Key Endpoints Research Articles

Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial.

The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy (oHCM) is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate effect of treatment with aficamten on biomarker concentrations. Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and to evaluate whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% CI 83%-76%, P < .001) and hs-cTnI by 41% (95% CI 49%-32%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. NT-proBNP reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. NT-proBNP and hs-cTnI concentrations are associated with key variables in oHCM. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy.

Acoustic-based rule out of stable coronary artery disease: the FILTER-SCAD trial.

Overtesting of low-risk patients with suspect chronic coronary syndrome (CCS) is widespread. The acoustic-based coronary artery disease (CAD) score has superior rule-out capabilities when added to pre-test probability (PTP). FILTER-SCAD tested whether providing a CAD score and PTP to cardiologists was superior to PTP alone in limiting testing. At six Danish and Swedish outpatient clinics, patients with suspected new-onset CCS were randomised to either standard diagnostic examination (SDE) with PTP, or SDE plus CAD score, and cardiologists provided with corresponding recommended diagnostic flowcharts. The primary endpoint was cumulative number of diagnostic tests at one year and key safety endpoint major adverse cardiac events (MACE). In total 2008 patients (46% male, median age 63 years) were randomised from October 2019 to September 2022. When randomised to CAD score (n=1002), it was successfully measured in 94.5%. Overall, 13.5% had PTP ≤5%, and 39.5% had CAD score ≤20. Testing was deferred in 22% with no differences in diagnostic tests between groups (p for superiority =0.56). In the PTP ≤5% subgroup, the proportion with deferred testing increased from 28% to 52% (p<0.001). Overall MACE was 2.4 per 100 person-years. Non-inferiority regarding safety was established, absolute risk difference 0.4% (95% CI -1.85 to 1.06) (p for non-inferiority = 0.005). No differences were seen in angina-related health status or quality of life. The implementation strategy of providing cardiologists with a CAD score alongside SDE did not reduce testing overall but indicated a possible role in patients with low CCS likelihood. Further strategies are warranted to address resistance to modifying diagnostic pathways in this patient population.

Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy

BackgroundObstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. ObjectivesThis study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy. MethodsSEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory. ResultsOf the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (−15 g/m2; 95% CI: −25 to −6 g/m2; P = 0.001), maximal LV wall thickness (−2.1 mm; 95% CI: −3.1 to −1.1 mm; P < 0.001), left atrial volume index (−13 mL/m2; 95% CI: −19 to −7 mL/m2; P < 0.001), native T1 relaxation time (−37 ms; 95% CI: −69 to −5 ms; P = 0.026), indexed extracellular volume fraction (−3.9 g/m2; 95% CI: −7.0 to −0.9 g/m2; P = 0.014), and indexed myocyte mass (−14 g/m2; 95% CI: −23 to −4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass −0.7 g; 95% CI: −2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: −2.2% to 3.6%; P = 0.61). ConclusionsThe CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818)

Digital Health Applications (DiGAs) on a Fast Track: Insights From a Data-Driven Analysis of Prescribable Digital Therapeutics in Germany From 2020 to Mid-2024.

This study aimed to analyze the rapidly evolving ecosystem of digital health applications (Digitale Gesundheitsanwendung; DiGAs) in Germany, spurred by the 2019 Digital Healthcare Act. With over 73 million people in Germany now having access to DiGAs, these prescribable digital health apps and web-based applications represent a substantial stride in health care modernization, supporting both patients and health care providers with digital solutions for disease management and care improvement. Through a data-driven approach, this research aimed to unpack the complexities of DiGA market dynamics, economic factors, and clinical evidence, offering insights into their impact over the past years. The analysis draws from a range of public data sources, including the DiGA directory, statutory health insurance reports, app store feedback, and clinical study results. As of July 1, 2024, there are 56 DiGAs listed by the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte), divided into 35 permanently and 21 preliminarily listed applications. Our findings reveal that a majority of DiGAs extend beyond the intended 1-year period to achieve permanent listing, reflecting the extensive effort required to demonstrate clinical efficacy. Economic analysis uncovered a dynamic pricing landscape, with initial prices ranging from approximately €200 to €700 (€1=US $1.07), averaging at a median of €514 for a 3-month DiGA prescription. Following negotiations or arbitration board decisions, prices typically see a 50% reduction, settling at a median of €221. Prescription data offer valuable insights into DiGA acceptance, with total prescriptions jumping from around 41,000 in the first period to 209,000 in the latest reporting period. The analysis of the top 15 DiGAs, representing 82% of the total prescriptions, shows that these best-performing apps receive from a minimum of 8 to a maximum of 77 daily prescriptions, with native apps and early market entrants achieving higher rates. Clinical evidence from all 35 permanently listed DiGAs indicates a uniform preference for randomized controlled trials to validate primary end points, with no noteworthy use of alternative study designs encouraged in the Digital Healthcare Act and related regulations. Moreover, all evaluated DiGAs focused on medical benefits, with health status improvement as a key end point, suggesting an underuse of patient-relevant structural and procedural improvement in demonstrating health care impact. This study highlights the growth and challenges within the DiGA sector, suggesting areas for future research, such as the exploration of new study designs and the potential impact of patient-relevant structural and procedural improvements. For DiGA manufacturers, the strategic advantage of early market entry is emphasized. Overall, this paper underscores the evolving landscape of digital health, advocating for a nuanced understanding of digital health technology integration in Germany and beyond.

A review of proton pump inhibitor use in cystic fibrosis and considerations for deprescribing.

Use of proton-pump inhibitors (PPIs) is common among people with cystic fibrosis (pwCF) both for the management of suspected GERD, as well as pancreatic enzyme replacement therapy augmentation. Despite their use, limited data exist to demonstrate a clinically significant impact of PPIs on key endpoints in pwCF. Furthermore, the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy may modify the need for use. These notions, coupled with the potential for adverse outcomes associated with long-term PPI use in pwCF, should facilitate re-evaluation of long-term PPI use in pwCF and promote potential deprescribing. Despite limited data on PPI deprescribing in pwCF, it intuitively mirrors the existing guidance in adults in the general population, but with added consideration given to tapering strategy, and monitoring for CF-specific outcomes such as nutritional and respiratory status. The development of a monitoring and re-initiation plan is key to reducing deprescribing inertia. This review aims to summarize the evidence that details the concern for long-term use of PPIs and provide CF clinicians with rationale and guidance on how to approach deprescribing in their practice.

Opicapone for the treatment of early wearing-off in levodopa-treated Parkinson’s disease: pooled analysis of patient level data from two randomized open-label studies

BackgroundThe wearing-off phenomenon is a key driver of medication change for patients with Parkinson’s disease (PD) treated with levodopa. Common first-line options include increasing the levodopa dose or adding a catechol-O-methyltransferase (COMT) inhibitor, but there are no trials comparing the efficacy of these approaches. We evaluated the effectiveness of adjunct opicapone versus an additional 100 mg levodopa dose in PD patients with early wearing-off using pooled data from 2 randomized studies.MethodsThe ADOPTION study program included two similarly designed 4-week, open-label studies conducted in South Korea (NCT04821687) and Europe (NCT04990284). Patients with PD, treated with 3–4 daily doses of levodopa therapy and with signs of early wearing-off were randomized (1:1) to adjunct opicapone 50 mg or an additional dose of levodopa 100 mg. Patient-level data from the two studies were pooled.ResultsThe adjusted mean [SE] change from baseline to week 4 in absolute OFF time (key endpoint) was − 62.8 min [8.8] in the opicapone group and − 33.8 min [9.0] in the levodopa 100 mg group, the difference significantly favoring opicapone (− 29.0 [− 53.8, − 4.2] min, p = 0.02). Significant differences in the Movement Disorder Society—Unified Parkinson’s Disease Rating Scale Part III subscore (− 4.1 with opicapone vs − 2.5 with levodopa 100 mg), also favored opicapone (− 1.7 [− 3.3, − 0.04], p < 0.05). Dyskinesia was the most frequently reported adverse event (opicapone 7.2% vs. levodopa 100 mg 4.2%).ConclusionsIn these short-term trials, introducing adjunct opicapone was more effective at reducing OFF time than adding another 100 mg levodopa dose in PD patients with early signs of wearing-off.

Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction

Elevated serum uric acid (SUA) level may contribute to endothelial dysfunction; therefore, SUA is an attractive target for heart failure with preserved ejection fraction (HFpEF). However, to the authors' knowledge, no prior randomized clinical trials have evaluated SUA lowering in HFpEF. To investigate the efficacy and safety of the novel urate transporter-1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level. This was a phase 2, double-blind, randomized clinical trial (32-week duration) conducted from May 2020 to April 2022. The study took place at 59 centers in 12 countries and included patients 40 years and older with HFpEF and SUA level greater than 6 mg/dL. Data were analyzed from August 2022 to May 2024. Eligible patients were randomized 1:1:1 to once-daily, oral verinurad, 12 mg, plus allopurinol, 300 mg; allopurinol, 300 mg, monotherapy; or placebo for 24 weeks after an 8-week titration period. Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, and the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group. All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization. Key end points included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level; and safety/tolerability (including adjudicated cardiovascular events). Among 159 randomized patients (53 per treatment group; median [IQR] age, 71 [40-86] years; 103 male [65%]) with median (IQR) N-terminal pro-brain natriuretic peptide level of 527 (239-1044) pg/mL and SUA level of 7.5 (6.6-8.4) mg/dL, verinurad plus allopurinol (mean change, -59.6%; 95% CI, -64.4% to -54.2%) lowered SUA level to a greater extent than allopurinol (mean change, -37.6%; 95% CI, -45.3% to -28.9%) or placebo (mean change, 0.8%; 95% CI, -11.8% to 15.2%; P < .001). Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; 95% CI, -0.56 to 1.10 mL/kg/min; allopurinol, -0.17 mL/kg/min; 95% CI, -1.03 to 0.69 mL/kg/min; placebo, 0.37 mL/kg/min; 95% CI, -0.45 to 1.19 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; 95% CI, 0.3-8.3; allopurinol, 4.5; 95% CI, 0.3-8.6; placebo, 1.2; 95% CI, -3.0 to 5.3) were similar across groups. There were no adverse safety signals. Deaths or cardiovascular events occurred in 3 patients (5.7%) in the verinurad plus allopurinol group, 8 patients (15.1%) in the allopurinol monotherapy group, and 6 patients (11.3%) in the placebo group. Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF. ClinicalTrials.gov Identifier: NCT04327024.

8 Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: 8-year follow-up with analyses in favorable risk patients from the phase 3 CheckMate 214 trial

Abstract Background First-line nivolumab plus ipilimumab (NIVO+IPI) has provided substantial long-term survival benefits over sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC) in CheckMate 214. With a median follow-up of 8 years, the longest follow-up to date for any phase 3 trial of immune checkpoint inhibitor combination therapy in patients with aRCC, we report survival, response per independent radiology review committee (IRRC), and safety in all randomized patients (intent-to-treat [ITT] population) and in patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk. Methods Patients with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W×4 doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Key study endpoints included overall survival (OS), IRRC-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (primary), ITT (secondary), and favorable-risk (exploratory) patients. Cancer-specific survival was evaluated in ITT patients by censoring all causes of death other than RCC. Post hoc exploratory analyses in patients with favorable risk were performed. Results With 8 years (99.1 months) median follow-up, OS with NIVO+IPI versus SUN remained superior in ITT patients (hazard ratio [HR], 0.72; Table). The HR for PFS with NIVO+IPI versus SUN was 0.88. ORR was higher with NIVO+IPI versus SUN (Table), with more complete responses (12% vs 3%) and a longer median duration of response (DOR) in the combination arm versus SUN. In patients with favorable risk, OS benefits were similar between arms (HR, 0.82; Table). The HR for PFS favored SUN (HR, 1.76). ORR was lower with NIVO+IPI versus SUN, yet more patients achieved complete responses (13% vs 6%, respectively) and median DOR was longer with NIVO+IPI. Median cancer-specific survival (95% CI) in ITT patients was 73.7 (62.8-91.2) months with NIVO+IPI versus 45.1 (37.8-53.3) months with SUN (HR, 0.69; 95% CI 0.59-0.82). In exploratory post hoc analyses of patients with favorable risk, 75/125 (60.0%) patients in the NIVO+IPI arm and 85/124 (68.5%) patients in the SUN arm died over 8 years of follow-up. Of these patients, 31 in the NIVO+IPI arm and 27 in the SUN arm died within 3 years of randomization; the primary reason for death was disease in either arm (71.0% and 85.2%, respectively). Furthermore, among 27 patients in the NIVO+IPI arm with favorable risk who died after disease progression within 3 years, 12 patients did not receive second-line systemic therapy. Beyond 3 years, only 2 of 43 patients who died after disease progression did not receive subsequent systemic therapy. Among all treated patients, incidence of any-grade and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. Table Conclusions With a median follow-up up of 8 years, NIVO+IPI continues to demonstrate sustained survival and more durable response benefits versus SUN in the ITT population, including a further reduction in the risk of death with NIVO+IPI as measured by cancer-specific survival. Long-term exploratory data in patients with favorable risk have shown a steady improvement in the HR for OS, and a marked improvement in median DOR and complete response rates with NIVO+IPI versus SUN, thus contributing to the survival and response benefits reported in the ITT population. Furthermore, the disproportionate number of patients with favorable risk who died within 3 years of randomization after documented progression without receiving subsequent therapy may have affected the HR for OS in this patient population early on. NIVO+IPI offers the potential for positive long-term outcomes, regardless of IMDC risk, and with no emergence of new safety signals.

The dimer effect: A refinement approach towards skin sensitization assessment in-chemico using Amino acid Derivative Reactivity Assay.

Skin sensitization is a key endpoint for safety assessment, especially for cosmetics and personal care products. The adverse outcome pathway for skin sensitization and the chemical and biological events driving the induction of human skin sensitization are now well understood. Several non-animal test methods have been developed to predict sensitizer potential by measuring the impact of chemical sensitizers on these key events. In this work, we have focused on Key Event 1 (the molecular initiating step), which is based on formation of a covalent adduct between skin sensitizers and endogenous proteins and/or peptides in the skin. There exists three in-chemico assays approved by the Organization for Economic Co-operation and Development-(1) Direct Peptide Reactivity Assay (DPRA), (2) Amino Acid Derivative Reactivity Assay (ADRA), and (3) Kinetic Direct Peptide Reactivity Assay (kDPRA) to quantify peptide/amino acid derivative depletion after incubation with test chemicals. However, overestimated depletion of the cysteine-based peptide/amino acid derivatives is known in such assays because of the dimerization of the thiol group. In this present work, we report the synthesis and structural confirmation of the dimer of N-(2-[1-naphthyl]acetyl)-L-cysteine (NAC) from the ADRA assay to allow simultaneous determination of (a) peptide depletion by quantifying NAC monomer and (b) peptide dimerization by quantifying NAC dimer thereby eliminating the overestimation. We present a case study with three chemicals to demonstrate the importance of this approach. Thus, this simultaneous assay gives a more informed view of the peptide reactivity of chemicals to better identify skin sensitizers.

Therapeutic Doses of Efzofitimod Demonstrate Efficacy in Pulmonary Sarcoidosis

BackgroundIn a phase 1b/2a clinical trial of efzofitimod in patients with corticosteroid-requiring pulmonary sarcoidosis, treatment resulted in dose-dependent improvement in key endpoints. We undertook a post hoc analysis pooling dose arms that achieved therapeutic concentrations of efzofitimod (Therapeutic group)versusthose that did not (Subtherapeutic group).MethodsPeripheral blood mononuclear cells incubated with tuberculin-coated beads were exposed to varying concentrations of efzofitimod in anin vitroassay to determine concentrations that inhibited granuloma formation. In the post hoc analysis, we compared time-to-first-relapse and changes in pulmonary function after a protocolised corticosteroid taper in the Therapeutic and Subtherapeutic groups.ResultsEfzofitimod at ≥300 nM (19 µg·mL−1) inhibited granuloma formationin vitro. Based on average efzofitimod serum concentrations achieved in the phase 1b/2a study, the 3 and 5 mg·kg−1dose arms were pooled as the Therapeutic group, while the 1 mg·kg−1arm was pooled with the placebo arm as the Subtherapeutic group. Relapse rates were 54.4% and 7.7% in the Subtherapeutic group and Therapeutic group, respectively. Median time-to-first-relapse in the Subtherapeutic group was 126 days, whereas in the Therapeutic group, only one of 17 patients relapsed by the end of the 24-week study (p=0.017). Slopes analysis showed that forced vital capacity increased in the Therapeutic group, but decreased in the Subtherapeutic group, over the course of the trial (p=0.035).ConclusionTreatment with efzofitimod at therapeutic doses, as compared with a subtherapeutic dose or placebo, was associated with a lower rate of relapse as corticosteroids were tapered.

Silk-Derived Protein-4 Versus Vehicle Control in Treating Patients With Moderate to Severe Dry Eye Disease: A Randomized Clinical Trial

In this study the safety and efficacy of silk-derived protein 4 (SDP-4), also known as amlisimod, eye drops against a vehicle control formulation in patients with moderate to severe dry eye disease (DED) was assessed. SDP-4 is a novel, naturally derived, anti-inflammatory wetting agent that enhances coating on the ocular surface. Exploratory Phase 2, 12- and 8-week, serial cohort, multicenter, double-masked, randomized, vehicle-controlled study. In the first cohort (N = 305), patients were randomized 1:1:1:1 to SDP-4 (0.1%, 1%, 3% wt./wt.) or vehicle control and dosed 2 times per day (BID), while in the second cohort patients were randomized 1:1 with 1% wt./wt. SDP-4, the best performing formulation from the first cohort, or vehicle control BID (N = 151). Diagnosed DED patients were treated in the United States between April 2019 and May 2021. The first cohort of subjects had moderate to severe baseline symptoms, while the second cohort had moderate baseline symptoms to study the impact of baseline symptoms on SDP-4 performance. Key sign and symptom end points were mean change from baseline in TBUT and total SANDE score (0-100 visual analog scale) throughout the study. SDP-4 (1%) significantly increased TBUT vs the vehicle control (P < .05) at days 28 and 56 in the first cohort, and patient symptomatology from baseline was reduced by 46% based on subject reported SANDE VAS scores at day 84. Patients with more severe baseline DED symptoms experienced a significantly greater amount of relief than when compared to patients with moderate DED (P < .05). All treatment groups were well tolerated with a 2.6% total discontinuation rate. To the best of our knowledge, this was the first-in-human use of SDP-4 in a clinical trial. SDP-4 is a first-in-class protein ingredient that offers a safe and multi-modal treatment approach for alleviating severe DED symptoms within a novel formulation.

Impact of the COVID-19 Pandemic on Conduct and Results of CLEAR Outcomes Trial.

The COVID-19 pandemic disrupted clinical research. CLEAROutcomes investigated the effect of bempedoic acid (BA) versus placebo in 13 970 patients with statin intolerance and high cardiovascular (CV) risk. BA reduced the risk of the primary endpoint (composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13%. CLEAROutcomes began beforeand continued for 2.7 years afterthe start of the pandemic. The impact of the COVID-19 pandemic on patient disposition, adverse events, and major adverse CV events (MACE) in CLEAROutcomes was assessed. Rates of severe infection, hospitalization, or first MACE associated with a positive COVID-19 test were low and balanced between treatment groups. Rates of all-cause death, non-CV death, and undetermined death increased in the pandemic period compared with the pre-pandemic period, while rates of CV death with a known etiology remained stable. A sensitivity analysis excluding undetermined deaths occurring after the onset of the pandemic from the CV death designation yielded hazard ratios of 0.84 (95% CI, 0.76-0.93) for the primary endpoint and 0.94 (95% CI, 0.76-1.16) for the secondary endpoint of CV death, compared with 0.87 (95% CI, 0.79-0.96) and 1.04 (95% CI, 0.88-1.24), respectively, in the original analysis. The CLEAR Outcomes trial continued uninterrupted throughout the COVID-19 pandemic. Certain trial endpoints may have been impacted by the pandemic. Specifically, the classification of undetermined deaths as CV deaths may have attenuated the effect of BA on key efficacy endpoints.

The graded multidimensional geometry of phenotypic variation and progression in neurodegenerative syndromes.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration. We included three time-point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate Alzheimer's disease and frontotemporal lobar degeneration variants (114 typical Alzheimer's disease; 107 behavioural variant frontotemporal dementia; 42 motor variants of frontotemporal lobar degeneration; and 103 primary progressive aphasia patients). On this data, we applied advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning clinical progression of Alzheimer's disease and frontotemporal lobar degeneration syndromes. To do so, we first used principal component analysis to derive six axes of graded longitudinal phenotypic variation capturing patient-specific movement along and across these axes. Then, we distilled these axes into a visualisable 2D manifold of longitudinal phenotypic variation using Uniform Manifold Approximation and Projection. Both geometries together enabled the assimilation and inter-relation of paradigmatic and mixed cases, capturing dynamic individual trajectories, and linking syndromic variability to neuropathology and key clinical end-points such as survival. Through these low-dimensional geometries, we show that (i) specific syndromes (Alzheimer's disease and primary progressive aphasia) converge over time into a de-differentiated pooled phenotype, while others (frontotemporal dementia variants) diverge to look different from this generic phenotype; (ii) phenotypic diversification is predicted by simultaneous progression along multiple axes, varying in a graded manner between individuals and syndromes; and (iii) movement along specific principal axes predicts survival at 36 months in a syndrome-specific manner and in individual pathological groupings. The resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in Alzheimer's disease and frontotemporal lobar degeneration.

Recombinant human nerve growth factor (cenegermin) for moderate-to-severe dry eye: phase II, randomized, vehicle-controlled, dose-ranging trial

BackgroundDry eye disease (DED) includes neurosensory abnormalities as part of its multifactorial etiology. Nerve growth factor is important for maintaining corneal nerve integrity and wound healing. Cenegermin (recombinant human nerve growth factor) is a topical biologic that promotes corneal healing in patients with neurotrophic keratitis. The purpose of this study was to evaluate efficacy and safety of cenegermin in moderate-to-severe DED and identify an optimal dosing strategy.MethodsThis was a phase II, multicenter, randomized, double-masked, vehicle-controlled, dose-ranging clinical trial in patients with moderate-to-severe DED, including Sjögren’s DED (NCT03982368). Patients received 1 drop of cenegermin 3 times daily (t.i.d.; 20 mcg/mL), cenegermin 2 times daily (b.i.d.; 20 mcg/mL) and vehicle once daily, or vehicle t.i.d. for 4 weeks. Follow-up continued for 12 additional weeks. The primary endpoint was change in Schirmer I score from baseline to week 4. Other key endpoints included rate of responders (Schirmer I test > 10 mm/5 min) after treatment and change in Symptoms Assessment iN Dry Eye (SANDE) scores from baseline to end of follow-up. A 1-sided test (α = 0.025) was used to evaluate statistical significance.ResultsAt week 4, mean changes in Schirmer I scores were not statistically significantly different in either cenegermin group versus vehicle (cenegermin vs vehicle [treatment difference; 95% CI]: t.i.d., 2.60 mm and b.i.d., 3.99 mm vs 1.68 mm [t.i.d.: 0.93; −1.47 to 3.32, P = 0.078; b.i.d.: 2.31; −0.08 to 4.70, P = 0.066]). More patients responded to treatment with cenegermin t.i.d. and b.i.d. versus vehicle (t.i.d.: 25.9% [21/81, P = 0.028]; b.i.d.: 29.3% [24/82, P = 0.007] vs 11.9% [10/84]), with statistical significance (set at P < 0.025) observed in the b.i.d. group. Only cenegermin t.i.d. yielded statistically significant (P < 0.025) reductions in SANDE scores versus vehicle, which were sustained up to the end of follow-up (P value range, 0.002–0.008). Eye pain, primarily mild and transient, was the most frequently observed treatment-emergent adverse event with cenegermin. Similar results were observed in patients with Sjögren’s DED.ConclusionsCenegermin was well tolerated and although this study did not meet its primary endpoint, significant improvement in patient-reported symptoms of dry eye was observed through follow-up. Larger studies evaluating cenegermin in patients with DED are warranted.Trial registrationNCT03982368; registered May 23, 2019.

Population pharmacokinetics and exposure-response analyses of SAF-189s in Chinese patients with ALK+/ROS1+ non-small cell lung cancer.

SAF-189s is a potent ALK/ROS1 inhibitor that is currently in clinical development for treating advanced ALK+/ROS1+ non-small cell lung cancer (NSCLC). Comprehensive population pharmacokinetics (PopPK) and exposure-response models were developed to evaluate the efficacy and safety of SAF-189s by integrating data from two clinical studies. The PopPK model was developed using plasma concentration data collected from patients with ALK+/ROS1+ advanced NSCLC (n = 299) and healthy subjects (n = 24). The covariates (demographics, laboratory values, subject types, and concomitant medications) were evaluated to determine their potential influence on the between-patient variability in the pharmacokinetics of SAF-189s. Individual exposure values were then used to investigate the relationships with the efficacy endpoints (overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR)) and key safety endpoints (adverse events of interest). The final PopPK model of SAF-189s was described by a one-compartment model with delayed first-order absorption and time-dependent elimination by allowing the clearance to decrease stepwise over time. Age was included as a covariate for apparent clearance (CL/F), while prior anti-cancer therapy in ALK+ patients (ALKPOT) was included for apparent volume of distribution (V/F). There were no apparent exposure-response relationships for any of the efficacy endpoints at doses of 80-210mg. The relationship between exposure and safety suggested that a higher steady-state exposure was associated with more frequent incidences of hyperglycemia and proteinuria; the 210-mg dose group was also less tolerated than the other low-dose groups. PopPK and exposure-response models were developed for SAF-189s, and their results demonstrate that SAF-189s exposures are at the plateau of exposure-response for efficacy. The 210-mg dose group had a significantly higher safety risk, while the 160-mg dose group was well-tolerated. Thus, 160mg of SAF-189s once daily was selected as the recommended phase III dose for the ALK+/ROS1+ or ROS1+ NSCLC patients.

Safety and efficacy of linaclotide in children aged 2-5 years with functional constipation: Phase 2, randomized study.

Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC. In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 μg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 μg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded. Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 μg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe. Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 μg versus placebo.

O-255 Ovarian Response Prediction Index (ORPI) as a predictor tool for ovarian response and clinical pregnancy in IVF/ICSI cycle : A Prospective Cohort Study

Abstract Study question Can incorporation of the Ovarian Response Prediction Index (ORPI), integrating AMH, AFC and age, offer a reliable prognostication of ovarian stimulation response in ART cycles? Summary answer The study affirms that ORPI, a three-variable index, emerges as a robust predictor for both ovarian response and clinical pregnancy rates within IVF/ICSI cycles. What is known already In the realm of individualized Controlled Ovarian Stimulation, precision in forecasting ovarian response proves pivotal. Ovarian reserve, influenced by age, AMH, and AFC, exhibits considerable heterogeneity among women of analogous age. While AMH and AFC function as pivotal markers, a holistic approach, exemplified by ORPI, stands out as a more comprehensive tool for predicting ovarian response. Study design, size, duration This prospective cohort study enrolled 302 subjects undergoing IVF cycles at a tertiary infertility center spanning from 1st January 2022 to 31st December 2023. Rigorous inclusion criteria mandated age ≤38 years, a BMI between 20–25 kg/m2, regular menstrual cycles, intact bilateral ovaries, no history of ovarian surgeries, absence of severe endometriosis, and no evidence of endocrine disorders. Participants/materials, setting, methods Subjects adhering to the inclusion criteria underwent venous blood sampling for AMH measurement and transvaginal ultrasound for AFC assessment. The ORPI was meticulously computed as (AMH × AFC) / patient age. Key endpoints encompassed the total oocytes retrieved, mature MII oocytes, and occurrences of clinical pregnancy. Rigorous statistical methodologies were employed for robust analysis. Main results and the role of chance The mean values for age (years), AMH (ng/mL), ORPI, AFC, and fertilized oocytes were 31.75 ± 4, 3.75 ± 3.39, 1.06 ± 1.22, 7.1 ± 2.94, and 6.11 ± 3.26, respectively. A highly significant positive correlation (p-value &amp;lt; 0.0001) was observed between ORPI and the numbers of oocytes and MII oocytes, with correlation coefficients of 0.714 and 0.746, respectively. Interpretation of the area under the ROC curve revealed that ORPI was a significant predictor of obtaining ≥4 oocytes at a cutoff point of &amp;gt; 0.2, with an area under the curve of 0.907. Similarly, for MII oocytes ≥4, ORPI was a significant predictor at a cutoff point of &amp;gt; 0.2, with an area under the curve of 0.937. In the case of positive clinical pregnancy, ORPI emerged as a significant predictor at a cutoff point of &amp;gt; 0.75, with an area under the curve of 0.822. The study underscored a substantial positive correlation between ORPI and both oocyte and MII oocyte counts, affirming ORPI’s pivotal role as a predictor for clinical pregnancy. Limitations, reasons for caution Limitations due to the constraint of sample size temper the generalizability of findings. The study did not account for live birth rates, and a comparative analysis with alternative markers was omitted. A more expansive, meticulously designed study is imperative. Wider implications of the findings ORPI, an innovative ovarian response biomarker, showcases considerable potential for predicting both ovarian response and clinical pregnancy rates. Its integration into individualized Controlled Ovarian Stimulation regimens holds promise for augmenting the counselling and prognostication process for patients embarking on IVF/ICSI cycles. Trial registration number MCDH/2023/28

Empagliflozin to prevent post-operative atrial fibrillation in patients undergoing coronary artery bypass graft surgery: Rationale and design of the EMPOAF trial.

Postoperative atrial fibrillation (POAF) is one of the most common types of acute AF and can complicate the treatment course of approximately one third of patients undergoing cardiac surgery. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are among the newest antidiabetic drugs which can be therapeutic options for preventing POAF by different mechanisms. Empagliflozin to Prevent POAF (EMPOAF) is an interventional, investigator-initiated, double-blind, placebo-controlled, multicenter, randomized controlled trial which will be conducted in two referral teaching cardiology hospitals in Tehran. Four-hundred ninety-two adult patients who are scheduled for elective isolated coronary artery bypass graft (CABG) surgery will be randomly assigned to one of the groups of intervention (empagliflozin 10mg daily) or placebo starting at least 3 days before surgery until discharge. Key exclusion criteria are a history of diabetes mellitus, AF, ketoacidosis, or recurrent urinary tract infections along with severe renal or hepatic impairment, unstable hemodynamics, and patients receiving SGLT2 inhibitors for another indication. The primary outcome will be the incidence of POAF. Key secondary endpoints will be the composite rate of life-threatening arrhythmias, postoperative acute kidney injury, hospitalization length, in-hospital mortality, stroke, and systemic embolization. Key safety endpoints will be the rate of life-threatening and/or genitourinary tract infections, hypoglycemia, and ketoacidosis. EMPOAF will prospectively evaluate whether empagliflozin 10mg daily can reduce the rate of POAF in patients undergoing elective CABG. Enrolment into this study has started by November 2023 and is expected to be ended before the end of 2025.

Unveiling The Myth of High Recurrence Rate of Extracranial Arteriovenous Malformations of The Head and Neck: Systematic Review of Case Reports and Case Series

Background Arteriovenous malformations (AVMs) in the head and neck pose a challenge in their management due to their local aggressiveness and high recurrence risk. This study aimed to analyze literature on head and neck AVM recurrence post-treatment and identify the most effective strategy with a lower recurrence rate. Objectives To analyse existing literature on the recurrence of head and neck AVMs following treatment. Our goal was to identify the most effective treatment option with a lower recurrence rate. Methods We conducted a thorough literature search using PubMed, ScienceDirect, and Scopus, from year 2000 to the present. Our analysis focused on key endpoints, specifically the recurrence rates of head and neck AVMs following various treatment approaches. Results Out of the initial pool of 108 screened articles, a total of 83 patients were deemed suitable for inclusion in the literature review. The reviewed articles demonstrated that appropriate diagnostic tests were documented in 95% of the included studies. Among the patients, 37.3% had previously undergone interventions and were currently dealing with regrowth masses. Notably, 56.6% of patients underwent a combined approach involving both endovascular and surgical methods, while 25.3% opted for a surgical-only approach, and only 18.1% pursued an endovascular-only approach. The studies showed a promising curing rate of AVMs, with a success rate of 94%, albeit with a complication rate of 32.5%. The average follow-up duration for all patients was 26 months, with a standard deviation of 20.5 months. Out of the 83 patients, 5 experienced recurrence, with single-modality approach. Interestingly, no patients who received a multi-modality of treatments experienced recurrence or regrowth of the AVM mass within the follow up period. Conclusion The multi-modality approach outperformed single-modality treatments in preventing AVM recurrence. These findings highlight the importance of a comprehensive and multidisciplinary approach in the management of these complex vascular anomalies. PROSPERO: CRD42023490871 registered on 17/12/2023

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC

ObjectivesFirst-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure. Materials and methodsPatients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018–30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS). ResultsA total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0–652) after progression on osimertinib.Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65).TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis. ConclusionsOur real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.