Analysis Of Secondary Endpoints Research Articles

IMPRESS-Norway: improving public cancer care by implementing precision medicine in Norway; inclusion rates and preliminary results.

In Norway, comprehensive molecular tumour profiling is implemented as part of the public healthcare system. A substantial number of tumours harbour potentially targetable molecular alterations. Therapy outcomes may improve if targeted treatments are matched with actionable genomic alterations. In the IMPRESS-Norway trial (NCT04817956), patients are treated with drugs outside the labelled indication based on their tumours molecular profile. IMPRESS-Norway is a national, prospective, non-randomised, precision cancer medicine trial, offering treatment to patients with advanced-stage disease, progressing on standard treatment. Comprehensive next-generation sequencing, TruSight Oncology 500, is used for screening. Patients with tumours harbouring molecular alterations with matched targeted therapies available in IMPRESS-Norway, are offered treatment. Currently, 24 drugs are available in the study. Primary study endpoints are percentage of patients offered treatment in the trial, and disease control rate (DCR) defined as complete or partial response or stable disease in evaluable patients at 16 weeks (W16) of treatment. Secondary endpoint presented is DCR in all treated patients. Between April 2021 and October 2023, 1,167 patients were screened, and an actionable mutation with matching drug was identified for 358 patients. By the data cut off 186 patients have initiated treatment, 170 had a minimum follow-up time of 16 weeks, and 145 also had evaluable disease. In patients with evaluable disease, the DCR was 40% (58/145). Secondary endpoint analysis of DCR in all treated patients, showed DCR of 34% (58/170). Precision cancer medicine demonstrates encouraging clinical effect in a subset of patients included in the IMPRESS-Norway trial.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

Abstract PS15-06: Results of the window-of-opportunity PIONEER trial evaluating addition of the progesterone receptor (PR) agonist megestrol to letrozole for early stage estrogen receptor (ER) positive breast cancer: exploiting ER-PR interaction

Abstract Background: Pre-clinical data suggest that combining anti-estrogen treatment with a progesterone receptor agonist leads to greater inhibition of tumor proliferation, due to molecular interactions between ER and PR [1]. A high dose of the PR agonist megestrol (160mg daily) is approved as monotherapy for the treatment of ER positive metastatic breast cancer. A lower dose of megestrol (20-40mg daily) can be an effective treatment for severe hot flashes associated with endocrine therapy [2] but whether this dose has anti-tumor activity is unknown. The PIONEER trial evaluated the potential anti-proliferative effect of low and high dose megestrol in combination with letrozole, relative to letrozole alone, using a short-term preoperative ‘window’ trial design assessing the direct effects of the trial treatment on tumor tissue before and after treatment. Methods: Eligible patients were post-menopausal women with histologically confirmed ER+ (Allred ≥ 3) HER2 negative breast cancer at least 10mm in size, with an ECOG performance status ≤ 2, planned for primary surgery or endocrine therapy. Enrolled patients were randomised 2:3:3 to Arm A: letrozole alone, Arm B: letrozole + lower-dose megestrol (40mg) or Arm C: letrozole + higher-dose megestrol (160mg). Treatment was given for 15 (13-19) days prior to surgery or end of treatment (EOT) core biopsy. The primary endpoint was change in tumor proliferation between baseline and EOT in Arm A vs (Arms B+C combined), measured by Ki67 immunohistochemistry (IHC). Secondary endpoints were comparison of Ki67 change in high versus low dose megestrol arms, absolute Ki67 at EOT, and change in tumor apoptosis (cleaved caspase 3 IHC), proliferation (Aurora Kinase A IHC), PR and androgen receptor expression. Exploratory analysis of ER chromatin binding (ChIP-Seq) was conducted on paired fresh-frozen samples from a subset of patients. Results: A total of 243 patients were randomised from July 2017 to October 2022 with recruitment paused for 3 months at onset of the COVID pandemic. 198 patients completed treatment and had evaluable tissue samples at baseline and EOT (Arm A: n = 51, Arm B: n = 74, Arm C: n = 73). Baseline mean Ki67 values were well balanced. Therapy was well tolerated and adverse events ≥ grade 3 were similarly rare across arms (A: 3.3%, B+C: 3.5%). The mean % reduction in Ki67 for each arm was: Arm A (letrozole): 71%, Arm B (letrozole + 40mg megestrol): 79%, Arm C (letrozole + 160mg megestrol): 80%. There was a statistically significantly greater reduction in Ki67 with megestrol combinations (B+C) versus letrozole alone (A) (P = 0.013). Analyses of secondary IHC endpoints and ER ChIP-Seq are ongoing and will be presented. Conclusion: Addition of the PR agonist megestrol enhanced the anti-proliferative effect of letrozole in this window-of opportunity trial. Megestrol combinations were well tolerated, and the anti-proliferative effect was observed in both low and high dose arms. These data support the potential use of low-dose megestrol as an inexpensive and well-tolerated means of improving aromatase inhibitor efficacy. Low dose megestrol can also ameliorate hot flashes and therefore might be a strategy to improve both treatment adherence and clinical outcomes for patients taking adjuvant endocrine therapy.

Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial

Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARCEX Therapy to improve arm and hand functions in people with chronic SCI. ARCEX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARCEX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARCEX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARCEX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472.

Eculizumab in Adolescent Patients With Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study

BackgroundThis study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). MethodsAdolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. ResultsEleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were −5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and −2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. ConclusionsEculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

Efficacy of early administration of sacubitril/valsartan after coronary artery revascularization in patients with acute myocardial infarction complicated by moderate-to-severe mitral regurgitation: a randomized controlled trial.

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12months (MRJA: - 3.21 ± 2.18 cm2 vs. - 1.83 ± 2.81 cm2, P < 0.05; MRV: - 27.22 ± 15.22mL vs. - 13.67 ± 21.02mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12-3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021.

Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

Effectiveness and safety of BCD180, anti-TRBV9&lt;sup&gt;+&lt;/sup&gt; T-lymphocytes monoclonal antibody in patients with active radiographic axial spondyloarthritis: 36-week results of double-blind randomized placebo-controlled phase II clinical study ELEFTA

The aim – to evaluate the clinical effectiveness, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of seniprutug (BCD-180) in patients with radiographic active axial spondyloarthritis (r-axSpA, or ankylosing spondylitis).Subjects and methods. 260 patients with active r-axSpA and inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) were randomized into three groups: seniprutug (BCD-180) at doses of 5 mg/kg or 7 mg/kg, or placebo. BCD-180 was administered on weeks 0–12–36. Patients in the placebo group were switched to BCD-180 at a dose of 5 mg/kg at week 24 and continued therapy at week 36. The primary endpoint was the proportion of patients achieving 40% improvement by Assessment in Spondyloarthritis International Society scale (ASAS40) at week 24. Secondary endpoints were proportion achieving ASAS20/40, improvement of 5 out of 6 criteria of ASAS (ASAS5/6), ASAS partial remission, clinically important improvement in ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score with C-reactive protein) (ASDAS-CII) and major improvement in ASDAS-CRP (ASDAS-MI). The dynamics of the disease activity status according to ASDAS-CRP, the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) indices, as well as the dynamics of laboratory markers (C-reactive protein anderythrocyte sedimentation rate (ESR)) were analyzed. Safety was assessed by the frequency and profile of adverse events (AEs) and adverse reactions (ARs).Results. The proportion of patients achieving ASAS40 at week 24 with seniprutug (BCD-180) at the dose of 7 mg/kg and 5 mg/kg was 51.4% and 40.8%, respectively, compared with 24% in the placebo group (p=0.0012 and p=0.0417, respectively). Analysis of secondary endpoints showed that in patients with r-axSpA, BCD-180 at both study doses was significantly superior to placebo at week 24 in the following measures: decrease in the proportion of subjects with very high disease activity (ASDAS-CRP&gt;3.5) achieving ASDAS-CII, ASAS20, ASAS5/6. A statistically significant decrease in the ASDAS-CRP, BASDAI, BASFI indices, as well as the concentration of CRP and ESR were demonstrated. Tolerability of seniprutug therapy was assessed as acceptable. Infusion reactions were the most common observed adverse events, the vast majority of which were mild to moderate in severity according to CTCAE 5.0 (Common Terminology Criteria for Adverse Events) and developed predominantly during the first administration. The proportion of patients with binding antibodies was 5.1%. However, no neutralizing antibodies were detected.Conclusion. Seniprutug (BCD-180) demonstrated superiority over placebo in clinical efficacy with a favorable safety profile and low immunogenicity as a treatment of r-axSpA.

Evaluating time until ligation in a novel tourniquet – A crossover randomized-controlled trial

Introduction and aimSevere external hemorrhage is a significant reason for morbidity and mortality in adults; thus, the swift and correct application of a tourniquet by laypersons can be lifesaving. We conducted this randomized-controlled cross-over study to investigate the use of a novel tourniquet. MethodsParticipants were recruited at the Heidelberg University Hospital. Eligible participants were ≥ 18 years old with a medical background but without prior experience in applying a tourniquet. Participants were 1:1 randomized to the intervention group (PAX tourniquet) or the control group (SAM or CAT tourniquet). In the control group, participants underwent another randomization to either the SAM or CAT tourniquet without a predefined allocation ratio. Hyperspectral measurements were undertaken (i) before ligation, (ii) 30 s after ligation, and (iii) 30 s after the reopening of the tourniquet. The primary outcome was time until ligation before crossover between the respective groups. The analysis of secondary endpoints included all attempts to assess a possible learning effect, intraoperator variability, and hyperspectral measurements. Participants were crossed to the other study group after a brief wash-out phase. ResultsIn total, 50 participants were recruited, resulting in 100 attempts. A success rate of 98% was observed across the study population. Time until ligation was 49 s and 56 s (p = 0.572) in the intervention and control group, respectively. However, there was a significant difference between the PAX and SAM (54 vs 75 s; p = 0.037) and the SAM and CAT tourniquet (75 vs. 47 s; p = 0.015). Further, we observed a significant learning effect in participants allocated to the control group first, with a median reduction of 9 s in the time until ligation. Hyperspectral measurements showed a significant decrease in perfusion and tissue oxygenation after ligation. Further, a significant increase in perfusion and tissue oxygenation was found after reopening the tourniquet compared to the baseline measurement. ConclusionThe novel PAX tourniquet can be applied quickly and effectively by medical personnel without prior experience in applying a tourniquet.

Intra-Articular Injection of Adipose-Derived Stromal Vascular Fraction in Osteoarthritic Temporomandibular Joints: Study Design of a Randomized Controlled Clinical Trial.

Temporomandibular joint (TMJ) osteoarthritis is a degenerative disease of the TMJ. It is characterized by progressive degradation of the extracellular matrix components of articular cartilage, with secondary inflammatory components leading to pain in the temporomandibular region and reduced mouth opening. Current treatments do not halt disease progression, hence the need for new therapies to reduce inflammation and, consequently, improve symptoms. The aim of our randomized controlled clinical trial protocol is to investigate the efficacy of adjuvant intra-articular injections of autologous tissue-like stromal vascular fraction (tSVF), compared to arthrocentesis alone, in reducing pain and improving mouth opening in TMJ osteoarthritis patients. The primary endpoint analysis will consist of the visual analogue scale (VAS) for pain. The secondary endpoint analyses will include maximal interincisal mouth opening measurements; assessment of oral health and mandibular function based on the oral health impact profile (OHIP) questionnaire and mandibular functional impairment questionnaire (MFIQ); complications during the follow up; synovial cytokine analysis at baseline and after 26 weeks; and nucleated cells and tSVF (immuno)histochemistry analyses of the intervention group. Our randomized clinical trial protocol will be applied to evaluate the efficacy of a new promising tSVF injection therapy for TMJ osteoarthritis. The safety of intra-articular injections of tSVF has been proven for knee osteoarthritis. However, since a tSVF injection is considered a heterologous application of cell therapy, the regulatory requirements are strict, which makes medical ethical approval challenging.

Alirocumab in Pediatric Patients With Heterozygous Familial Hypercholesterolemia

Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. ClinicalTrials.gov Identifier: NCT03510884.

Abstract 9: Efficacy of Colchicine for Prevention of Stroke and Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease: A Meta-Analysis of 15 Randomized Controlled Trials

Background: Clinical evidence supports the role of Inflammation in atherosclerosis and associated complications. Colchicine as a potential anti-inflammatory treatment among such patients has attracted much attention in recent years. However, its efficacy on cerebrovascular and cardiovascular events is still controversial. Objective: We sought to evaluate the efficacy of Colchicine for coronary artery disease patients. Methods: We performed a systematic literature search on PubMed, EMBASE, and Clinicaltrial.gov for relevant randomized controlled trials (RCTs) from inception until August 30th, 2023. Odds ratios (OR) were pooled using a random-effect model, and a p-value of &lt;0.05 was considered statistically significant. Results: A total of 15 randomized controlled trials were included (6863 in Colchicine and 6756 in the control group) in the analysis. Pooled analysis of primary and secondary endpoints showed that Colchicine significantly reduced the risk of incidence of stroke by 50% (OR, 0.50 (95%CI: 0.31-0.81), P&gt;0.001), myocardial infarction by 40% (OR, 0.60 (95%CI: 0.44-0.84), P&gt;0.001), new acute coronary syndrome by 53% (OR, 0.47(95%CI: 0.47-0.85), P&gt;0.001), and major adverse cardiovascular events 45% (OR, 0.55(95%CI: 0.39-0.78), P&gt;0.001) compared with control. However, the risk of all-cause mortality (OR, 1.06(95%CI: 0.83-1.35), P=0.55) was comparable between both groups of patients. Conclusion: Colchicine was associated with an overall reduction in the risk of incidence of stroke, MI, MACE, ACS in patients with coronary heart disease. However, no such effect was observed with mortality.

Abstract TP181: Endovascular Therapy for Acute Ischemic Stroke With Large Infarct: A Meta Analysis of Randomized Controlled Trials

Background: The efficacy of endovascular thrombectomy (EVT) in patients with large infarct among acute ischemic stroke patients has not been exclusively studied, with conflicting results till date. Objective: We sought to evaluate the outcomes comparing EVT and medical therapy among stroke patients with large infarcts. Methods: We performed a systematic literature search on PubMed, EMBASE, and Clinicaltrial.gov for relevant randomized controlled trials (RCTs) from inception until August 30th, 2023. Odds ratios (OR) were pooled using a random-effect model, and a p-value of &lt;0.05 was considered statistically significant. Results: A total of 3 randomized controlled trials with 1010 patients (509 in EVT and 501 in MT) were included in the analysis. Pooled analysis of primary and secondary endpoints showed that ET was associated with a significantly greater rate of MRS 0-2 (OR, 2.53(95%CI: 1.76-3.64), P&lt;0.001), MRS 0-3 (OR, 1.75(95%CI: 1.28-2.39), P&lt;0.001). ET group of patients were having a significantly higher risk of any intracranial hemorrhage (OR, 2.34(95%CI: 1.53-3.58), P&gt;0.001), and a trend of higher risk of incidence of symptomatic intracranial hemorrhage (OR, 1.83(95%CI: 0.90-3.70), P=0.09) compared to medical therapy. However, the risk of incidence of 90 days mortality (OR, 0.95(95%CI: 0.73-1.24), P=0.71), hemi craniotomy (OR, 0.97(95%CI: 0.45-2.12), P=0.95), and adverse cardiovascular event (OR, 1.68(95%CI: 0.50-5.59), P=0.40) was comparable between ET and MT group. Conclusion: Patients with large infarcts had better functional outcomes with ET than with MT alone. However, intracranial hemorrhage was higher among ET compared with MT group, while 90 days mortality being comparable between both groups of patients.

Abstract WMP96: When to Change? Altering Strategies in Mechanical Thrombectomy May Impact Reperfusion Rates

Introduction: Earlier and greater reperfusion in mechanical thrombectomy (MT) leads to better clinical outcomes. The timing and potential benefit of switching thrombectomy techniques after failed device passes remains unclear. Methods: Retrospective analysis of a prospective comprehensive stroke center database including patients with intracranial ICA, MCA M1/M2, or Basilar occlusions undergoing MT with either Stent-Retriever (SR), Contact Aspiration (CA) or Combined technique (CT) from 2015 to 2023. Our primary endpoint was complete/near-complete reperfusion (eTICI 2c-3) at pass #2 (after pass #1 failure). Secondary endpoints included 1) eTICI2b-3 at pass#2, and 2) eTICI2c-3 with pass #3 (following failure in two consecutive passes with the same technique). We used logistic or Firth regression to compare reperfusion rates and Kaplan-Meier analysis for cumulative rates. Results: Among 3130 MTs in the study period, 1810 met inclusion criteria. Median age [IQR] was 65 [55 - 76] years and 51.5% were male. Following a failed first pass, switching from CA to either CT or SR was associated with higher eTICI 2c-3 (aOR [95%CI] 2.8 [1.3 - 6.5] and 7.4 [1.4-54.8], respectively). Changing from CT or SR to any other technique was not associated with higher reperfusion. Secondary endpoint analysis for eTICI2b-3 yielded comparable results. For the third pass, switching to CT after two repeated failed SR or two repeated failed CA attempts was associated with higher eTICI 2c-3 as compared to repeating the original strategy (SR aOR 5.8 [1.4 - 33.3]; AC aOR 5.6 [1.1 - 41.2]). We did not observe benefit in switching to alternative technique following one or two consecutive passes with CT. After three repeated attempts with the same technique, CT led to greater eTICI 2c-3 as compared to SR and CA (83% vs. 72% vs. 64%, p &lt; 0.001). Conclusions: While limited by small subgroup sample sizes, our study strengthens the hypothesis that early changes in MT technique may have an impact on reperfusion. Our data indicates that if CA fails on first pass, transition to SR or CT should be considered. After two failed consecutive SR or CA passes, transition to CT should be contemplated.

P1017 Upadacitinib as rescue therapy for the treatment of Acute Severe Colitis in an acute care setting

Abstract Background Inflammatory bowel disease is a chronic, relapsing and remitting inflammatory disorder that despite advances in medical therapy often requires hospitalization for treatment of acute flares with intravenous corticosteroids. Many patients will not respond to corticosteroids and require infliximab or cyclosporine as rescue therapy. If medical therapy fails, definitive surgical management is required. Recently, Janus Kinase inhibitors, including upadacitinib, have been proposed as an alternative rescue therapy given their rapid onset of action. The aim of this study was to evaluate the efficacy of upadacitinib as an alternative rescue therapy for acute severe colitis. Methods We conducted a retrospective review of 12 inflammatory bowel disease patients admitted for acute severe colitis who received upadacitinib induction therapy. The rates of surgery, repeat or prolonged steroid use, and re-admission within 90 days of index hospitalization were measured. The need for re-induction with upadacitinib, change in medical therapy, rates of clinical remission, change in 6-point partial Mayo score, and laboratory markers of inflammation were measured as secondary outcomes. Statistical analysis of primary and secondary endpoints was performed with descriptive analysis. Results Five patients met the primary composite endpoint including four patients requiring surgery and one additional patient being unable to withdraw steroids within 90 days of hospital discharge. One patient required re-induction with upadacitinib within 90 days and no patients required change in medical therapy within 90 days. Of the patients who did not undergo surgery, 63% were in clinical remission within 90 days and showed clinical improvement with decreased 6-point partial Mayo scores at the post-discharge visit (4.75 during admission vs. 1.25 at post discharge visit, p&amp;lt;0.0001). There were no adverse reactions reported in relation to upadacitinib administration during the study period. Conclusion We found that two-thirds of patients treated with upadacitinib 45mg daily for acute severe colitis were able to avoid surgery during the index admission and within 90 days post-discharge. Of the patients who were able to avoid surgery, most were able to taper steroids, did not require readmission within 90 days of index hospitalization and were in clinical remission within 90 days. Upadacitinib may be effective salvage therapy for acute severe colitis, but larger controlled trials are required to validate these results.

Randomized open-label trial of semaglutide and dapagliflozin in patients with type 2 diabetes of different pathophysiology

The limited understanding of the heterogeneity in the treatment response to antidiabetic drugs contributes to metabolic deterioration and cardiovascular complications1,2, stressing the need for more personalized treatment1. Although recent attempts have been made to classify diabetes into subgroups, the utility of such stratification in predicting treatment response is unknown3. We enrolled participants with type 2 diabetes (n = 239, 74 women and 165 men) and features of severe insulin-deficient diabetes (SIDD) or severe insulin-resistant diabetes (SIRD). Participants were randomly assigned to treatment with the glucagon-like peptide 1 receptor agonist semaglutide or the sodium–glucose cotransporter 2 inhibitor dapagliflozin for 6 months (open label). The primary endpoint was the change in glycated haemoglobin (HbA1c). Semaglutide induced a larger reduction in HbA1c levels than dapagliflozin (mean difference, 8.2 mmol mol−1; 95% confidence interval, −10.0 to −6.3 mmol mol−1), with a pronounced effect in those with SIDD. No difference in adverse events was observed between participants with SIDD and those with SIRD. Analysis of secondary endpoints showed greater reductions in fasting and postprandial glucose concentrations in response to semaglutide in participants with SIDD than in those with SIRD and a more pronounced effect on postprandial glucose by dapagliflozin in participants with SIDD than in those with SIRD. However, no significant interaction was found between drug assignment and the SIDD or SIRD subgroup. In contrast, continuous measures of body mass index, blood pressure, insulin secretion and insulin resistance were useful in identifying those likely to have the largest improvements in glycaemic control and cardiovascular risk factors by adding semaglutide or dapagliflozin. Thus, systematic evaluation of continuous pathophysiological variables can guide the prediction of the treatment response to these drugs and provide more information than stratified subgroups (NCT04451837).

Ablation for atrial fibrillation improves the outcomes in patients with heart failure with preserved ejection fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) have worse clinical outcomes than those with sinus rhythm (SR). We aim to investigate whether maintaining SR in patients with HFpEF through a strategy such as AF ablation would improve outcomes. This is a cohort study that analysed 1034 patients (median age 69 [63-76] years, 46.2% [478/1034] female) with HFpEF and AF. Of these, 392 patients who underwent first-time AF ablation were assigned to the ablation group, and the remaining 642 patients, who received only medical therapy, were assigned to the no ablation group. The primary endpoint was a composite of all-cause death or rehospitalization for worsening heart failure. After a median follow-up of 39 months, the cumulative incidence of the primary endpoint was significantly lower in the ablation group compared to the no ablation group (adjusted hazard ratio [HR], 0.55 [95% CI, 0.37-0.82], P = 0.003) in the propensity score-matched model. Secondary endpoint analysis showed that the benefit of AF ablation was mainly driven by a reduction in rehospitalization for worsening heart failure (adjusted HR, 0.52 [95% CI, 0.34-0.80], P = 0.003). Patients in the ablation group showed a 33% relative decrease in atrial tachycardia/AF recurrence compared to the no ablation group (adjusted HR, 0.67 [95% CI, 0.54-0.84], P < 0.001). Among patients with HFpEF and AF, the strategy of AF ablation to maintain SR was associated with a lower risk of the composite outcome of all-cause death or rehospitalization for worsening heart failure.

The effect of body mass index on complications in cardiac implantable electronic device surgery.

Cardiac implantable electronic device (CIED) procedures are prone to complications. In our study, we investigated the effect of body mass index (BMI) on CIED-related complications. 1676 patients who had undergone CIED surgery (de novo implantation, system upgrade, generator change, pocket revision or lead replacement) at two heart centers in Turkey and met the study criteria were included in our study. For analysis of primary and secondary endpoints, patients were classified as non-obese (BMI<25kg/m2 ), overweight (25 ≤ BMI<30kg/m2 ), and obese (BMI ≥ 30kg/m2 ). The primary endpoint was accepted as cumulative events, including the composite of clinically significant hematoma (CSH), pericardial effusion or tamponade, pneumothorax, and infection related to the device system. Secondary outcomes included each component of cumulative events. The rate of cumulative events, defined as primary outcome, was higher in the obese patient group, and we found a significant difference between the groups (3.0%, 4.3%, 8.9%, p=.001). CSH and pneumothorax rates were significantly higher in the obese patient group (0.3%, 0.9%, 1.9%, p=.04; 1.0%, 1.4%, 3.3%, p=.04, respectively). According to our multivariate model analysis; gender (OR:1.882, 95%CI:1.156-3.064, p=.01), hypertension (OR:4.768, 95%CI:2.470-9.204, p<.001), BMI (OR:1.069, 95%CI:1.012-1.129, p=.01) were independent predictors of cumulative events rates. Periprocedural complications associated with CIED (especially hematoma and pneumothorax) are more common in the group with high BMI.

Results of Phase III Clinical Trial: a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Direkord in Ischemic Stroke Patients in Early Recovery Period

Direkord is an original drug containing the active substance of dicholine succinate, which improves the sensitivity of insulin receptors in neurons to insulin. The aim of this work was to evaluate the efficacy and safety of the drug in ischemic stroke patients in the early recovery period. In total, 160 patients after the first ischemic stroke in the carotid system, confirmed by computed or magnetic resonance imaging, with a stroke duration from 3 weeks to 2 months, mean age 63.2±8.4 years, were randomized into two treatment groups. The first group (n=80) received Direkord intramuscularly at a dose of 600 mg/day for two weeks; the second group (n=80) received a placebo. Treatment response was defined as an improvement in neurological status, functional status, and cognitive function of the patients: at least a two-fold decrease in the total NIHSS score, the total Barthel score ≥ 95, and the total MoCA score ≥ 26. The analysis of the primary endpoint of the study using exact Fisher’s test showed that Direkord was statistically significantly superior to the placebo (p=0.017) in the number of patients who responded to the therapy — 23.7 and 8.7% of patients in groups, respectively. The secondary end point analysis revealed a statistically significant superiority of Direkord over the placebo in reducing neurological deficits on the NIHSS scale (p=0.004), on the Rankin scale (p=0.0357), and on the CGI-I (p&lt;0.001) and PGI-I (p&lt;0.001) global clinical impression scales. Direkord has a good safety profile; thus, no statistically significant differences were found with the placebo in any of the safety parameters, including the number of adverse events, vital signs, laboratory parameters, and ECG. Overall, Direkord is statistically significantly more effective than placebo in recovering function and daily activities after ischemic stroke.