For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow.Methods:This was a phase 2 study following the two-stage “minimax” trial design. Participants received IV NAC (150 mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) ≤10 μmol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel events.Results:There were 12 participants in stage 1 who received treatment, with none achieving TSBAs ≤10 μmol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2. There were 32 adverse events in 11 participants, including 5 serious adverse events which were considered part of the participants’ natural clinical course and not directly attributable to NAC treatment. Analyses of secondary outcomes demonstrated no difference in clinical markers or occurrence of sentinel events between study participants and matched historical controls.Conclusions:This study demonstrates how the two-stage “minimax” trial design can be used to efficiently evaluate potential therapies for BA. Although the primary endpoint was not met, NAC therapy was generally well-tolerated. NAC therapy may prove efficacious in future trials with (i) a less stringent primary endpoint and/or (ii) a longer course of treatment (NCT03499249).

OP0056 MAINTENANCE OF CLINICAL RESPONSE IN INDIVIDUAL CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS TREATED WITH SUBCUTANEOUS ABATACEPT

INTRODUCTION: Randomized clinical trials (RCTs) represent the gold standard for clinical evidence. However, they have also raised concerns over generalizability due to unrealistic patient selection and endpoints. Real-world data (RWD) is receiving growing interest from the FDA as a complementary source of evidence. However, the suitability of these data for RCT-grade evidence and best practices in their use remain unclear. Here we compare the real-world effectiveness of Tofacitinib with efficacy assessed by RCTs of Inflammatory Bowel Disease (IBD). METHODS: Electronic health records (EHR) at the University of California San Francisco (UCSF) were reviewed for IBD patients prescribed Tofacitinib following a pre-protocol. The primary outcome was drug effectiveness measured by continued use and by RCT endpoints. Secondary outcomes assessed the completeness of RWD to measure RCT endpoints and the number of patients meeting RCT inclusion criteria. RESULTS: 68 Ulcerative Colitis (UC) and 18 Crohn’s Disease (CD) patients received Tofacitinib (Figure 1). Most of the data needed to calculate the RCT endpoints was available in the EHR (77% and 91%) with the remainder imputed. The baseline characteristics of the UCSF and trial cohorts were similar, except for greater disease duration and 100% TNFi failure in UCSF patients (Table 1). However, 0% of the real-world UC cohort met the RCT inclusion criteria (Table 2). The rate of continued treatment at 1 year was greater than 50% irrespective of disease subtype. Time-to-treatment-failure curves were nearly identical for UC and CD, with all drop-off occurring within the first 6 months. This rate of continued treatment in practice was significantly greater than the RCT primary endpoint and least stringent secondary endpoint (P-values 0.003 and 0.08) for UC, and for CD (P-value 0.02). However, the rates of meeting the primary endpoint for both subtypes using the Mayo score and CDAI were identical (P-values 0.5 and 1.0). CONCLUSION: Routinely collected data is sufficiently detailed to measure IBD trial endpoints. Analysis of RWD reproduced Tofacitinib efficacy measured by RCTs, despite trial selection criteria excluding most UCSF patients. However, real-world use patterns indicate much greater treatment durability than that suggested by trial endpoints, likely related to different treatment failure thresholds used in clinical care. These results support a role for JAK inhibition in CD, and overall highlight the value of real-world evidence to complement that obtained by RCTs.

Endoscopic Sphincterotomy for Sphincter of Oddi Dysfunction: Inefficacious Therapy for a Fictitious Disease

GFR Decline as an End Point in Trials of CKD: A Viewpoint From the FDA

The present review presents an overview of the evolution in trial design from mainly randomized placebo-controlled efficacy trials to more strategic clinical trials in rheumatoid arthritis and spondyloarthritis. Additionally, it relates to how these differently designed trials have affected clinical practice. Placebo-controlled clinical trials, comparing a new agent to placebo on a stable background, have resulted in the development of a wide array of therapeutic agents in rheumatoid arthritis and spondyloarthritis. However, these kind of trials do have some down sides as they do not provide evidence on the optimal strategy to use this multitude of treatments in daily clinical practice and the ethics concerning a placebo phase are often discussed. These and other concerns resulted in the emergence of various different types of trials in rheumatoid arthritis. A similar change of focus is now observed in spondyloarthritis clinical trials. We address literature on direct comparison ('head-to-head'), noninferiority trials, induction-maintenance, discontinuation, and treat-to-target/tight control clinical trials. In recent years various clinical trials have been published with a design different from placebo-controlled clinical trials. These novel trial designs aimed to provide guidance on the optimal way to use the full range of targeted treatments available and to make it possible, in some design, to leave out the placebo. In rheumatoid arthritis, some of these more strategic type of trials have had a large impact on common practice. In spondyloarthritis, the first steps toward trials with a more strategic design have been taken, and it stands to reason that more will follow.

Background: Immune checkpoint inhibitors (ICI) are rarely administered as first-line monotherapies for cancer. ICI are currently being trialed as combination ICI therapies, ICI in combination with standard chemo-(or other) therapies, or as second-line therapies following relapse, but many of these trials fail due to lack of optimal design. Here we sought to identify which checkpoint genes are differentially expressed (DE) in the presence of therapeutically targetable DNA mutations prior to treatment in order to facilitate the rational design of clinical trials for first-line ICI combination therapies. Methods: Whole-exome (WES) variant calls and whole-transcriptome expression values (RNAseq) were acquired for 5767 samples across 28 solid tumor subtypes from TCGA sources including breast (N=981), thymic (N=404), melanoma (N=344), prostate (N=331), gliobastoma multiforme (GBM, N=289) among others. A curated list of 274 targetable single nucleotide variants (SNVs) was obtained from ImmunityBio sources based on FDA labels, literature review, and trial notes. Ten checkpoint genes significantly DE between targetable SNV mutant (mt) vs. wild-type (wt) were identified by t-tests corrected for multiple hypothesis testing. Checkpoint DE was then validated as significant in an external cohort of 2739 unselected later-stage clinical cases from the NantHealth database with similarly profiled paired WES &amp; RNAseq, comprised of breast (N=576), colon (N=314), lung (N=283), pancreatic (N=221), ovarian (N=196), among others. Tissue subtype enrichment for targetable mutations was assessed by Fisher's exact test. Results: Twenty-three significant associations between targetable mt and DE checkpoint genes were identified in TCGA cases; 10 were validated in the external cohort. The vemurafenib target BRAF V600E was found coinciding with increased PD1, PDL1, and CTLA4 (adj. p=2.4e-3, 1.1e-23, 6.6e-7 respectively) as well as decreased IDO1 (adj. p=3.4e-6), and the effect size was larger than that of tissue-type. TIM3 was found significantly elevated in lapatinib-sensitive EGFR G598V patients (adj. p=1.0e-5) most prevalent in GBM, and conversely suppressed in FGFR3 S249C patients (adj. p=0.04) that are significantly enriched in bladder cancers. PIK3CA E545K patients, mostly cervical cancers, showed higher IDO1 expression (adj. p=3.3e-4) suggesting sensitivity to combined alpelisib/epacadostat. Conclusions: NGS data inform decisions for use of gene mutation-targeted therapies; use of similar analysis when paired with RNAseq may support efforts to replace chemotherapy with more efficacious/safer combined immuno- and mutation-targeted therapies. Our findings here suggest future studies may result in the optimization of ICI - gene targeted therapy trials. Citation Format: Jacob J. Adashek, Christopher W. Szeto, Saihitha Veerapaneni, Andrea Preble, Sandeep K. Reddy, Philippe E. Spiess. Validated differential expression of immunoregulatory molecules that coincide with targetable mutations may provide novel insights into strategic trial design for therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2224.

Background Over the past decade, therapeutic goals in ulcerative colitis (UC) have shifted from mere symptom control towards achieving deeper, multidimensional remission. This has led to a critical re-evaluation of the validity of traditional single endpoints in representing disease activity and therapeutic success [1,2]. A Delphi consensus process has proposed a new concept of comprehensive disease control (CDC), combining multiple clinical, endoscopic, and patient-centered endpoints to define a state of disease inactivity [3]. We hypothesized that this stringent combined endpoint might identify a molecular signature of minimal residual inflammation. To test this, we analyzed mRNA and mucosa-associated microbiota signatures in a cohort of UC patients across different remission categories. Methods A total of 211 colonic biopsies were collected from 173 UC patients between 2010 and 2020 at Kiel University Hospital. Bulk mRNA sequencing and mucosal 16S rRNA analysis was performed. Patients were categorized according to the following remission criteria: Biochemical: CRP &amp;lt; 5mg/dL and leukocytes 2.5–9/nL; Clinical: pMayo 0–1; Histological: Nancy Index 0–1; Endoscopic: eMayo 0. Patients fulfilling all the above remission criteria were defined as achieving CDC. A random forest approach (80% training/20% testing) was iteratively applied to identify molecular features predictive of CDC. Results Microbial and transcriptomic data reflected gradients of inflammation. Comparative analyses revealed overlapping yet distinct molecular and microbial signatures across individual and combined remission categories. None of the 31 CDC patients required IBD-related hospitalization or surgery during 2-year follow-up, supporting its relevance as a state of deep disease inactivity. Linear mixed model analysis identified IBD-related Lachnoclostridium and Lachnospiraceae FC020 as differentially abundant in CDC. Transcriptomic profiling identified a molecular gradient between CDC and non-CDC patients, enriched for pathways related to fatty acid metabolism and downregulated immune responses. The random forest model identified 19 transcriptomic features predictive of CDC (AUC 0.856), including CXCL1, KRT7, SLC6A14, ESRRA, FGFR3, ITPKA, which were previously linked with IBD and regulated in line with existing literature. Conclusion CDC represents a biologically, deeply inactive state of UC that extends to the molecular and microbial level of the intestinal mucosa. The molecular gradient signature points to a continuum of mucosal healing and supports the development of objective biomarkers capable of quantifying minimal residual disease activity. Validation of this molecular signature in external cohorts will clarify its prognostic relevance for long-term disease outcomes.

ObjectiveSecukinumab 150 mg has demonstrated significant improvement in signs and symptoms of ankylosing spondylitis (AS), with response rates sustained for up to 5 years. Here, we report end‐of‐study 3‐year efficacy and safety results of secukinumab 150 and 300 mg from the MEASURE 3 study.MethodsA total of 226 patients was randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous (s.c.) secukinumab 300/150 mg every 4 weeks or a matched placebo. At week 16, placebo patients were re‐randomized to s.c. secukinumab 300/150 mg. Analysis at week 156 included patients initially randomized to secukinumab and those who switched from placebo to secukinumab at week 16 (any secukinumab 300/150 mg). Outcome measures at week 156 included Assessment of Spondyloarthritis International Society (ASAS) 20/40, Bath Ankylosing Spondylitis Disease Activity Index, ASAS partial remission (PR), ASAS 5/6, and Ankylosing Spondylitis Disease Activity Score–C‐reactive protein inactive disease.ResultsThe retention rates from weeks 16 to 156 were 80.5% and 80.9% in secukinumab 300 and 150 mg, respectively. ASAS 20/40 response rates at week 156 were 75.0%/56.5% and 68.2%/47.7% for secukinumab 300 and 150 mg, respectively. At week 156, response rates on more stringent clinical end points (eg, ASAS 40, ASAS‐PR) were higher with the 300‐mg dose, particularly in tumor necrosis factor (TNF)–inadequate responder (IR) patients. No new safety findings were observed.ConclusionSecukinumab (300 and 150 mg) provided sustained improvements through 3 years in the signs and symptoms of active AS. Improvements with secukinumab 300 mg were numerically higher compared with the 150‐mg dose for some higher hurdle end points and in TNF‐IR patients. The safety profile of secukinumab was consistent with previous reports.

Background/Aims: Pro-/pre-/synbiotics supplementation seems to provide beneficial effects in various aspects of abdominal pathology. Skepticism exists with respect to their effects on colorectal cancer (CRC) patients. This review presents the potential clinical applications of pro-/pre-/synbiotics in CRC surgery. Methods: A literature search of electronic databases was conducted and all studies published on ‘probiotics’, ‘prebiotics’ and ‘synbiotics’ were collected. Among them, the ones referring to CRC and which had any clinical relevance offering information on perioperative parameters were used. Results: Incorporation of pre-/pro-/synbiotic formulations in the preoperative mechanical bowel preparation cannot be supported by the current evidence. Limited clinical studies may be promising in supporting their potentially protective role against postoperative infectious complications. Encouraging are the results on their protective role against adjuvant (chemo)radiation-induced diarrhea. Such supplementation may also hold promise to improve postcolectomy gastrointestinal related quality of life. Conclusions: Despite the positive results and plethora of agents, bacterial combinations and concentrations, the inconsistency in administration, the inhomogeneity of comparison groups and lack of stringent clinical endpoints remain obstacles in the effort to establish a definitive clinical strategy at this time. Further work is warranted to gain a keen understanding of their clinical value in CRC patients.

27571 Dupilumab provides clinically meaningful responses in adults with moderate-to-severe atopic dermatitis (AD): Results from LIBERTY AD CHRONOS study