Prespecified Success Criteria Research Articles

A multivalent RSV vaccine based on the modified vaccinia Ankara vector shows moderate protection against disease caused by RSV in older adults in a phase 3 clinical study

Respiratory syncytial virus (RSV) causes a significant disease burden in older adults. The live recombinant vaccine based on a nonreplicating modified vaccinia Ankara (MVA-BN) poxvirus, MVA-BN-RSV, encoding for multiple proteins of RSV subtypes A and B, was assessed for efficacy against respiratory disease caused by RSV.Adults aged ≥60 years, with or without underlying chronic conditions, were enrolled and randomized in a 1:1 ratio to receive a single dose of vaccine or placebo and were followed for disease caused by RSV infection during the 2022–2023 season. The 2 primary endpoints were RSV-associated lower respiratory tract disease (LRTD) with ≥3 and ≥ 2 symptoms; acute respiratory disease (ARD) was a key secondary endpoint. The humoral RSV-specific immune response was assessed at baseline and 14 days post-vaccination. Safety was evaluated by collection of solicited adverse events (AEs) and unsolicited AEs for 7 and 28 days post-vaccination respectively, and SAEs for the entire study period.In total, 18,348 participants were included in the final efficacy and safety analyses. Vaccine efficacy was 42.9 % (95 % CI: −16.1; 71.9) against RSV-associated LRTD with ≥3 symptoms, 59.0 % (95 % CI: 34.7; 74.3) against LRTD with ≥2 symptoms, and 48.8 % (95 % CI: 25.8; 64.7) against ARD. The primary objective was not met for LRTD with ≥3 symptoms since the lower bound of the 95 % CI was below 20 %, the prespecified success criterion. The vaccine-elicited immune response showed mean fold-increases of 1.7 for RSV A and B neutralizing antibodies and 2.9 and 4.3 for RSV-specific IgG and IgA, respectively. The vaccine displayed mild to moderate reactogenicity, and no safety concerns were identified.MVA-BN-RSV induced suboptimal protection against RSV-associated LRTD, likely due to suboptimal neutralizing antibody response. The vaccine had an acceptable safety profile and confirmed immunogenicity, overall showing promise for MVA-BN-vectored constructs targeting other diseases.Trial Registration:Clinicaltrials.gov Identifier NCT05238025 (Registered February 14, 2022).

Reducing Preventable Bleeding Visits and Institutional Factor Costs for Patients with Bleeding Disorders with a Prospective Quality Improvement Project

Providing optimal care to patients with bleeding disorders requires specialized physician, laboratory, pharmacy, nursing, and institutional resources best achieved at Hemophilia Treatment Centers (HTCs). Current systems for managing the care of a resource intensive patient population may be suboptimal. We observed frequent bleeding related hospitalizations and emergency room (ER) visits in patients with bleeding disorders treated at our HTC that could have been potentially prevented by changes in outpatient care delivery. We initiated a prospective quality improvement (QI) project to improve care delivery and to reduce preventable bleeding related hospitalizations and ER visits for adult patients treated at our HTC. The interventions targeted patient-level and systems-level factors contributing to preventable visits, and barriers to care in our patient population. We compared preventable bleeding related hospitalizations and ER visits, institutional factor cost, use of prophylaxis in severe hemophilia, primary care physician attainment, and patient electronic portal enrollment before and after the QI intervention. In our population of adult patients with bleeding disorders (N=88), the intervention significantly reduced the primary outcome of preventable bleeding hospitalization or ER visit (P=0.0082, Figure), and reduced such visits by 85.4%, meeting the pre-specified criteria for success. Institutional factor acquisition costs to treat preventable bleeding were reduced by 94.5%, from $11,800 to $640 per patient per year; a projected savings of $982,088 yearly. Use of factor prophylaxis in patients with severe hemophilia increased from 58.8% to 100%, attainment of a primary care physician increased from 69.4% to 86.4%, and use of the electronic patient portal increased from 53.2% to 83%; all secondary outcomes met pre-specified criteria of success and were statistically significant. HTC clinic visit attendance was low at 55.2%. The majority of patients (71.6%) had at least one outpatient urgent episode (mean 0.72 episode per year), and 93% had non-urgent management (mean 9.3 episodes per year) occurring outside of a clinic visit. These data demonstrate that concerted outpatient management of patients with bleeding disorders with a quality improvement framework can reduce preventable hospitalization and ER visits. Decreased inpatient utilization resulted in substantial reductions in factor costs at the health system level. The clinical effort required to achieve these results was substantial, and required frequent provider engagement outside of regular clinic visits. The HTC can improve patient outcomes and reduce institutional costs from preventable bleeding episodes by supporting a collaborative quality improvement process led by physician, nursing, and laboratory coagulation experts.

Hyperthyroidism therapy: What can decision support systems already achieve?

AbstractCurrently, only a few theoretical support systems exist for the treatment of hyperthyroidism. They are typically not practically applicable and solely focus on Graves’ disease. The recently developed DigiThy software framework can be used to assist physicians for methimazole dose titration during the treatment of Graves’ disease. In this study, a pool of 60 virtual patients was created to compare physicians’ individual treatment approaches by 8 different physicians and students (including three colleagues, unexperienced with care of Graves’ disease) with the decision support system DigiThy in terms of already defined performance indices. These indices are used to assess the deviation of FT4 from the reference range throughout the treatment. The computer aided treatment algorithms outperformed the usual care approach according to different prespecified criteria for treatment success. Two out of the three unexperienced colleagues improved their treatment success over time, i.e. with more patients treated. In conclusion, our findings suggest that the DigiThy software may be a useful tool for use as a decision support system in routine care of patients with Graves’ disease, while also serving as an effective training tool for the education of physicians. Randomized controlled studies are required before implementation of DigiThy in daily clinical practice.

Abstract 15606: Effectiveness and Safety of the Dual Epicardial & Endocardial Procedure (DEEP) Approach for Treatment of Subjects With Persistent or Long Standing Persistent Atrial Fibrillation (PersAF/LSPAF) With Radiofrequency Ablation

Background: A collaborative approach between Electrophysiologists (EP) and Cardiothoracic Surgeons (CTS) to effectively target pulmonary veins (PVs) and substrate beyond PVs may improve outcomes for persistent and longstanding persistent AF (PersAF/LSPerAF). Hypothesis: A minimally invasive hybrid approach of bilateral thoracoscopic epicardial ablation and left atrial appendage exclusion (LAAE) with endocardial mapping/ablation (Hybrid approach) is safe and effective to treat advanced AF patients who have failed medical therapy. Aim: DEEP (NCT02393885) aims to establish safety and effectiveness of a Bipolar Radiofrequency (RF) System in a Hybrid approach to treat PersAF/LSPerAF. Methods: DEEP is a prospective, international, single arm trial at 17 sites. Key eligibility: adults with drug refractory PersAF/LSPerAF, left atrial diameter (LAD) ≤5.5cm, failed class I/III AAD, and ≤2 previous failed endocardial catheter ablations (CA). Epicardial surgical ablation included PV isolation, roof and floor lines (posterior LA box), left superior PV to LAA lesion, ganglionic plexi and Ligament of Marshall ablation and LAAE. CA followed 91-121 D post epicardial procedure. After 90 D blanking and 90 D AAD optimization periods, 24-hr rhythm monitoring and ECG were performed 6 and 12 M post CA with symptom driven monitoring between. Primary effectiveness was defined as freedom from atrial arrhythmia (>30 sec) absent new/increased dose of previously failed AAD through 12 M. Safety was device/procedure-related SAEs within 30 D of epicardial ablation and 7 D of CA in all who received anesthesia. Results: Ninety patients were enrolled in 2015-2020, 83.3% PersAF, 16.7% LSPerAF, mean age 63.4±7.74 yrs, 83.3% male, mean BMI 29.9, CHAD2DS2-VASc median 2.0 (1.0, 3.0), 48% failed CA, median AF duration 3.8 yrs, mean LAD 4.5cm. Primary effectiveness 70.6% (60/85; 95% CI 60.9%, 80.3%, p=0.0232) and freedom from AF through 12 M 78.8% (p=0.0002). The adverse event rate was 6.7% (6/90); equal in epi- and endocardial cohort. Both primary endpoints met prespecified success criteria. Conclusion: A collaborative approach between EP and CTS to Hybrid ablation is effective for PersAF/LSerPAF when benefit-risk is deemed favorable, given limited alternative treatments.

Original SARS-CoV-2 monovalent and Omicron BA.4/BA.5 bivalent COVID-19 mRNA vaccines: phase 2/3 trial interim results

This ongoing, open-label, phase 2/3 trial compared the safety and immunogenicity of the Omicron BA.4/BA.5-containing bivalent mRNA-1273.222 vaccine with the ancestral Wuhan-Hu-1 mRNA-1273 as booster doses. Two groups of adults who previously received mRNA-1273 as primary vaccination series and booster doses were enrolled in a sequential, nonrandomized manner and received single-second boosters of mRNA-1273 (n = 376) or bivalent mRNA-1273.222 (n = 511). Primary objectives were safety and the noninferiority or superiority of neutralizing antibody (nAb) responses against Omicron BA.4/BA.5 and ancestral SARS-CoV-2 with the D614G mutation (ancestral SARS-CoV-2 (D614G)), 28 days post boost. Superiority and noninferiority were based on prespecified success criteria (lower bounds of 95% CI > 1 and < 0.677, respectively) of the mRNA-1273.222:mRNA-1273 geometric mean ratios. Bivalent Omicron BA.4/BA.5-containing mRNA-1273.222 elicited superior nAb responses against BA.4/BA.5 versus mRNA-1273 and noninferior responses against ancestral SARS-CoV-2 (D614G) at day 29 post boost in participants without detectable prior SARS-CoV-2 infection. Day 29 seroresponses against Omicron BA.4/BA.5 were higher for mRNA-1273.222 than for mRNA-1273 and similar against ancestral SARS-CoV-2 (D614G), both meeting noninferiority criterion. The safety profile of mRNA-1273.222 was similar to that previously reported for mRNA-1273 with no new safety concerns identified. Continued monitoring of neutralization and real-world vaccine effectiveness are needed as additional divergent-virus variants emerge. ClinicalTrials.gov registration: NCT04927065.

Randomized phase II trial of dabrafenib and trametinib with or without navitoclax in patients (pts) with BRAF-mutant (MT) metastatic melanoma (MM) (CTEP P9466).

9511 Background: Standard MAPK-targeted therapy (tx) for pts with BRAF MT MM involves combined BRAF and MEK inhibition with high efficacy in advanced melanoma, but durability of response is limited by acquired resistance. One combination, dabrafenib and trametinib (DT), was shown to be less effective in the frontline setting than combined immune checkpoint inhibition (ICI) but did achieve a 48% objective response rate (ORR) after ICI. (Atkins et al., JCO 2022) Preclinical data show that targeting mediators of apoptosis improves response and survival with BRAF-targeted tx. Navitoclax (N) is a BH3-mimetic that inhibits BCL-2, BCL-xL, and BCL-W. We previously demonstrated the safety of DTN in patients with BRAF MT solid tumors in a phase I trial. This randomized phase II study compared DTN to DT. (NCT01989585). Methods: Pts with BRAF MT MM were randomized 1:1 to either DT (standard dosing D 150 mg BID and T 2 mg QD) or DTN (standard DT plus N 225 mg QD) and stratified by maximal tumor burden (RECIST 1.1 sum of diameter of target lesions ≥ 100 mm or &lt; 100 mm). The target sample size was 50 evaluable pts (25 per arm). Prior ICI, but not prior BRAF targeted therapy, was permitted. The co-primary endpoints were to estimate complete response (CR) rate for DTN compared to historic controls and to assess maximal tumor shrinkage of pts treated with DTN vs DT. Secondary endpoints included ORR, progression-free survival (PFS) and overall survival (OS). Results: Fifty-six pts were enrolled and 50 treated (25 DTN, 25 DT) from 1/11/19 – 3/25/22 at 13 sites. Seventeen pts (68%) in each arm received prior ICI. The ORR was 84% for DTN and 80% for DT. The CR rate for DTN was 20% and 15% for DT; this met pre-specified criteria for success of the primary CR endpoint. There was no difference in the maximal tumor shrinkage in pts treated with DTN vs DT. With median follow up of 25.9 months (mo), there was a trend for improved OS with DTN vs DT (median 36 vs 25 mo, log-rank p = 0.07). In the stratification cohort of 37 pts (74%) with smaller baseline tumor burden, there was a statistically significant improvement in OS among pts receiving DTN (log-rank p = 0.05), with two-year estimates of OS of 78% (95% CI: 0.46 to 0.93) for DTN and 57% (95% CI: 0.29 to 0.77) for DT. There was no difference in PFS between the two groups. The most common treatment-related toxicities ( &gt; 50% of pts) were nausea (36), diarrhea (31), fatigue (30), fever (28), and vomiting (27), which were not different in pts treated with DTN vs DT. Conclusions: In pts with BRAF MT MM, DTN was associated with a CR rate of 20% and ORR of 84%. There was a trend for improved OS in pts treated with DTN compared to DT; the difference in OS was significant in pts with smaller tumor burden. The DTN regimen may be considered for further exploration in the post-ICI setting. Updated data on survival and translational studies will be presented. Clinical trial information: NCT01989585 .

A prospective validation of a deep learning-based automated workflow for the interpretation of the echocardiogram

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Us2.ai Background. Deep learning can automate the interpretation of medical imaging tests. This study aimed to prospectively assess the interchangeability of deep learning algorithms with expert human measurements for interpreting echocardiographic studies, the primary method for assessing cardiac structure and function. Methods. We compared a deep learning interpretation of 23 echocardiographic parameters—including cardiac volumes, ejection fraction, and Doppler measurements—with three repeated measurements by core lab human experts in a prospective study for submission to the United States Food and Drug Administration (FDA). The primary outcome metric was the individual equivalence coefficient (IEC), which compares the disagreement between deep learning and human readers relative to the disagreement among human readers. The pre-determined non-inferiority criterion was 0.25 for the upper bound of the 95% confidence interval (CI). Secondary outcomes included measures of agreement, including the mean absolute deviation. Results. We included 602 studies from 600 participants (421 with heart failure, 179 controls, 69% women) with a mean age of 57 ± 16 years. The point estimates of IEC were all &amp;lt;0, indicating that the disagreement between the deep learning and human measures were lower than the disagreement among three core lab readers, and the upper bound of the 95% CI of IECs fell below the prespecified success criterion of 0.25. Secondary endpoints showed good agreement of automated with human expert measurements (Figure), with comparable or lower mean absolute deviations between automated and human experts relative to the mean absolute deviation among human experts. Conclusion. This prospective validation study demonstrated excellent agreement between deep learning and expert human interpretation for a wide range of echocardiographic measurements. These results highlight the potential of deep learning algorithms to improve efficiency and reduce costs of echocardiography. Abstract Figure.

Internet and telerehabilitation management of rotator cuff tendinopathy: a randomised pilot and feasibility trial

Introduction: Rotator cuff tendinopathy is a common and disabling musculoskeletal condition. Internet-based and telerehabilitation delivery of recommended care may improve access to care and improve adherence and outcomes. The primary aim of this pilot randomised controlled trial was to assess the feasibility of a 12-week internet delivered intervention for rotator cuff tendinopathy comparing advice only, recommended care and recommended care with group-based telerehabilitation. Methods: Reporting was in accordance with the CONSORT checklist for pilot and feasibility trials and the trial was prospectively registered (ACTRN12620000248965). People with a primary complaint of rotator cuff tendinopathy for ≥3 months were identified via a paid Facebook strategy. Screening involved an online questionnaire followed by a 20-minute telehealth assessment. Participants were randomly allocated to receive: advice only, recommended care delivered via the internet or recommended care delivered via a weekly group teleconference session. Progression criteria for a full-scale trial included (i) recruitment of ≥20% of eligible participants; (ii) acceptable adherence (≥two of the three prescribed weekly sessions) among ≥70% of participants; (iii) ≥80% retention; (iv) absence of intervention-related serious adverse events; and (v) ≥80% response rates to questionnaires. Secondary clinical outcomes were collected at baseline, six and 12 weeks and within group change was reported descriptively. Results: Twelve participants were allocated to each trial arms (36 in total, mean age between 51 and 56, 83% [10/12] to 92% [11/12] female). We enrolled 36 of 38 (95%) eligible participants and all participants were recruited within a three-week period. Retention at the 12-week endpoint was 94% (34/36) and response to email questionnaires at other timepoints was ≥83%. We found acceptable adherence (defined as >70% performing exercise two or three times/week) in the recommended care group with telerehabilitation but not the recommended care group without telerehabilitation. There was a total of 24 adverse events over 108 person-months of observation. All adverse events were mild or moderate (mainly muscle and shoulder symptoms) aside from one instance of elective surgery (unrelated to the person’s shoulder condition). Discussion: Our pre-specified success criteria were met or exceeded but there was a gender imbalance towards women. It is feasible to progress to a fully powered trial but strategies to address the gender imbalance need to be implemented. Conflict of interest statement: The authors have no conflict of interest of relevance to the submission of this abstract.

Integrating case-finding and initial management for osteoarthritis, anxiety, and depression into primary care long-term condition reviews: results from the ENHANCE pilot trial.

Multimorbidity is increasingly the norm; however, primary care remains focused on single diseases. Osteoarthritis, anxiety, and depression are frequently comorbid with other long-term conditions (LTCs), but rarely prioritized by clinicians. To test the feasibility of a randomized controlled trial (RCT) of an intervention integrating case-finding and management for osteoarthritis, anxiety, and depression within LTC reviews. A pilot stepped-wedge RCT across 4 general practices recruited patients aged ≥45 years attending routine LTC reviews. General practice nurses provided usual LTC reviews (control period), then, following training, delivered the ENHANCE LTC review (intervention period). Questionnaires, an ENHANCE EMIS-embedded template and consultation audio-recordings, were used in the evaluation. General practice recruitment and training attendance reached prespecified success criteria. Three hundred and eighteen of 466 (68%) of patients invited responded; however, more patients were recruited during the control period (206 control, 112 intervention). Eighty-two percent and 78% returned their 6-week and 6-month questionnaires, respectively. Integration of the ENHANCE LTC review into routine LTC reviews varied. Case-finding questions were generally used as intended for joint pain, but to a lesser extent for anxiety and depression. Initial management through referrals and signposting were lacking, and advice was more frequently provided for joint pain. The stepped-wedge design meant timing of the training was challenging and yielded differential recruitment. This pilot trial suggests that it is feasible to deliver a fully powered trial in primary care. Areas to optimize include improving the training and reconsidering the stepped-wedge design and the approach to recruitment by targeting those with greatest need. ISRCTN registry (ISRCTN: 12154418). Date registered: 6 August 15. Date first participant was enrolled: 13 July 2015. https://www.isrctn.com/ISRCTN12154418?q=depression%20schizophrenia&filters=conditionCategory:Not%20Applicable&sort=&offset=5&totalResults=9&page=1&pageSize=20&searchType=basic-search.

OP0115 EFFICACY AND SAFETY OF ABBV-3373, A NOVEL ANTI-TNF GLUCOCORTICOID RECEPTOR MODULATOR ANTIBODY DRUG CONJUGATE, IN PATIENTS WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS DESPITE METHOTREXATE THERAPY: A PHASE 2A PROOF OF CONCEPT STUDY

Background:ABBV-3373 is a novel antibody drug conjugate composed of adalimumab (ADA) linked to a proprietary and highly potent glucocorticoid receptor modulator (the anti-inflammatory payload) currently evaluated for the treatment of rheumatoid arthritis (RA).Objectives:To assess the efficacy and safety of ABBV-3373 vs ADA in RA patients (pts).Methods:This was a 24-week (wk) randomized, double-blind, double-dummy, active-controlled Phase 2a study of intravenously (IV)-administered ABBV-3373 100 mg (for 12 wks followed by placebo [PBO] for 12 wks) vs subcutaneous injections of ADA 80 mg every other wk (for 24 wks) in pts on background methotrexate. The primary endpoint was the change from baseline (BL) in DAS28(CRP) at Wk 12. Pre-planned statistical methods incorporating pre-specified historical ADA data both alone (pre-specified success criterion, 2-sided P ≤0.1) and supplemented with in-trial ADA data (pre-specified success criterion, probability &gt;95%) were used to achieve adequate statistical power with a reduced trial size. Assay sensitivity was evaluated through construction of a synthetic PBO arm by propensity score matching, using individual pt-level PBO data from 3 recent sponsor-run trials of similar populations and trial settings. Secondary endpoints at Wk 12 included 1) mean change from BL in CDAI, SDAI, DAS28(ESR), HAQ-DI; 2) proportion of pts achieving DAS28(CRP)≤3.2, ACR20/50/70 responses, HAQ-DI≤-0.22. Continuous and categorical efficacy variables were analyzed using mixed effect model repeated measurements and Cochran-Mantel-Haenszel test, respectively; non-responder imputation was applied to missing categorical data. Treatment-emergent adverse events were summarized through Wk 12.Results:A total of 48 pts were randomized and treated (ABBV-3373: 31; ADA: 17); 46 pts (96%) completed 12 wks of study treatment. BL demographics and disease characteristics were indicative of established RA and similar among the 2 treatment arms and the synthetic PBO arm. ABBV-3373 demonstrated significant improvement in mean DAS28(CRP) at Wk 12 vs the pre-specified historical ADA (-2.65 vs -2.13; P=0.022) and numerically greater improvement vs the combined in-trial and historical ADA arm (-2.65 vs -2.29; probability 90%; Figure). Comparable improvements in disease activity and targets were observed for ABBV-3373 and in-trial ADA. Assay sensitivity was supported by the fact that both ABBV-3373 and ADA arms were superior to synthetic PBO (P&lt;0.001). For secondary endpoints, greater efficacy was observed with ABBV-3373 vs historical ADA; ABBV-3373 was predicted with 79-99% probability to be better than ADA based on the combined in-trial and historical ADA data. 2 serious infections were reported with ABBV-3373 (pneumonia, upper respiratory tract infection) and none with ADA through Wk 12 (Table). 1 event of anaphylactic shock reaction was reported with ABBV-3373. After increasing the duration of IV administration from 3 min to 15-30 min, no similar events were observed.Table 1.Treatment Emergent Adverse Events up to Week 12Event, n (%)ADA(N = 17)ABBV-3373(N = 31)Adverse event (AE)12 (70.6)11 (35.5)AE with reasonable possibility of being drug related$3 (17.6)2 (6.5)Severe AE01 (3.2)Serious AE04 (12.9) #AE leading to Discontinuation of Study Drug1 (5.9)1 (3.2)Serious infections02 (6.5)Opportunistic infection excluding Tuberculosis00Allergic Reactions Including Hypersensitivity, Angioedema, and Anaphylaxis2 (11.8) &amp;1 (3.2) ^Systemic glucocorticoid events00All deaths00$As assessed by investigator. #Serious AEs: 1 non-cardiac chest pain, 1 pneumonia, 1 upper respiratory tract disease and 1 anaphylactic shock. &amp;1 Type I hypersensitivity, 1 Pruritus ^1 Anaphylactic shockConclusion:These data demonstrate the clinical efficacy of ABBV-3373 and its potential to provide improved outcomes for RA pts compared to ADA. The safety profile of ABBV-3373 was generally similar to ADA.Acknowledgements:AbbVie and the authors we thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis &amp; interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Yang Yang of AbbVie Inc for supporting the statistical analysis and data reporting. Medical writing support was provided by Ramona Vladea, PhD of AbbVie, Inc.Disclosure of Interests:Frank Buttgereit Consultant of: AstraZeneca, AbbVie, Grünenthal, Horizon Pharma, Pfizer, and Roche, Grant/research support from: AbbVie, Horizon Pharma, Pfizer, and Roche, Jacob Aelion Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Eli Lilly, Galapagos/Gilead, Genentech, GlaxoSmithKline, Horizon, Janssen, Mallinckrodt, Nektar, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, Selecta, UCB, Bernadette Rojkovich: None declared, Anna Zubrzycka-Sienkiewicz Consultant of: Astellas and Roche, Grant/research support from: AbbVie, Astellas, Galapagos NV, Gilead Sciences, Janssen, Lilly, Mabion, Pfizer, Roche, and UCB SA, Timothy Radstake Shareholder of: AbbVie, Employee of: AbbVie, Su Chen Shareholder of: AbbVie, Employee of: AbbVie, Dilek Arikan Shareholder of: AbbVie, Employee of: AbbVie, Hartmut Kupper Shareholder of: AbbVie, Employee of: AbbVie, Howard Amital Consultant of: Abbvie, Janssen, Novartis, Roche, Perrigo, Pfizer, Neopharm, Elly Lilly, Gilead, Sanofi, Teva and Rafa, Grant/research support from: Yansen, Pfizer

Profile of respiratory syncytial virus prefusogenic fusion protein nanoparticle vaccine

ABSTRACT Introduction Respiratory Syncytial Virus (RSV) is a leading cause of acute lower respiratory infections worldwide. The RSV fusion (F) glycoprotein is a major focus of vaccine development. Despite over 60 years of research, there is no licensed vaccine for RSV. Areas covered The primary focus of this review is a novel RSV-F recombinant nanoparticle vaccine from Novavax utilizing the F protein, a conserved and immunodominant surface glycoprotein. This RSV F recombinant nanoparticle vaccine adsorbed to 0.4 mg of aluminum phosphate was ultimately administered by a single intramuscular injection during the third trimester of pregnancy in an effort to induce passive immunity in newborns. Its mechanism, performance in clinical trials, and place in RSV vaccine history are discussed. Expert opinion The vaccine was safe and well tolerated in pregnant women and the results suggest potential benefits with respect to other medically relevant end-point events involving RSV-associated respiratory and all-cause disease in infants. However, the RSV-F recombinant nanoparticle vaccine did not meet the pre-specified primary success criteria for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The potential benefits to infants from maternal immunization and excellent safety profile warrant further confirmatory studies.

Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial

Malignant mesothelioma remains an incurable cancer, with no effective treatments in the setting of relapsed disease. Homologous recombination deficiency predicts sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In mesothelioma, BRCA1-associated protein 1 carboxy-terminal hydrolase (BAP1), which regulates DNA repair, is frequently mutated. We aimed to test the hypothesis that BAP1-deficient or BRCA1-deficient mesotheliomas would be sensitive to PARP inhibition by rucaparib. We did a single-centre, open-label, single-arm, phase 2a trial in Leicester, UK, with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]). Patients aged 18 years or older who had radiologically progressing, histologically confirmed, malignant mesothelioma after at least one course of systemic treatment; with cytoplasmic-BAP1-deficient or BRCA1-deficient mesothelioma (pleural or peritoneal or other primary localisation), and who met the other inclusion criteria, were deemed eligible. All eligible patients who consented to take part were given rucaparib 600 mg twice a day orally, for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response was measured by CT scan every 6 weeks. The primary outcome was disease control (complete response, partial response, or stable disease) at 12 weeks in all patients who received study drug; secondary outcomes were the safety and toxicity profile, objective response rate (proportion of complete or partial responses), and disease control rate at 24 weeks. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03654833. Between Feb 9 and June 10, 2019, we enrolled 26 molecularly and clinically eligible patients. Ten (38%) of 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative, and 13 patients (50%) were BRCA1 negative. Disease control rate at 12 weeks was 58% (95% CI 37-77; 15 of 26 patients), and at 24 weeks was 23% (9-44; six of 26 patients). Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients, and there were no deaths. The most common grade 1-2 adverse events were nausea (18 [69%] of 26 patients), fatigue (14 patients [54%]), and decreased appetite (ten patients [38%]). The most common grade 3-4 adverse events were upper respiratory tract infection (three patients [12%]) and anaemia (three patients [12%]). All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%). Rucaparib in patients with BAP1-negative or BRCA1-negative mesothelioma met the prespecified criteria for success, showing promising activity with manageable toxicity. Further investigation of homologous recombination deficiency mutations is planned to refine the identification of predictive biomarkers for PARP inhibition in mesothelioma. University of Leicester (Leicester, UK), Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation (Toronto, ON, Canada).

A pilot study of a nurse-led integrated care review (the INCLUDE review) for people with inflammatory rheumatological conditions in primary care: feasibility study findings

BackgroundPeople with inflammatory rheumatological conditions such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polymyalgia rheumatica and giant cell arteritis are at an increased risk of common comorbidities including cardiovascular disease, osteoporosis and mood problems, leading to increased morbidity and mortality. Identifying and treating these problems could lead to improved patient quality of life and outcomes. Despite these risks being well-established, patients currently are not systematically targeted for management interventions for these morbidities. This study aimed to assess the feasibility of conducting a randomised controlled trial (RCT) of a nurse-led integrated care review in primary care to identify and manage these morbidities.MethodsA pilot cluster RCT was delivered across four UK general practices. Patients with a diagnostic Read code for one of the inflammatory rheumatological conditions of interest were recruited by post. In intervention practices (n = 2), eligible patients were invited to attend the INCLUDE review. Outcome measures included health-related quality of life (EQ-5D-5L), patient activation, self-efficacy and treatment burden. A sample (n = 24) of INCLUDE review consultations were audio-recorded and assessed against a fidelity checklist.Results453/789 (57%) patients responded to the invitation, although 114/453 (25%) were excluded as they either did not fulfil eligibility criteria or failed to provide full written consent. In the intervention practices, uptake of the INCLUDE review was high at 72%. Retention at 3 and 6 months both reached pre-specified success criteria. Participants in intervention practices had more primary care contacts than controls (mean 29 vs 22) over the 12 months, with higher prescribing of all relevant medication classes in participants in intervention practices, particularly so for osteoporosis medication (baseline 29% vs 12 month 46%). The intervention was delivered with fidelity, although potential areas for improvement were identified.ConclusionsThe findings of this pilot study suggest it is feasible to deliver an RCT of the nurse-led integrated care (INCLUDE) review in primary care. A significant morbidity burden was identified. Early results suggest the INCLUDE review was associated with changes in practice. Lessons have been learnt around Read codes for patient identification and refining the nurse training.Trial registrationISRCTN, ISRCTN12765345

Internet and Telerehabilitation-Delivered Management of Rotator Cuff-Related Shoulder Pain (INTEL Trial): Randomized Controlled Pilot and Feasibility Trial.

BackgroundRotator cuff–related shoulder pain (RCRSP) is a common and disabling musculoskeletal condition. Internet-based and telerehabilitation delivery of recommended care may improve access to care and improve adherence and outcomes.ObjectiveThe primary aim of this pilot randomized controlled trial was to assess the feasibility of a 12-week internet-delivered intervention for RCRSP comparing advice only, recommended care, and recommended care with group-based telerehabilitation.MethodsReporting was in accordance with the Consolidated Standards of Reporting Trials (CONSORT) checklist for pilot and feasibility trials. People with a primary complaint of RCRSP for 3 months or longer were identified via a paid Facebook strategy. Screening involved an online questionnaire followed by a 20-minute telehealth assessment. Participants were randomly allocated (via a Zelen design) to receive (1) advice only, (2) recommended care (internet-delivered evidence-based exercise and education), or (3) recommended care and telerehabilitation (including a weekly group teleconference session). Progression criteria for a full-scale trial included (1) recruitment of 20% or greater of eligible participants, (2) acceptable adherence (two or more of the three prescribed weekly sessions) among 70% or greater of participants, (3) 80% or greater retention of participants, (4) absence of intervention-related serious adverse events, and (5) 80% or greater response rates to questionnaires. Secondary clinical and patient knowledge outcomes were collected (via email or text) at baseline, six weeks, and 12 weeks (for clinical and patient knowledge), and within-group change was reported descriptively.ResultsWe enrolled 36 of 38 (95%) eligible participants and all participants were recruited within a 3-week period. Of the 36 participants, 12 participants were allocated to each of the three trial arms. The mean age of participants was between 51 and 56 years, and 83% (10/12) to 92% (11/12) were female. Retention at the 12-week endpoint was 94% (34/36) and response to email questionnaires at other time points was 83% or greater. We found acceptable adherence (defined as greater than 70% of participants performing exercise 2 or 3 times/week) in the recommended care group with telerehabilitation but not in the recommended care group without telerehabilitation. There was a total of 24 adverse events over 108 person-months of observation. All adverse events were mild or moderate (mainly muscle and shoulder symptoms), with the exception of one instance of elective surgery (unrelated to the person’s shoulder condition).ConclusionsOur prespecified success criteria were met or exceeded, but there was a gender imbalance toward women. It is feasible to progress to a fully powered trial, but strategies to address the gender imbalance need to be implemented.Trial RegistrationAustralian New Zealand Clinical Trials Registry (ACTRN12620000248965); https://tinyurl.com/yy6eztf5

Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge

BackgroundAcute Respiratory Distress Syndrome (ARDS) is associated with increased pulmonary-vascular permeability. In the lung, transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable cation channel, is a regulator of endothelial permeability and pulmonary edema. We performed a Phase I, placebo-controlled, double-blind, randomized, parallel group, proof-of-mechanism study to investigate the effects of TRPV4 channel blocker, GSK2798745, on pulmonary-vascular barrier permeability using a model of lipopolysaccharide (LPS)-induced lung inflammation. MethodsHealthy participants were randomized 1:1 to receive 2 single doses of GSK2798745 or placebo, 12 h apart. Two hours after the first dose, participants underwent bronchoscopy and segmental LPS instillation. Total protein concentration and neutrophil counts were measured in bronchoalveolar lavage (BAL) samples collected before and 24 h after LPS challenge, as markers of barrier permeability and inflammation, respectively. The primary endpoint was baseline adjusted total protein concentration in BAL at 24 h after LPS challenge. A Bayesian framework was used to estimate the posterior probability of any percentage reduction (GSK2798745 relative to placebo). Safety endpoints included the incidence of adverse events (AEs), vital signs, 12-lead electrocardiogram, clinical laboratory and haematological evaluations, and spirometry. ResultsForty-seven participants were dosed and 45 completed the study (22 on GSK2798745 and 23 on placebo). Overall, GSK2798745 was well tolerated. Small reductions in mean baseline adjusted BAL total protein (~9%) and neutrophils (~7%) in the LPS-challenged segment were observed in the GSK2798745 group compared with the placebo group; however, the reductions did not meet pre-specified success criteria of at least a 95% posterior probability that the percentage reduction in the mean 24-h post LPS BAL total protein level (GSK2798745 relative to placebo) exceeded zero. Median plasma concentrations of GSK2798745 were predicted to inhibit TRPV4 on lung vascular endothelial cells by ~70–85% during the 24 h after LPS challenge; median urea-corrected BAL concentrations of GSK2798745 were 3.0- to 8.7-fold higher than those in plasma. ConclusionsGSK2798745 did not affect segmental LPS-induced elevation of BAL total protein or neutrophils, despite blood and lung exposures that were predicted to be efficacious. Clinicaltrials.gov identifierNCT03511105.

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants

BackgroundRespiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants.MethodsHealthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%).ResultsA total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, −1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, −8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups.ConclusionsRSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.)

Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes

Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD). To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy. This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy. [18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-β plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event. This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

Tissue/Site-Agnostic Study of Ribociclib for Tumors With Cyclin D-CDK4/6 Pathway Genomic Alterations: A Phase II, Open-Label, Single-Arm Basket Study.

As part of the Novartis Signature Program, this study evaluated the efficacy of ribociclib (selective cyclin-dependent kinase 4/6 [CDK4/6] inhibitor) in patients with cyclin D-CDK4/6 pathway-aberrant tumors. This was a phase II, single-arm, signal-seeking study in patients with advanced malignancies that had progressed on or after standard treatment. Prior identification of tumor CDK4/6 mutation or amplification, CCND1/3 amplification, or CDKN2A mutation or loss was required. Clinical benefit (defined as the proportion of patients with response or stable disease at ≥ 16 weeks) was the primary end point. From 61 centers in the United States, 106 patients (median age, 62.5 years) were enrolled across multiple malignancies. The patient population was heavily pretreated (median number of prior therapies, three; range, 0 to 19). Median progression-free survival was 1.8 months (95% CI, 1.8 to 1.9). In patients with solid tumors, the clinical benefit rate was 18.1% (n = 19 of 105) and the overall response rate was 2.9% (n = 3 of 105); three partial responses occurred in patients with adenocarcinoma (unknown primary), soft tissue sarcoma, and urothelial carcinoma. No tumor cohort met the prespecified criteria for success. The most common adverse events suspected to be related to treatment were neutropenia (30.2%; decreased neutrophils, 15.1%), fatigue (31.1%), and nausea (29.2%). Fatigue and nausea were typically mild. Only one incident of febrile neutropenia was experienced (grade 3). No new or unexpected safety signals were observed in this heavily pretreated patient population. Although responses were seen in tumors with CCND1-CDK4/6 amplifications, the primary end point was not met, suggesting additional evaluation of ribociclib, possibly as combination therapy, is needed.

Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial

Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies. This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89). Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI -1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI -17·8 to 41·3). The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. Merck & Co, Inc.

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration.

The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI)=0.87; 95% CI=0.799-0.93] marginally met the prespecified success criterion (lower 95% CI≥0.8), while the ICC for the hot-spot method (0.83; 95% CI=0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6min for global and hot-spot methods, respectively. The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.