Clinical Efficacy Endpoints Research Articles

Preventing the Progression of Episodic Migraine to Chronic Migraine with Acute Treatment Optimization.

To evaluate the evidence regarding acute migraine treatment optimization to prevent the progression of episodic migraine to chronic migraine. This review also provides a summary of evidence-based acute migraine treatments and how to tailor a regimen based on an individual patient's needs. Several acute migraine treatments have been food and drug administration (FDA)-approved since 2020. This review summarizes pain freedom data at 2h for these medications and devices and examines the classic acute migraine treatments. This review presents the existing data about acute treatment optimization and its preventive role in the progression of episodic migraine to chronic migraine. We present updated clinical trial efficacy endpoints from the American Headache Society (AHS) and the FDA and review the evidence for acute migraine treatments currently available in clinical practice.

P341 Pharmacokinetics and exposure-response analyses of upadacitinib in patients with moderate to severe ulcerative colitis – Analyses of induction and maintenance clinical trials

Abstract Background Upadacitinib (UPA), an oral selective and reversible JAK1 inhibitor, showed favorable efficacy and safety profile in Phase, 2b and, 3 studies in subjects with moderate to severe ulcerative colitis (UC). Population pharmacokinetics and exposure-response analyses were performed to characterize the relationships between UPA plasma exposures and key efficacy and safety endpoints using data from these studies. Methods The pharmacokinetics (PK), efficacy, and safety of UPA for induction and maintenance treatment in UC were evaluated in a Phase, 2b induction, two replicate Phase, 3 induction, and a Phase, 3 maintenance clinical trials. UPA PK was characterized using data from, 978 UC patients. UPA exposure-response relationships for key efficacy and safety endpoints at the end of induction and maintenance periods were characterized using data from, 1,234 and, 449 UC patients, respectively. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across UPA doses of, 7.5 mg to, 45 mg once daily (QD) for induction and, 15 mg to, 30 mg QD for maintenance. Results UPA PK in UC patients was consistent with other patient populations and between the induction and maintenance periods. The percentage of subjects achieving clinical and endoscopic efficacy endpoints at the end of the induction increased with increasing UPA average plasma concentration (Cavg), and became mostly flat at Cavg values approximately equivalent to the, 45 mg QD (Figure, 1). For maintenance treatment, there was a trend for increasing the percentage of subjects achieving clinical remission, steroid-free remission, endoscopic improvement, and histo-endoscopic mucosal improvement within the range of UPA plasma exposures evaluated. Exposures associated with UPA, 30 mg QD were estimated to provide a, 8% to, 10% increase in the percentage of subjects achieving these endpoints compared to, 15 mg QD (Figure, 2). There was no trend for exposure-response relationships within the range of evaluated UPA exposures for any of the evaluated safety endpoints (>2 g/dL decrease in hemoglobin and >2 g/dL decrease in hemoglobin and < lower limit for normal, hemoglobin <, 8 g/dL, lymphopenia ≥ Grade, 3, neutropenia ≥ Grade, 3, Herpes Zoster infection, serious infections, and pneumonia) at the end of induction or maintenance periods. Conclusion UPA plasma exposures associated with the, 45 mg QD induction dose maximized efficacy for clinical and endoscopic endpoints at Week, 8. Plasma exposures associated with UPA, 30 mg maintenance dose provide additional incremental benefit compared to, 15 mg QD. No trends were observed for increase in the evaluated safety events with increasing UPA plasma exposures at the end of induction or maintenance periods.

HPV vaccination among seropositive, DNA negative cohorts: a systematic review & meta-analysis.

ObjectiveVaccine efficacy among previously exposed, but currently uninfected women, i.e., those who have serological evidence of a prior human papillomavirus (HPV) infection without corresponding detectable HPV DNA, remains incompletely defined. This meta-analysis assessed the serotype-specific efficacy of prophylactic HPV vaccination against HPV16/18 persistent infection (PI) and cervical intraepithelial neoplasia (CIN) among seropositive, DNA negative (SPDN) women enrolled to randomized controlled trials (RCTs) of HPV L1-based vaccines.MethodsSearches were conducted on 08/16/20 on MEDLINE, Embase, Scopus and CENTRAL. RCTs of L1-based prophylactic bivalent or quadrivalent HPV vaccines, reporting serotype-specific clinical efficacy endpoints in the HPV16/18 seropositive, DNA-negative populations were included. Relative risks (RRs) of 6-month PI (6mPI), 12-month PI (12mPI), CIN1+ and CIN2+ were pooled using a random-effects model.ResultsA total of 1,727 citations were reviewed. 8 studies, with a total of 9,569 SPDN participants, met all eligibility criteria. The RR of 6mPI (RR=0.22; 95% confidence interval [CI]=0.08–0.61; p=0.018), 12mPI (RR=0.20; 95% CI=0.05–0.80; p=0.035), CIN1+ (RR=0.13; 95% CI=0.05–0.30; p=0.003) and CIN2+ (RR=0.15; 95% CI=0.04–0.59; p=0.022) was significantly reduced in the vaccinated compared to the unvaccinated group.ConclusionOur findings suggest high serotype-specific efficacy for HPV vaccination among cohorts of women with evidence of prior HPV16/18 infections, including 87% efficacy (95% CI=70%–95%; p=0.003) against HPV16/18 cervical dysplasia. HPV vaccination is highly effective among uninfected women, regardless of prior exposure history.Trial RegistrationPROSPERO Identifier: CRD42020206888

Population pharmacokinetics and exposure‐response modeling analyses of guselkumab in patients with psoriatic arthritis

Guselkumab is an anti‐interleukin‐23 human monoclonal antibody effective in treating psoriatic arthritis (PsA). To characterize the pharmacokinetics (PKs) and exposure‐response relationship of guselkumab in PsA, population PKs, and exposure‐response modeling, analyses were conducted using data from pivotal phase III studies of subcutaneous guselkumab in patients with PsA. The observed serum concentration‐time data of guselkumab were adequately described by a one‐compartment linear PK model with first‐order absorption and elimination. Covariates identified as contributing to the observed guselkumab PK variability were body weight and diabetes comorbidity; however, the magnitude of the effects of these covariates was not considered clinically relevant, and dose adjustment was not warranted for the patient population investigated. Positive exposure‐response relationships were demonstrated with landmark and longitudinal exposure‐response analyses between guselkumab exposure and clinical efficacy end points (American College of Rheumatology [ACR] 20%, 50%, and 70% improvement criteria and Investigator’s Global Assessment [IGA] of psoriasis) at weeks 20 and/or 24, with no clinically relevant differences observed in improvement of PsA signs and symptoms between the two guselkumab treatment regimens evaluated (100 mg every 4 weeks or 100 mg at weeks 0 and 4, then every 8 weeks). Baseline Disease Activity Score in 28 joints (DAS28), Psoriasis Area and Severity Index (PASI) score, and/or C‐reactive protein level were identified as influencing covariates on guselkumab exposure‐response model parameters. These results provide a comprehensive evaluation of subcutaneous guselkumab PKs and exposure‐response relationship that supports the dose regimen of 100 mg at weeks 0 and 4, then every 8 weeks in patients with PsA.

Item‐level analysis of clinical measures in patients with early symptomatic Alzheimer’s disease following treatment with high‐dose aducanumab in the phase 3 study EMERGE

AbstractBackgroundEMERGE (NCT02484547), 1 of 2 Phase 3 trials evaluating aducanumab in patients with early Alzheimer’s disease (AD), demonstrated a statistically significant drug‐placebo difference in the prespecified primary and secondary clinical endpoints. We examined in EMERGE participants the change from baseline item‐level scores in primary, secondary, and tertiary clinical endpoints that, in combination, comprised a set of cognitive, functional, and neuropsychiatric instruments that provide a comprehensive assessment of AD.MethodEMERGE (N=1643) included participants aged 50‐85 years who met clinical criteria for MCI due to AD or mild AD dementia, with confirmed amyloid pathology. Participants were randomized to receive high‐dose aducanumab, low‐dose aducanumab, or placebo. The primary endpoint was change from baseline in CDR‐SB score at Week 78. Secondary outcome measures included MMSE, ADAS‐Cog13, and ADCS‐ADL‐MCI scores. NPI‐10 score was a tertiary outcome. Item‐level analyses using mixed model for repeated measures (MMRM) were conducted on these clinical efficacy endpoints using the ITT population. This analysis is considered descriptive due to its deviation from the normality assumption and thus no multiplicity adjustment was considered.ResultThe aducanumab high‐dose group demonstrated a consistent drug‐placebo difference across 5 clinical efficacy endpoints, slowing clinical decline over 78 weeks. Treatment effects were observed across all 6 domains of the CDR. An aducanumab treatment effect was evident by slowing of decline on the ADAS‐Cog13 items sensitive to change in early symptomatic AD (e.g., orientation, word recall [immediate and delayed], word recognition, and number cancellation). Additionally, clinical benefit of aducanumab with respect to preserving daily function was observed across a broad range of items on the ADCS‐ADL‐MCI. Finally, aducanumab treatment was associated with an attenuation of behavioral and psychiatric symptoms associated with AD, as measured by NPI‐10, and an accompanying decrease in caregiver distress.ConclusionAducanumab treatment effects, observed across a broad array of outcome measures, are clinically relevant. Item‐level analyses demonstrated consistency across cognitive, function, and behavioral domains sensitive to impairments that are detectable even in the early stages of AD. Holistically, these measures reflect the perspectives of patients, caregivers, and clinicians, thereby supporting the importance and meaningfulness of an aducanumab treatment effect in early AD.

DIPS (Dystonia Image-based Programming of Stimulation: a prospective, randomized, double-blind crossover trial)

IntroductionDeep brain stimulation of the internal globus pallidus is an effective treatment for dystonia. However, there is a large variability in clinical outcome with up to 25% non-responders even in highly selected primary dystonia patients. In a large cohort of patients we recently demonstrated that the variable clinical outcomes of pallidal DBS for dystonia may result to a large degree by the exact location and stimulation volume within the pallidal region. Here we test a novel approach of programing based on these insights: we first defined probabilistic maps of anti-dystonic effects by aggregating individual electrode locations and volumes of tissue activated of > 80 patients collected in a multicentre effort. We subsequently modified the algorithms to be able to test all possible stimulation settings of de novo patients in silico based on the expected clinical outcome and thus potentially predict the best possible stimulation parameters for the individual patients.MethodsWithin the framework of a BMBF-funded study, this concept of a computer-based prediction of optimal stimulation parameters for patients with dystonia will be tested in a randomized, controlled crossover study. The main parameter for clinical efficacy and primary endpoint is based on the blinded physician rating of dystonia severity reflected by Clinical Dystonia Rating Scales for both interventions (best clinical settings and model predicted settings) after 4 weeks of continuous stimulation. The primary endpoint is defined as “successful treatment with model predicted settings” (yes or no). The value is “yes” if the motor symptoms with model predicted settings are equal or better (tolerance 5% of absolute difference in percentages) to clinical settings. Secondary endpoints will include measures of quality of life, calculated energy consumption of the neurostimulation system and physician time for programming.PerspectiveWe envision, that computer-guided deep brain stimulation programming in silico might provide optimal stimulation settings for patients with dystonia without the burden of months of programming sessions. The study protocol is designed to evaluate which programming method is more effective in controlling motor symptom severity and improving quality of life in dystonia (best clinical settings and model predicted settings).Trial registration Registered with ClinicalTrials.gov on Oct 27, 2021 (NCT05097001).

A Randomized Controlled Trial to Evaluate the Safety and Efficacy of a Novel Inhaled Biologic Therapeutic in Adults with Respiratory Distress Secondary to COVID-19 Infection

IntroductionInhaled therapeutics may act to directly target and attenuate lung inflammation due to COVID-19. An inhalation form of a novel biologic drug, AMP5A, is being developed as an immunomodulatory agent to treat dysregulated immune responses and is being studied in hospitalized patients to treat respiratory complications due to COVID-19.MethodsA randomized, controlled, phase I trial was conducted to evaluate hospitalized adults with respiratory distress secondary to COVID-19. Patients received the standard care (SOC) for COVID-19, including respiratory therapy, corticosteroids, and antiviral therapies such as remdesivir. Patients were randomized 1:1 to inhalation treatment with AMP5A as an adjunct to SOC or to SOC alone (control). AMP5A was administered via inhalation daily for 5 days via hand-held nebulizer, non-invasive ventilator, or mechanical ventilation. Safety and clinical efficacy endpoints were evaluated.ResultsForty subjects were enrolled and randomized (n = 19 AMP5A, n = 21 control). Remdesivir was used in fewer AMP5A subjects (26%) than control (52%), and dexamethasone was administered for most subjects (84% AMP5A, 71% control). The study met its primary endpoint with no AMP5A treatment-related adverse events (AEs), and the incidence and severity of AEs were comparable between groups: 18 AEs for control (8 mild, 1 moderate, 9 severe) and 19 AEs for AMP5A (7 mild, 7 moderate, 5 severe). Notably, subjects treated with AMP5A had fewer deaths (5% vs. 24%), shorter hospital stay (8 days vs. 12 days), fewer ICU admissions (21% vs. 33%), and a greater proportion with improved clinical outcomes than control.ConclusionThe phase I clinical results indicate inhaled AMP5A is safe, is well tolerated, and could lead to fewer patients experiencing deterioration or death. Based on the treatment effect (i.e., reduced mortality), a phase II trial has been initiated.Trial RegistrationClinicaltrials.gov identifier: NCT04606784.

Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: Post Hoc Analyses from MAIA

Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: Post Hoc Analyses from MAIA

Experience with various occluder types for endovascular hemodynamic isolation of the left atrium appendage in patients with non-valvular atrial fibrillation

The aimof our study was to evaluate implantation efficacy and safety across various occluder types and to identify factors determining device selection.Methods. This single-site prospective observational study included patients above the age of 40 years with non-valvular atrial fibrillation (AF) and high thromboembolic risk, undergoing endovascular isolation of the left atrium appendage (LAA) with Watchman or Amplatzer Cardiac Plug/Amulet devices. Occluders were implanted to patients without either had contraindications to anticoagulant therapy (ACT) or refused ACT. We evaluated technical aspects of device implantation, short- and long-term outcomes of the intervention over 3 years of follow-up.Results. 90 patients were enrolled in the study (62 into the Watchman arm and 28 into the Amplatzer arm). Interventions were technically successful in 89 cases. In 1 patient (1/90, 1.1%) technical success was not achieved due to device migration (Amplatzer Amulet). The incidence of early (occurring within˂ 24 hours) implantation complications was 0% in the Watchman arm, and 3.6% in the Amplatzer arm (1/28) (р=0.135) (device migration). The cumulative incidence of all in-hospital complications was 11.3% and 14.3%, respectively (р=0.734). No significant differences between arms were found in the incidence of device thrombosis within 90 days post-implantation (3.3% in the Watchman’s arm and 8.3% in the Amplatzer arm, р=0.316). During the observation period, there were no significant differences in comparison groups in the incidence of net clinical efficacy endpoint events (р=0.58). The bleeding rate was 17.7% and 14.3%, respectively, р=0.769. No factors influencing the choice of the device could be identified reliably; however, there was a trend towards Watchman preference for appendage anatomic variants such as broccoli and cactus. Amplatzer was preferred in patients with contraindications to ACT.Conclusion.Implantation of Watchman and Amplatzer Amulet occluders is equally effective and safe in preventing thromboembolism in patients with AF not receiving ACT for various reasons. The individual choice of a device may be influenced by appendage anatomy and indications to occluder implantation.

Next-generation balloon-expandable Myval transcatheter heart valve in low-risk aortic stenosis patients.

We aimed to describe hemodynamic performance and clinical outcomes at 30-day follow-up of the balloon-expandable (BE) Myval transcatheter heart valve (THV) in low-risk patients. The results of the next-generation BE Myval THV in low-risk aortic stenosis (AS) patients are still unknown. Retrospective registry performed in nine European centers including patients with low predicted operative mortality risk according to Society of thoracic surgeons (STS) and European system for cardiac operative risk evaluation (EuroSCORE-II) scores. Between September 2019 and February 2021, a total of 100 patients (51% males, mean age 80 ± 6.5 years) were included. Mean STS score and EuroSCORE-II were 2.4 ± 0.8% and 2.2 ± 0.7%, respectively. Intermediate sizes were used in 39% (21.5 mm: 8%, 24.5 mm: 15%, 27.5 mm: 15%). There were no cases of valve embolization, coronary artery occlusion, annulus rupture, or procedural death. A definitive pacemaker implantation was needed in eight patients (8%). At 30-day follow-up aortic valve area (0.7 ± 0.2 vs. 2.1 ± 0.6cm2 ) and mean aortic valve gradient (43.4 ± 11.1 vs. 9.0 ± 3.7 mmHg) improved significantly (p < 0.001). Moderate aortic regurgitation occurred in 4%. Endpoints of early safety and clinical efficacy were 3 and 1%, respectively. Hemodynamic performance and 30-day clinical outcomes of the BE Myval THV in low-risk AS patients were favorable. Longer-term follow-up is warranted.

Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors

Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors. To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020. Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile. ClinicalTrials.gov Identifier: NCT02401815.

The ACURATE neo2 valve system for transcatheter aortic valve implantation: 30-day and 1-year outcomes

BackgroundTranscatheter aortic valve implantation (TAVI) has become standard treatment for elderly patients with symptomatic severe aortic valve stenosis. The ACURATE neo AS study evaluates 30-day and 1-year clinical and hemodynamic outcomes in patients treated with the ACURATE neo2 valve.MethodsThe primary endpoint of this single-arm multicenter study is 30-day all-cause mortality. Other key endpoints include device performance, echocardiographic measures assessed by an independent core laboratory, and VARC-2 clinical efficacy and safety endpoints through 12 months.ResultsThe study enrolled 120 patients (mean age 82.1 ± 4.0 years; 67.5% female, mean baseline STS score 4.8 ± 3.8%). The VARC-2 composite safety endpoint at 30 days occurred in 13.3% of patients. All-cause mortality was 3.3% at 30 days and 11.9% at 1 year. The 30-day stroke rate was 2.5% (disabling stroke 1.7%); there were no new strokes between 30 days and 12 months. The rate of permanent pacemaker implantation was 15.0% (18/120) at 30 days and 17.8% (21/120) at 1 year. No patients required re-intervention for valve-related dysfunction and there were no cases of valve thrombosis or endocarditis. Patients demonstrated significant improvement in mean aortic valve gradient (baseline 38.9 ± 13.1 mmHg, 1 year 7.8 ± 3.5 mmHg; P < 0.001 in a paired analysis). In the overall population, paravalvular leak was evaluated at 1 year as none/trace in 60.5%, mild in 37.0%, and moderate in 2.5%; no patients had severe PVL.ConclusionsOne-year outcomes from the ACURATE neo AS study support the safety and performance of TAVI with the ACURATE neo2 valve.Graphic

A phase I/II, multicenter, open-label study of REGN5668 (mucin [MUC]16 x CD28 bispecific antibody [bsAb]) with cemiplimab (programmed death [PD]-1 Ab) or REGN4018 (MUC16 x CD3 bsAb) in recurrent ovarian cancer (rOVCA).

TPS5602 Background: There is a high unmet need in rOVCA treatment, with 14,000 deaths/year in the US and a 30%‒40% 5-year overall survival rate in patients (pts) with advanced disease. REGN5668 and REGN4018 are human IgG4-based bsAbs that bridge ovarian MUC16+ tumor cells to CD28 and CD3, respectively, on T-cells to stimulate cytotoxicity. Cemiplimab is a human monoclonal Ab that blocks PD-1 binding to PD-ligand(L)1 and PD-L2. REGN5668 demonstrated increased preclinical anti-tumor activity with PD-1 inhibition or REGN4018 relative to each monotherapy. A Phase I/II study of REGN4018 alone or with cemiplimab is ongoing. Methods: This first-in-human study (NCT04590326) will assess safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN5668 with cemiplimab (Module 1) or REGN4018 (Module 2) in pts with rOVCA. Key inclusion criteria include histologically confirmed diagnosis of advanced epithelial ovarian (except carcinosarcoma), fallopian tube, or primary peritoneal cancer; serum CA-125 level ≥2x upper normal limit; ≥1 prior-line of platinum-based therapy; prior treatment with or intolerance to available standard-of-care therapy. Exclusion criteria include recent biologic therapy ( &lt; 5 half-lives or 28 days, whichever is longer, except &lt; 3 half-lives for bevacizumab or other nonimmunomodulatory Abs with half-lives &gt; 7 days); approved conventional therapy (except biologics or immunotherapy) &lt; 3 weeks (wks) or investigational agents &lt; 4 wks prior to first study dose; and anti–PD-L1 therapy &lt; 5 half-lives prior to first study dose. This two-phase study includes dose escalation (a 4+3 design modified from 3+3) and expansion phases. In Module 1, ≤84 pts will receive 3–4 wks of REGN5668 monotherapy lead-in at assigned intravenous (IV) weekly (QW) dose levels, followed by REGN5668 QW combined with cemiplimab IV every 3 wks. In Module 2, ≤106 pts will receive 4–5 wks of REGN4018 QW IV lead-in, followed by REGN4018 full QW dose combined with REGN5668 at initial and full assigned QW doses. In expansion, REGN5668+cemiplimab and REGN5668+REGN4018 combination regimens will each recruit 20 pts in stage 1 and 30 pts in stage 2 using a Simon two-stage design. In escalation, primary endpoints are dose-limiting toxicities, serious and treatment-emergent adverse events (TEAEs), deaths, laboratory abnormalities (Grade ≥3), concentrations of REGN5668 in serum alone and in each combination regimen; key secondary endpoint is objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. In expansion, primary endpoint is ORR by RECIST 1.1 for each combination; key secondary endpoints are TEAEs, serious AEs, deaths. Key exploratory endpoints are correlation between clinical efficacy endpoints and baseline protein expression levels of MUC16 and PD-L1. Clinical trial information: NCT04590326.

Efficacy of HPV vaccination among seropositive, DNA negative cohorts.

10552 Background: Prophylactic HPV vaccination of naïve cohorts is known to be highly effective in the prevention of incident HPV infection and HPV-associated cervical premalignancy. Conversely, vaccination of women with active (DNA+) HPV infections has been demonstrated to be ineffective. Vaccine efficacy among previously exposed, but currently uninfected women, i.e. those who have serological evidence of a prior HPV infection without corresponding detectable HPV DNA, remains incompletely defined. This meta-analysis assessed the serotype-specific efficacy of prophylactic HPV vaccination against HPV16/18 persistent infection (PI) and cervical intraepithelial neoplasia (CIN) among seropositive, DNA negative (SPDN) women enrolled to RCTs of HPV L1-based vaccines. Methods: The study protocol was prospectively registered on PROSPERO (CRD42020206888). Searches were conducted on 08/16/20 on MEDLINE, EMBASE, SCOPUS and CENTRAL. RCTs of L1-based prophylactic bivalent or quadrivalent HPV vaccines, reporting serotype-specific clinical efficacy endpoints in the HPV16/18 seropositive, DNA-negative populations were included. Two authors independently screened studies, extracted data and assessed for bias. Data for SPDN women were extracted from subgroup analyses within primary and secondary publications, publication supplements, and manufacturers' clinical study reports. Relative risks (RR) of 6-month persistent infection (6mPI), 12-month persistent infection (12mPI), CIN1+ and CIN2+ were pooled using a random-effects model. Results: A total of 1727 citations were reviewed. 8 studies, with a total of 9569 SPDN participants, met all eligibility criteria. The relative risk of 6mPI (RR: 0.22, 95% CI 0.08-0.61, p = 0.018), 12mPI (RR: 0.20, 95% CI 0.05-0.80, p = 0.035), CIN1+ (RR:0.13, 95% CI 0.05-0.30, p = 0.003) and CIN2+ (RR: 0.15, 95% CI 0.04-0.59, p = 0.022) was significantly reduced in the vaccinated compared to the unvaccinated group. The number needed to vaccinate (NNV) to prevent one case of CIN1+ and CIN2+ was 152 and 208 respectively. Conclusions: Our findings suggest high serotype-specific efficacy for HPV vaccination among cohorts of women with evidence of prior HPV 16/18 infections. Women without DNA evidence of active infection may be seronegative, implying naïve status and &gt; 99% efficacy; or seropositive, implying SPDN status and 87% efficacy against CIN1+ for HPV 16/18. Women without DNA evidence of HPV 16/18 infection should be offered prophylactic HPV vaccination regardless of prior exposure history.

Pharmacological Interventions for the Prevention and Treatment of Immune Checkpoint Inhibitor-Associated Enterocolitis: A Systematic Review.

Patients treated with immune checkpoint inhibitors (ICIs) may develop ICI-associated enterocolitis, for which there is no approved treatment. We aimed to systematically review the efficacy and safety of medical interventions for the prevention and treatment of ICI-associated enterocolitis. MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials (RCTs), cohort and case-control studies, and case series/reports, evaluating interventions (including corticosteroids, biologics, aminosalicylates, immunosuppressants, and fecal transplantation) for ICI-associated enterocolitis. Clinical, endoscopic, and histologic efficacy endpoints were evaluated. The Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to assess overall quality of evidence. A total of 160 studies (n = 1514) were included (one RCT, 3 retrospective cohort studies, 156 case reports/case series). Very low quality evidence from one RCT suggests budesonide is not effective for prevention of ICI-associated enterocolitis in ipilimumab-treated patients (relative risk 0.93 [95% confidence interval 0.56, 1.56]). Very low quality evidence suggests that corticosteroids, infliximab, and vedolizumab may be effective for treatment of ICI-associated enterocolitis by inducing clinical response and remission. No validated indices for measuring disease activity were used. Biologic treatment was used in 42% (641/1528) of patients, as reported in 97 studies. ICIs were discontinued in 65% (457/702) of patients, as reported in 63 studies. Current treatment recommendations for ICI-associated enterocolitis are based on very low quality evidence, primarily from case reports and case series. Large-scale prospective cohort studies and RCTs are needed to develop prophylactic and therapeutic treatments to minimize interruption or discontinuation of oncological therapies.

Outcomes of Mild Aortic Regurgitation After Transcatheter Aortic Valve Replacement

ABSTRACT Background: There has been an explosion in the clinical application of transcatheter aortic valve replacement (TAVR) worldwide. While moderate and severe grades of paravalvular regurgitation (PVR) are established as poor prognostic indicators, the impact of mild PVR is unclear. We therefore aimed to compare outcomes after TAVR between those who develop mild PVR versus none or trivial PVR. Methods: We identified 1,098 consecutive patients who underwent TAVR from January 2014 to December 2017. The primary outcome was all-cause mortality using Kaplan Meier curves. The secondary outcomes included heart failure readmissions and the composite endpoints of early safety and clinical efficacy according to VARC-2 definitions. Results: The median age was 82 years, 43% were females, and 94% were Caucasian. The procedure was done through a transfemoral approach, the indication for TAVR was severe AS in 97% of cases, and 72% had an Edwards SAPIEN 3 Transcatheter Heart Valve implanted. Mild PVR was seen in 191 (17.4%) patients, and the rest (82.6%) had no or trivial post-TAVR PVR. Mortality at 30-days and 1 year was similar between none/trivial and mild PVR groups (1.6% vs 1.7%, p = 0.93 & 6.3% vs 8.8%, p = 0.31). HF-related hospitalizations were the same at 30 days as well as 1 year in both groups (1.9% vs 0.8%, p = 0.209 and 4.5% vs 6.3%, p = 0.461). Conclusion: Although mild PVR is seen in approximately one-fifth of patients after TAVR, patients with mild PVR have similar outcomes compared to those with none or trivial PVR. Abbreviations: AR: Aortic Regurgitation; AV: Aortic Valve; HF: Heart Failure; VARC: Valve Academic Research Consortium; LVOT: Left Ventricular Outflow Tract; LVEF: Left Ventricular Ejection Fraction; PVR: Paravalvular Aortic Regurgitation; TAVR: Transcatheter Aortic Valve Replacement; TF: Transfemoral

Transcatheter pulmonary denervation in patients with left heart failure with reduced ejection fraction and combined precapillary and postcapillary pulmonary hypertension: A prospective single center experience.

The present study was a prospective, single-center, single-arm study to investigate the efficacy of transcatheter pulmonary artery denervation (TPADN) in patients with combined postcapillary and precapillary PH (Cpc-PH) associated with left heart failure with reduced ejection fraction (HF-rEF). Pulmonary hypertension (PH) in patients with left ventricular systolic dysfunction has a negative impact on outcome. The combination of pulmonary artery systolic pressure (PAPs) ≥60 mmHg, transpulmonary pressure gradient (TPG) ≥12 mmHg, nonreversible mean PAP, and pulmonary vascular resistance (PVR) ≥3.5 Wood Units was considered as too high risk for heart transplantation (HTx). The clinical efficacy endpoint was an improvement in 6-min walking test and the hemodynamic endpoints were changes in PAPs, PVR, and TPG between baseline and 6months. Circumferential radiofrequency applications were delivered around distal main, left and right pulmonary arteries. At each ablation point temperature was 45°C and energy 10W. TPADN was performed in 10 patients. At 6-month in 5 patients we observed reduction in PAP, PVR, TPG, and DPG and then 1 had successful HTx, 2 are on HTx waiting list, 2 received LVADs, 2 patients did not improve, and 3 patients died. TPADN may be beneficial in selected patients with HF-rEF and Cpc-PH.

Endpoints for Perianal Crohn's Disease Trials: Past, Present and Future.

Since the 1980s, many studies have evaluated the efficacy of therapies to improve the outcomes of patients with perianal Crohn's disease. We performed a systematic review to describe the evolution of endpoints in perianal fistulizing Crohn's disease. Efficacy outcomes, definitions and measurement tools were assessed. Electronic databases were searched up to November 1, 2020. All published randomized placebo-controlled trials enrolling patients with perianal fistula and Crohn's disease were eligible for inclusion. Ongoing randomized clinical trials were also described. Nineteen randomized controlled trials were included. Clinical efficacy endpoints were reported in all trials. Clinical response was the most frequent primary endpoint [6/19 studies, 31.6%], followed by clinical remission in four studies [21%]. Clinical response was defined as closure of at least 50% of fistulas, while remission was defined as closure of all fistulas. A combined clinical and radiological primary endpoint was used to assess fistula healing in four studies [21%]. The Perianal Disease Activity Index was a primary endpoint in only one study [5.5%]. In addition, eight ongoing controlled trials were identified. Combined clinical and radiological remission was the most frequent primary endpoint in these studies [4/8, 50%]. In this systematic review, significant changes in outcomes used in randomized clinical trials of perianal Crohn's disease were observed. Radiological endpoints are increasingly used in perianal fistulizing Crohn's disease trials.

Comparison of the Efficacy and Safety of Sacubitril/Valsartan versus Ramipril in Patients With ST-Segment Elevation Myocardial Infarction

The role of sacubitril and/or valsartan in patient with heart failure (HF) is established. Whether sacubitril and/or valsartan plays a role in improving outcomes in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. The current study aims to comparing the efficacy and safety of sacubitril and/or valsartan versus ramipril in post-STEMI patients. Patients presenting with STEMI were randomized to receive either sacubitril and/or valsartan or ramipril after primary percutaneous coronary intervention. The main efficacy endpoint was major adverse cardiac events (MACE) at 30 days and 6 months, defined as a composite of cardiac death, myocardial infarction, and HF hospitalizations. Multiple secondary clinical safety and efficacy endpoints were examined. A total of 200 patients were randomized from January 2018 to March 2019, mean age 54.5±10.4, 87% men, 75% presented with anterior wall STEMI. Baseline clinical and echocardiographic characteristics were comparable between groups. The primary endpoint of MACE was similar with sacubitril/valsartan versus ramipril at 30 days (p = 0.18); however, at 6 months, sacubitril/valsartan was associated with significant reduction of MACE (p = 0.005), mainly driven by reduction in HF hospitalizations (18% vs 36%, OR 0.40, 95% 0.22 to 0.75; p = 0.004). At 6 months, LV ejection fraction was higher with sacubitril/valsartan (46.8±12.5% vs 42.09±13.8%; p = 0.012), with improved LV remodelling (LV end diastolic dimension 50.6±3.9 mm vs 53.2±2.7 mm, p = 0.047; and LV end systolic dimension 36.1±3.4 mm versus 39.9±6.3 mm, p = 0.001) compared with ramipril. No difference in other efficacy or safety clinical endpoints was observed. In conclusion, early initiation of sacubitril/valsartan may offer clinical benefit and improvement in myocardial remodelling in post-STEMI patients.

Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer.

The advent of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment of patients with locally advanced unresectable and metastatic non-small cell lung cancer (NSCLC). Now, ICIs are undergoing evaluation as neoadjuvant therapy in patients with early-stage, resectable NSCLC using candidate surrogate endpoints of clinical efficacy, i.e., major pathologic response (MPR, ≤10% viable tumor cells in resected tumors). The initial results from early, small-scale trials are encouraging; however, they also reveal that a substantial number of patients with operable disease may not benefit from neoadjuvant ICIs. Consequently, much investigative effort is currently directed toward identifying mechanisms of resistance to ICI therapy in resectable NSCLC. There is also an urgent need for biomarkers that could be used to guide the clinical decision-making process and maximize the clinical benefit of ICIs in patients with early-stage, resectable NSCLC. Here, we summarize the initial results from the trials of neoadjuvant ICIs in patients with early-stage and locally advanced operable NSCLC and review the findings of studies investigating emerging biomarkers associated with those trials.