Least-squares Mean Difference Research Articles

Switching treatment to cipaglucosidase alfa plus miglustat positively affects patient-reported outcome measures in patients with late-onset Pompe disease.

Late-onset Pompe disease (LOPD), a rare autosomal recessive multisystemic disorder, substantially impacts patients' day-to-day activities, outcomes, and health-related quality of life (HRQoL). The PROPEL trial compared cipaglucosidase alfa plus miglustat (cipa+mig) with alglucosidase alfa plus placebo (alg+pbo) in adult patients with LOPD over 52weeks and showed improved motor and respiratory function in patients switching treatment from standard-of-care enzyme replacement therapy (ERT) to cipa+mig at baseline. This study evaluated the impact of cipa+mig on patient-reported outcomes (PROs), including HRQoL in ERT-experienced patients, using data from PROPEL. PROs evaluated included the Subject's Global Impression of Change (SGIC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a, PROMIS Fatigue Short Form 8a, Rasch-built Pompe-specific Activity (R-PAct), and European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L). The proportions of responders in the cipa+mig arm and the alg+pbo arm were compared via chi-squared or Fisher's exact test (patient-level responder analysis), and least squares (LS) mean differences were calculated for change from baseline at Week 52 of the PRO measures (group-level analysis). At Week 52, patient-level SGIC responder and group-level SGIC analyses favored cipa+mig compared with alg+pbo across all SGIC domains (e.g. 90 vs. 59% responders in the cipa+mig vs. the alg+pbo group for SGIC ability to move around; P = 0.0005; and LS mean difference 0.385; P = 0.02). Similarly, PROMIS Physical Function and Fatigue domains numerically favored cipa+mig in both analyses (e.g. 50 vs. 40% responders in the cipa+mig vs. alg+pbo arm for PROMIS Physical Function; P = 0.37; and LS mean difference 3.1; P = 0.11). R-PAct for both treatment groups was similar in the patient-level responder analysis, but numerically favored alg+pbo in the group-level analysis (35% responders in both arms; P = 0.95; and LS mean difference -0.8; P = 0.48). Self-care, usual activities, and depression/anxiety domains of EQ-5D-5L numerically favored cipa+mig in both analyses (e.g. 20 vs. 12% responders in the cipa+mig vs. alg+pbo arm for EQ-5D-5L self-care; P = 0.54; and LS mean difference -0.108; P = 0.52). Overall, switching treatment from alglucosidase alfa to cipa+mig positively impacted PRO measurements during the double-blind period of PROPEL. NCT03729362; Registration date: November 1, 2018; https://clinicaltrials.gov/study/NCT03729362.

Use of insitu simulation to improve team performance and utilization of a rapid sequence intubation checklist.

Intubation checklists have emerged as tools to reduce adverse events and improve efficiency during rapid sequence intubation (RSI) in pediatric emergency departments (PEDs). This study aimed to use multidisciplinary simulation (SIM) training as an educational tool to improve PED team performance during RSI scenarios through utilization of an RSI checklist. We created a checklist modeled after previously published PED checklists. PED multidisciplinary teams participated in video-recorded SIM training sessions involving a scenario requiring intubation three times, first without interruption then while receiving our intervention of rapid-cycle deliberate practice (RCDP) debriefing focusing on checklist utilization and team dynamics. Learners went through the scenario once more uninterrupted to apply learned skills. Team performance was evaluated via video review using the Simulation Team Assessment Tool (STAT) focusing on airway management and human factors sections. Scores were compared before and after intervention along with pre- and postintervention surveys. A total of 483 learners participated in 64 SIM training sessions, 44 of whom met inclusion criteria and were included for data analysis. Scores increased postintervention for airway management, human factors and in total. Least-squares mean differences for total, airway, and human factors scores were 9.55 (95% confidence interval [CI] 7.24-11.85), 4.22 (95% CI 2.91-5.52), and 5.33 (95% CI 3.86-6.8), respectively, which was statistically significant with p-value of <0.001 across all categories. Surveys demonstrated improved role understanding and checklist utilization comfort postintervention. This study supports the benefit of multidisciplinary SIM training with RCDP-style methodology as an educational method for improving airway management, teamwork skills, and RSI checklist utilization for PED staff. Incorporation of additional maintenance SIM sessions for ongoing education is likely to be further beneficial and would allow evaluation of degradation of skills over time following initial training.

Effect of Cariprazine on Anhedonia in Patients with BipolarI Depression: Post Hoc Analysis of Three Randomized Placebo-Controlled Clinical Trials.

Anhedonic symptoms in bipolarI (BP-I) depression are associated with decreased quality of life and impaired functioning. We evaluated the effects of cariprazine in patients with BP-I depression with lower or higher levels of anhedonia at baseline. Data were pooled from three clinical trials (NCT01396447, NCT02670538, NCT02670551) analyzing the effects of cariprazine 1.5 and 3mg/day in adults with BP-I depression. During post hoc analysis, patients were stratified by baseline median Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia factor score into a lower (score < median) or higher (score ≥ median) anhedonia subgroup. Outcomes included change from baseline to week6 in MADRS total and anhedonia factor score, with the latter also evaluated after adjusting for other depressive symptoms. Between-group differences in change from baseline to week6 were compared using least-squares mean differences (LSMD) analyzed via a mixed-effect model for repeated measures. Median baseline anhedonia factor score was 19, defining the lower (placebo = 211; cariprazine 1.5mg/day = 200, 3mg/day = 212) and higher (placebo = 249; cariprazine 1.5mg/day = 261, 3mg/day = 250) anhedonia subgroups. In the lower subgroup, cariprazine 1.5mg/day but not 3mg/day was superior to placebo in reducing MADRS total (LSMD [95%CI] 1.5mg/day = - 2.61 [- 4.28, - 0.93], P = .0024) and anhedonia factor scores (- 1.70 [- 2.77, - 0.62], P = .0021) at week6. In the higher subgroup, both cariprazine doses were associated with significantly greater reductions than placebo in MADRS total (1.5mg/day = - 3.01 [- 4.84, - 1.19], P = .0012; 3mg/day = - 3.26 [- 5.12, - 1.40], P = .0006) and anhedonia factor scores (1.5mg/day = - 1.97 [- 3.13, - 0.81], P = .0009; 3mg/day = - 2.07 [- 3.26, - 0.89], P = .0006). Anti-anhedonic effects were preserved after adjusting for other depressive symptoms, suggesting the effect was not pseudospecific. Patients in the higher subgroup had higher baseline depression and therefore the lower subgroup may have had a floor effect. Cariprazine demonstrated antidepressant and specific anti-anhedonic effects regardless of baseline anhedonia symptoms in patients with BP-I depression. ClinicalTrials.gov identifiers, NCT02670538, NCT02670551, NCT01396447.

Effect of Tezepelumab on Sino-Nasal Outcome Test (SNOT)-22 Domain and Symptom-Specific Scores in Patients with Severe, Uncontrolled Asthma and a History of Chronic Rhinosinusitis with Nasal Polyps.

Tezepelumab blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine implicated in the pathogenesis of asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). In a previous analysis, tezepelumab improved asthma and rhinosinusitis symptoms compared with placebo in patients with severe, uncontrolled asthma and a history of CRSwNP in the 2years before randomization in the NAVIGATOR study. This post hoc analysis of patients with a CRSwNP diagnosis at any time before randomization in NAVIGATOR enabled domain and symptom-specific analyses of Sino-Nasal Outcome Test (SNOT)-22 outcomes. Patients (aged 12-80years) with severe, uncontrolled asthma were randomized to tezepelumab 210mg or placebo subcutaneously every 4weeks for 52weeks. SNOT-22 total, domain, and item scores were assessed in patients with a history of CRSwNP. Annualized asthma exacerbation rate (primary efficacy outcome), pre-bronchodilator forced expiratory volume in 1s, and Asthma Control Questionnaire-6, Asthma Quality of Life Questionnaire (standardized) for patients 12years and older, and Asthma Symptom Diary scores were also assessed in patients with and without a history of CRSwNP. Of 1059 patients with severe asthma, 165 (15.6%) had a history of CRSwNP. Tezepelumab treatment resulted in sustained improvements versus placebo in SNOT-22 total score throughout the 52-week study period [least-squares mean difference (95% confidence interval) - 11.08 (- 17.80, - 4.35)]. Tezepelumab improved all five SNOT-22 domain scores (sleep, nasal, function, ear/facial, and emotion) and the five SNOT-22 item scores of most clinical interest (decreased sense of smell/taste, nasal blockage, reduced productivity, waking up tired, and cough). Tezepelumab improved asthma-related clinical outcomes in patients with and without a history of CRSwNP. In patients with severe, uncontrolled asthma and a history of CRSwNP, tezepelumab improved rhinosinusitis symptoms across multiple domains, as well as asthma exacerbations, lung function, asthma control, and health-related quality of life. NCT03347279 ( https://classic. gov/ct2/show/NCT03347279 ).

A pooled analysis of the efficacy of sertraline in women, with a focus on those of childbearing age

IntroductionGender- and age-specific research on medications is essential for personalizing treatment plans, optimizing dosing, minimizing adverse effects and improving outcomes. Women are twice as likely to be diagnosed with major depressive disorder (MDD), and it is commonly reported during their reproductive years. This post-hoc pooled analysis evaluated the efficacy of sertraline (one of the most studied medications in women) in women of reproductive age (18–44 years).MethodsData was pooled from nine clinical trials of sertraline that included 1832 subjects with MDD. The analysis set included 1097 women, 651 of those were of reproductive age. Sertraline was compared with placebo for changes in total HAM-D17 and CGI scores measured over time through MMRM analysis. The change from baseline to the end of study (-week 8) was assessed using ANCOVA.ResultsThe changes from baseline in total HAM-D17 and CGI scores were significantly higher for sertraline than for placebo at the end of 8 weeks for all women (LS Mean difference, 95% CI: -1.81(-3.01,-0.62), P = 0.0029; -0.38(-0.55,-0.20), P < 0.0001, respectively). For women of reproductive age these changes (LS Mean difference, 95% CI: -2.08(-3.52,-0.64), P = 0.0047; -0.44(-0.66,-0.22), P < 0.0001, respectively), were significant from week 2 (HAM-D17) and week 1 (CGI) till the end of study.LimitationsOnly sertraline and placebo arms were included in the analysis. The dosing varied between studies, and the effect of dose was not addressed.ConclusionsSertraline is an effective option for treatment of MDD in women, including those in the childbearing age.

Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial

BackgroundCurrently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia. ObjectivesREMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia. MethodsREMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level. ResultsA total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups. ConclusionsRecaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.

Subgroup results from KARDIA-2: impact of demographic and baseline disease characteristics on zilebesiran response in patients with hypertension uncontrolled by a standard oral antihypertensive

Abstract Background Zilebesiran is an investigational RNA interference therapeutic targeting hepatic angiotensinogen synthesis. In KARDIA-1, a single subcutaneous (SC) dose of zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to Months 3 and 6 versus placebo. The Phase 2 KARDIA-2 study assessed efficacy and safety of zilebesiran with a standard oral antihypertensive in patients with uncontrolled hypertension. Purpose Uncontrolled hypertension is a leading cause of cardiovascular morbidity and mortality, and medication non-adherence affects blood pressure control. Developing effective, long-lasting treatments is crucial for patients with hypertension uncontrolled by standard therapy. Methods KARDIA-2 enrolled adults with mild-to-moderate hypertension who were untreated or receiving stable therapy with ≤2 antihypertensives. Patients discontinued prior antihypertensive medication and were randomized 10:7:4 to open-label, once-daily oral treatment with 40 mg olmesartan, 5 mg amlodipine, or 2.5 mg indapamide. After ≥4 weeks on protocol-specified medication, patients with a 24-hr mean ambulatory SBP of 130–160 mmHg were randomized 1:1 in a double-blind manner to a single SC dose of zilebesiran 600 mg or placebo as add-on therapy. The primary endpoint was change from baseline to Month 3 in 24-hr mean ambulatory SBP versus placebo for each group. Efficacy and safety were also assessed in pre-specified subgroups: age (&amp;lt;65; ≥65 years), sex, race (Black; other), baseline 24-hr mean ambulatory SBP (&amp;lt;145; ≥145 mmHg), and baseline estimated glomerular filtration rate (≥60; &amp;lt;60 mL/min/1.73m2). Results The primary analysis included 667 patients (median age [range] 59 [27–75] years; 57% male, 28% Black). At Month 3, least-squares mean differences (LSMD) (95% confidence interval [CI]) between zilebesiran and placebo for the olmesartan, amlodipine, and indapamide groups were −4.0 (−7.6, −0.3), −9.7 (−12.9, −6.6), and −12.1 (−16.5, −7.6) mmHg, respectively, for 24-hr mean ambulatory SBP (all p&amp;lt;0.05). LSMD (95% CI) in office SBP for the same groups were −7.0 (−10.4, −3.6), −10.2 (−13.5, −6.9), and −18.5 (−22.8, −14.2) mmHg, respectively, (all p&amp;lt;0.001). SBP reductions were consistent across subgroups, except for a trend towards an attenuated response observed in Black patients (Figs 1, 2). More patients receiving zilebesiran (49–58%) than placebo (39–48%) experienced ≥1 adverse event through Month 6, with low rates of hyperkalaemia, hypotension, or acute kidney injury reported across all groups. Conclusion In KARDIA-2, a single dose of zilebesiran significantly reduced SBP versus placebo at Month 3 on top of a standard oral antihypertensive, with encouraging safety data. SBP reduction was consistent across most subgroups. Treatment with zilebesiran combined with standard antihypertensives may be effective for a broad population of patients with hypertension uncontrolled on monotherapy.

Efficacy and safety of cofrogliptin once every 2 weeks in Chinese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, phase 3 trial.

We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long-acting dipeptidyl peptidase-4 inhibitor, in patients with drug-naïve type 2 diabetes (T2D). Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24-week double-blind period. Eligible patients then received cofrogliptin 25 mg in a 28-week open-label extension. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg (n = 158), cofrogliptin 25 mg (n = 158) or placebo (n = 159); 401 patients entered the open-label extension. At week 24, the least-squares (LS) mean difference (95% confidence interval [CI]) in HbA1c versus placebo was -0.63% (-0.81, -0.46) with cofrogliptin 10 mg and -0.59% (-0.77, -0.42) with cofrogliptin 25 mg (both p < 0.0001). The LS mean (standard error) change in HbA1c from baseline was maintained at the end of the study in patients given open-label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: -0.86% (0.07); cofrogliptin 25 mg: -0.74% (0.07); placebo: -0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups. Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D. Registered on Clinicaltrials.gov with the registration number NCT04556851 (https://clinicaltrials.gov/study/NCT04556851).

Effectiveness and safety of insulin glargine 300 U/mL in insulin-naïve individuals according to diabetes duration: Results from the REALI European pooled data analysis.

To evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) initiation according to diabetes duration (DD). We analysed patient-level data from 2381 insulin-naïve individuals with type 2 diabetes (T2D), of whom 2349 (98.7%) were treated with Gla-300 for 24 weeks. Of the 2381 participants, 1048 (44.0%) had a DD of less than 8 years and 1333 (56.0%) had a DD of 8 years or longer. We further analysed the subgroups of participants having a DD of less than 4 years (N = 450), 4-8 years (N = 598), 8-12 years (N = 627) and 12 years or longer (N = 706). Mean ± standard deviation age was 60.2 ± 9.0 years in participants with a DD less than 8 years and 64.2 ± 8.8 years in those with a DD of 8 years or longer. At 24 weeks of Gla-300 therapy, HbA1c improved with a least-squares (LS) mean change from baseline of -1.88% (95% confidence interval [CI], -1.95 to -1.80) and -1.71% (95% CI, -1.77 to -1.65), respectively, resulting in a LS mean difference between groups of 0.17% (95% CI, 0.07 to 0.26; P = .0005). In the subgroup analysis, LS mean HbA1c reduction from baseline to week 24 was highest in participants with a DD of less than 4 years and lowest in participants with a DD of 12 years or longer. Overall, incidences of symptomatic and severe hypoglycaemia were low, irrespective of DD, without body weight changes. Gla-300 was effective and safe in insulin-naïve individuals with T2D, regardless of DD. Improvement in HbA1c was greater when Gla-300 was initiated in participants with a DD of less than 4 years, although the difference between the groups was modest.

Effects of fortified eggs and time-restricted eating on cardiometabolic health: The prosperity trial

BackgroundGiven the increasing interest in dietary interventions to improve cardiovascular health, this trial assessed the impact of fortified eggs (FE) versus non-egg supplemented diet and time-restricted eating (TRE) versus usual care diet on cardiovascular biomarkers. MethodsThe study was a unblinded, 2-by-2 factorial design, which randomized patients, with either a prior cardiovascular event or two cardiovascular risk factors, to FE or a non-egg supplemented diet and TRE or usual care diet. Patients randomized to FE were instructed to consume at least 12 FE/week (with eggs provided); those on a non-egg supplemented diet restricted egg consumption to <2 eggs/week. TRE participants were instructed to consume all calories within an 8-hour window daily and fasted for the remaining 16 hours. Patients randomized to usual diet were advised to maintain current dietary habits. Follow-up was performed in-person at 1 and 4 months, and telephone calls at 2 and 3 months. Co-primary endpoints were 4-month LDL- and HDL-cholesterol. Secondary endpoints included additional lipids, cardiometabolic- and inflammatory biomarkers and micronutrient levels at 4-months. ResultsOverall, 140 patients were randomized with median (25th, 75th percentiles) age 66 (58, 73) years; 72 (51%) women, 38 (27%) Black, and 33 (24%) with diabetes mellitus. The difference in least squares (LS) means from baseline to 4-months for HDL and LDL levels revealed no significant clinical difference between FE vs. non-egg supplemented diet (HDL: -0.64 mg/dL [95% CI: -3.86, 2.58]; LDL: -3.14 mg/dL [-10.81, 4.52]) and TRE vs. usual care diet (HDL: 1.51 mg/dL [-1.65, 4.68]; LDL 1.17 mg/dL [-6.36, 8.70]). Pre-specified subgroups revealed a non-significant HDL increase and LDL decrease with FE in patients ≥65 years. ConclusionsThese data did not demonstrate clinically relevant differences in changes in LDL and HDL levels over 4 months with FE and TRE compared with non-egg supplemented diet and usual care diet, respectively, providing evidence that adverse short-term lipid and biomarker changes did not occur with FE consumption. Trial RegistrationClinicalTrials.gov Identifier: NCT04673721.

Brexpiprazole treatment for agitation in Alzheimer's dementia: A randomized study.

We evaluated the efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia (AAD) in Japanese patients. This was a phase 2/3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Patients with AAD were randomized to receive brexpiprazole 1 mg/day or 2mg/day, or placebo (3:4:4) for 10weeks. For the primary endpoint (change in Cohen-Mansfield Agitation Inventory [CMAI] total score from baseline to Week 10), both brexpiprazole 1 mg and 2mg groups demonstrated statistically significant improvement versus placebo (2mg: least squares [LS] mean difference -7.2 [95% confidence interval (CI): -10.0 to -4.3], p-value<0.0001, 1mg: LS mean difference -3.7 [95% CI: -6.8 to -0.7], p-value=0.0175). The incidences of treatment-emergent adverse events reported in the brexpiprazole 1mg, 2mg, and placebo groups were 76.8%, 84.6%, and 73.8%, respectively. Brexpiprazole 1mg/day and 2mg/day for 10weeks was efficacious and well tolerated. Brexpiprazole treatment for 10weeks improved agitation in Alzheimer's dementia. The efficacy of brexpiprazole 1mg/day has been confirmed for the first time. The incidence of adverse events was higher compared to the previous studies. Both brexpiprazole 1mg/day and 2mg/day were generally well tolerated.

12542 Results Of The Foresight Trial Support The Efficacy And Safety Of Once-weekly Lonapegsomatropin In Adults With Growth Hormone Deficiency (ghd)

Abstract Disclosure: B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Novartis Pharmaceuticals, Sparrow, Strongbridge Biopharma. Grant Recipient; Self; Strongbridge Biopharma. A. Gilis-Januszewska: Speaker; Self; Ipsen, Novartis Pharmaceuticals, Novo Nordisk, Recordati, Teva Pharmaceutical Industries Ltd.. M. Doknic: None. A.M. Pico: None. M. Fleseriu: Consulting Fee; Self; Ascendis, GlaxoSmithKline, Johnson &amp;Johnson, Karyopharm, Novo Nordisk, Pfizer, Inc., Pharmacosmos. Research Investigator; Self; Ascendis. G. Raverot: None. A.M. Isidori: None. Y. Takahashi: None. J.M. Garcia: None. J.M. Silverstein: None. I. Bancos: None. E. Huang: Employee; Self; Ascendis Pharma, Inc. J. Kang: Employee; Self; Ascendis Pharma, Inc. A.S. Komirenko: Employee; Self; Ascendis Pharma, Inc. L. Domrzalski: Employee; Self; Ascendis Pharma, Inc. A. Shu: Employee; Self; Ascendis Pharma, Inc. K. Yuen: Advisory Board Member; Self; Amryt, Ascendis, Corcept, Crinetics, Novo Nordisk, Recordati, Strongbridge, Xeris. Grant Recipient; Self; Amryt, Ascendis, Corcept, Crinetics. Speaker; Self; Corcept, Novo Nordisk, Recordati. Background: Adult GHD (aGHD) is characterized by metabolic abnormalities due to insufficient growth hormone (GH) production. Lonapegsomatropin was designed to provide sustained release of unmodified somatropin, with the identical amino acid sequence as endogenous GH, and once-weekly injection reduces the burden of daily GH replacement therapy. MethodsForesiGHt was a randomized, parallel-3-arm, placebo(PL)-controlled (double-blind) and active-controlled (open-label) trial designed to establish the efficacy and safety of lonapegsomatropin in aGHD. It evaluated 259 adults with GHD across 21 countries who were GH treatment-naïve or not treated with GH in the prior year, randomized 1:1:1 to receive lonapegsomatropin, once-weekly PL, or daily somatropin (dGH). Fixed dosing was based on age and oral estrogen intake, and designed to be comparable across lonapegsomatropin and dGH arms. Following a 12-week (w) titration period to target maintenance dose, fixed doses were administered for 26w. ResultsBaseline (BL) characteristics were similar between arms. Lonapegsomatropin demonstrated superiority on the primary efficacy endpoint of change from BL in trunk percent fat at Week 38 vs PL (lonapegsomatropin -1.7% vs PL 0.4%, LS mean difference -2.0%, p &amp;lt; 0.0001) and on the key secondary efficacy endpoints of change from BL in total body lean mass (lonapegsomatropin 1.6 kg vs PL -0.1 kg, LS mean difference 1.7 kg, p &amp;lt; 0.0001) and change from BL in trunk fat mass (lonapegsomatropin -0.5 kg vs PL 0.2 kg, LS mean difference -0.7 kg, p = 0.0053). Mean total exposure and maintenance doses were similar for lonapegsomatropin and dGH arms, with larger changes from BL in average IGF-I SDS mean at Week 38 in the lonapegsomatropin arm (1.4) vs dGH arm (0.5). To assess outcomes at comparable weekly IGF-I exposure, a post-hoc analysis was performed in a subset of participants with average IGF-I SDS ≤1.75 SDS at Week 38. Mean IGF-I SDS for these subsets were similar (lonapegsomatropin -0.1, dGH -0.5), and comparable effects in fat and lean tissue compartments were demonstrated (change from BL in trunk percent fat mean -2.4% and -2.6% respectively; change from BL in total body lean mass mean 1.7 kg and 1.4 kg respectively). In the safety population, the incidence of severe AEs was low (lonapegsomatropin, 3.4%; placebo, 1.2%; dGH, 2.3%) and the incidence of treatment-related AEs was similar (lonapegsomatropin 24.7%, dGH 22.1%). Injection site reaction incidence was low and similar for lonapegsomatropin (4.5%), dGH (5.8%) and placebo (4.8%), and A1c levels remained stable in all treatment arms. ConclusionsThe results of the foresiGHt trial indicate that lonapegsomatropin is a safe, efficacious, and tolerable replacement for endogenous GH. Once-weekly dosing may be impactful for adults with GHD who typically manage multiple other medical therapies. Presentation: 6/3/2024

7519 Withdrawal of DCCR (Diazoxide Choline) Extended-Release Tablets Worsens Hyperphagia and Increases Weight and BMI in a 16-week Double-blind, Placebo-controlled, Randomized Withdrawal Period in Patients with Prader Willi Syndrome

Abstract Disclosure: E.F. Gevers: Advisory Board Member; Self; Pfizer, Inc., Soleno. Research Investigator; Self; Soleno Therapeutics, Inc.. Speaker; Self; Pfizer, Inc., Novo Nordisk, Soleno Therapeutics, Inc. J.L. Miller: Research Investigator; Self; Soleno Therapeutics, Inc. N.A. Bridges: Research Investigator; Self; Soleno Therapeutics, Inc. E.I. Felner: Research Investigator; Self; Soleno Therapeutics, Inc. P. Salehi: Research Investigator; Self; Soleno Therapeutics, Inc. D. Stevenson: Research Investigator; Self; Soleno Therapeutics, Inc. J. Yanovski: Research Investigator; Self; Soleno Therapeutics, Inc. L. Bird: Research Investigator; Self; Soleno Therapeutics, Inc. V. Kimonis: Research Investigator; Self; Soleno Therapeutics, Inc. A.H. Shoemaker: Research Investigator; Self; Soleno Therapeutics, Inc. K.S. Obrynba: Research Investigator; Self; Soleno Therapeutics, Inc. M. Lah: Research Investigator; Self; Soleno Therapeutics, Inc. E. Littlejohn: Research Investigator; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. K. Yen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. S. Ballal: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. P. Hirano: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. M. Huang: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. A. Bhatnagar: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc.. Background: Prader-Willi syndrome (PWS) is a rare genetic neurobehavioral-metabolic disease characterized by hyperphagia, endocrinopathies, weight gain, hypotonia, behavioral problems, and an increased risk of mortality and reduced life expectancy. There are currently no approved treatments for hyperphagia in PWS. Diazoxide choline extended-release (DCCR) is a novel, once daily oral therapy being developed for the treatment of PWS. Herein, we present results of the Randomized Withdrawal Period (RWP) of Clinical Study C602, a long-term treatment study of DCCR in people with PWS. Objectives and Methods: This was a 16-week multi-center, double-blind, placebo-controlled RWP that enrolled participants ≥4 years of age who were actively enrolled in the open label period of Clinical Study C602 and had received 2-4 years of DCCR treatment (target dose: ≥3.3 mg/kg; optimal range: 4.2-5.8 mg/kg) at the time of RWP entry. RWP-eligible participants were randomized 1:1 to continue DCCR or withdraw from DCCR and receive Placebo. The primary objective was to evaluate the effect of continued DCCR administration versus Placebo on hyperphagia based on the change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score from Baseline to Week 16. Additional endpoints included: the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) at Week 16; changes in body composition (weight, BMI, and BMI z-scores) at Week 16; and the safety profile of DCCR. Results: DCCR (n=38) and Placebo (n=39) groups were generally balanced for demographic and baseline characteristics. At Week 16, a statistically significant difference in change from baseline in HQ-CT Total Score was observed between DCCR and Placebo groups with HQ-CT Total Scores increasing markedly (indicating worsening hyperphagia) in the Placebo group compared to the DCCR group (LSMean difference [SE] -5.0 [1.57], p=0.002). CGI-S and CGI-I showed trends towards worsening in the Placebo group versus the DCCR group (p=0.079 and 0.092, respectively). The Placebo group also experienced significantly greater increases in weight, BMI, and BMI z-scores (p=0.035, 0.034, and 0.023, respectively) than the DCCR group. DCCR was well-tolerated, with no new or unexpected safety signals, and no serious adverse events or discontinuations due to adverse events in the DCCR group. Conclusions: In this 16-week RWP, the Placebo group experienced significant worsening in hyperphagia and increases in body weight, BMI, and BMI z-scores, along with worsening trends for the CGI-S and CGI-I, compared to the DCCR group. DCCR was well tolerated, with a safety profile that was consistent with prior experience. These data suggest treatment with DCCR may lead to clinical benefits in people with PWS by reducing hyperphagia and improving body composition. Presentation: 6/2/2024

Clinical efficacy and safety of a silver ion-releasing foam dressing on hard-to-heal wounds: a meta-analysis.

Delayed or stalled healing in open wounds can result from persisting chronic inflammation related to infection and/or persistent bacterial colonisation and biofilm. Treatment of hard-to-heal wounds focuses on debridement and exudate management, but also on infection prevention and control. Silver dressings have been evaluated in randomised clinical trials (RCTs); this meta-analysis evaluated the efficacy and safety of a silver ion-releasing foam dressing (Biatain Ag; Coloplast A/S, Denmark) to treat hard-to-heal wounds. Literature databases (PubMed and Cochrane Library) were searched for studies on silver ion-releasing foam dressings in the treatment of hard-to-heal wounds. Individual patient data from four RCTs were obtained and included in the meta-analysis. Findings showed that treatment with the silver ion-releasing foam dressing was associated with a significantly higher relative reduction in wound area after four (least squares-mean difference (LS-MD): -12.55%, 95% confidence interval (CI): (-15.95, -9.16); p<0.01) and six weeks of treatment (LS-MD: -11.94%, 95%CI: (-17.21, -6.68); p<0.01) compared with controls. Significant benefits were also observed for time to disappearance of odour (hazard ratio: 1.61, 95%CI: (1.31, 1.98); p<0.01), relative reduction of exudate (LS-MD: -5.15, 95%CI: (-7.36, -2.94); p<0.01), proportion of patients with periwound erythema (relative risk (RR): 0.81, 95%CI: (0.69; 0.94); p<0.01), and less pain at dressing removal (LS-MD: -0.35, 95%CI: (-0.63, -0.06); p=0.02). No differences regarding safety outcomes were identified. This meta-analysis has demonstrated beneficial outcomes and a good tolerability profile for silver ion-releasing foam dressings in the treatment of moderate-to-highly exuding wounds with delayed healing compared with control dressings.

Aflibercept Biosimilar MYL-1701P vs Reference Aflibercept in Diabetic Macular Edema

Biosimilars may be lower-cost alternatives to originator biologic products, potentially offering expanded access or reduced economic burden, but have not been evaluated with aflibercept in diabetic macular edema (DME). To compare efficacy and safety of MYL-1701P, an aflibercept biosimilar, with reference aflibercept (Eylea [Regeneron]) in DME. This was a double-masked, randomized clinical trial that included participants at 77 centers across the US, Europe, Japan, and India. Included in the analysis were individuals 18 years and older with type 1 or type 2 diabetes with central DME and best-corrected visual acuity (BCVA) letter score of 73 to 38 in the study eye using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Study data were analyzed from October to December 2021. Formulations of MYL-1701P (0.5-mg vial) or reference aflibercept every 4 weeks for 5 consecutive intravitreal injections, followed by every 8 weeks through week 52. The primary outcome was the adjusted difference in least squares mean (SE) change from baseline BCVA letter score at week 8 with an equivalence margin of -3 to +3 letters. Secondary outcomes included change in central subfield thickness (CST), BCVA, number of injections over 52 weeks, incidence of adverse events (AEs), and antidrug antibodies (ADAs). A total of 355 participants (mean [SD] age, 62.2 [9.2] years; 216 male [60.8%]) were randomized to MYL-1701P (179 participants [50.4%]) and aflibercept (176 participants [49.6%]). At week 8, mean (SE) change in BCVA was 6.60 (0.55) letters vs 6.56 (0.55) letters in the MYL-1701P vs aflibercept groups. The adjusted mean difference of 0.04 letters (90% CI, -1.16 to 1.24 letters) met the primary outcome. At week 8, mean (SE) change in CST was -112 (7) μm vs -124 (7) μm in the MYL-1701P vs aflibercept groups (adjusted mean difference, 12 μm; 90% CI, -3 to 26 μm). The incidence of treatment-emergent AEs in the MYL-1701P and aflibercept arms were ocular (30.9% [55 of 178] vs 29.5% [52 of 176]), serious ocular (0.6% [1 of 178] vs 1.1% [2 of 176]), nonocular (65.2% [116 of 178] vs 65.3% [115 of 176]), and serious nonocular (16.9% [30 of 178] vs 11.9% [21 of 176]). The mean (SD) total number of injections was 8.4 (2.1) vs 8.7 (1.8) in the MYL-1701P vs aflibercept groups. The incidence of treatment-induced or treatment-boosted ADAs was 2.8% (5 of 177) vs 5.7% (10 of 176) in the MYL-1701P vs aflibercept arms. MYL-1701P demonstrated clinical equivalence in regard to efficacy, with comparable safety and immunogenicity, to reference aflibercept. These findings support use of MLY-1701P as an alternative to reference aflibercept. ClinicalTrials.gov Identifier: NCT03610646.

Safety and efficacy of a novel 0.5% epinastine topical eyelid cream in allergic conjunctivitis: a phase 3 trial.

The high prevalence of allergic conjunctivitis in Japan necessitates novel, easy-to-use treatment options for prophylactic use. We evaluated the safety and efficacy of a newly-developed 0.5% epinastine topical eyelid cream to prevent the development of allergic conjunctivitis. This was a phase 3, single-centre, double-masked, intra-patient randomised trial in asymptomatic adults (aged 20-65 years) with seasonal allergic conjunctivitis in Japan. The left and right eyes of eligible patients were randomised to receive a topical application of either 0.5% epinastine cream (~ 30mg per dose) to one eye or placebo cream to the other (on the outer skin of the upper and lower eyelids) after a conjunctival antigen challenge (CAC) test. Symptom severity was assessed up to 24h post-treatment. Primary efficacy endpoints were mean ocular itching and conjunctival hyperaemia severity scores in each eye; safety endpoints included adverse events (AEs) and adverse drug reaction (ADRs). In total, 30 patients (60 eyes) were included in the study. The 0.5% epinastine topical eyelid cream reduced mean ocular itching scores (difference in least squares means ± standard error, - 1.12 ± 0.214; p < 0.0001) and mean conjunctival hyperaemia scores (- 0.54 ± 0.197; p = 0.0097) 24h after treatment versus placebo. The 0.5% epinastine topical eyelid cream was well tolerated, with no AEs or ADRs reported. With its novel route of administration, 0.5% epinastine topical eyelid cream may be considered a unique, easy-to-use, once-daily treatment option to prevent the onset of seasonal allergic conjunctivitis.

Insights on prevalence and incidence of anemia and rapid up-titration of oral heart failure treatment from the STRONG-HF study.

Anemia is one of the most frequent comorbidities in patients with heart failure (HF), which potentially can interfere with the effect of guideline-recommended HF medical therapy and can be associated with the use of neurohormonal blockers. The aim of this analysis was to determine the prevalence and changes of anemia status in the STRONG-HF study, its association with clinical endpoints, and possible interaction of the presence of anemia with the efficacy and safety of high-intensity HF treatment. The design and main results of the study have been previously described. Patients were randomized within 2days prior to anticipated hospital discharge after HF worsening in a 1:1 fashion to either high-intensity care (HIC) or usual care (UC). Baseline characteristics, clinical and safety outcomes, and treatment effect of HIC vs. UC on the primary and secondary outcomes were compared in groups based on baseline anemia. In addition, dynamics of hemoglobin during the study follow-up and predictors of incident anemia at 90days were investigated. The proportion of anemia in 1077 STRONG-HF patients at enrollment was 27.2%, while at 90days, it changed to 32.1%. The primary composite outcome occurred in 18.2% of patients without baseline anemia, and 22.5% of patients with baseline anemia (unadjusted HR 1.27; 95% CI 0.90-1.80), a difference that did not reach statistical significance. However, patients with baseline anemia had significantly less improvement of EQ-VAS questionnaire values from baseline to day 90 (adjusted LS-Mean difference -2.34 (-4.37, -0.31), P = 0.02). During the study, anemia developed in 19.4 and 14.6% in HIC and UC groups, respectively. The opposite phenomenon-recovery of anemia-occurred in 27.6 and 28.8% in HIC and UC groups (P = 0.1379). The predictors of incident anemia at 90days were male sex, geographical region other than Europe, ischemic etiology, higher glucose, and elevated uric acid at baseline. The percentages of optimal doses of renin-angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists were not different between anemic and non-anemic patients. High-intensity care strategy did not increase rate of incident anemia at 90days and reduced the rate of primary and secondary endpoints regardless of baseline hemoglobin. Hemoglobin level and status of anemia have a dynamic nature in the acute HF patients in the post-discharge period dependent on multiple factors. High-intensity HF treatment is safe and beneficial regardless of baseline hemoglobin level and presence of anemia. The improvement of quality of life is significantly lower in anemic HF patients implying specific attention to correction of this condition.

579. DUPILUMAB IMPROVES ENDOSCOPIC FEATURES OF EOSINOPHILIC OESOPHAGITIS IN CHILDREN WITH EOSINOPHILIC OESOPHAGITIS: 52-WEEK ANALYSIS OF THE EOE KIDS STUDY

Abstract Introduction Eosinophilic oesophagitis (EoE) is a chronic type 2 inflammatory disease. Dupilumab, a fully human monoclonal antibody that blocks drivers of type 2 inflammation, is approved in the USA for EoE patients aged ≥1 year, weighing ≥15 kg, and in the EU for adult and adolescent EoE patients aged ≥12 years, weighing ≥40 kg. The EoE-Endoscopic Reference Score (EREFS) is a validated tool for assessing oesophageal features of EoE, with subscores for inflammation and remodelling. This study assessed the impact of dupilumab on EREFS in children aged 1–&amp;lt;12 years with active EoE in the phase 3 EoE KIDS trial. Methods In Part A, 102 patients (mean [SD] age: 7.1 [3.05] years) were randomised 2:2:1:1 to receive weight-tiered dupilumab higher-exposure (HE) or lower-exposure, or placebo (two groups) for 16 weeks. In Part B, all patients received dupilumab at their preassigned dupilumab regimen for a further 36 weeks. This analysis focused on the dupilumab HE and placebo groups. EREFS were scored centrally by reviewers blinded to both treatment allocation and time point. Absolute change from baseline in EREFS total score (0−18), and EREFS inflammation (0−10) and remodelling (0−8) subscores were assessed at Weeks 16 and 52. Results A total of 37 and 34 patients received dupilumab HE and placebo, respectively; baseline mean EREFS scores were similar across treatment groups (6.8 vs 7.3) with EREFS inflammation subscores higher than remodelling subscores (6.0 vs 0.9 in the total population). EREFS total score was significantly reduced at Week 16 with dupilumab HE versus placebo (LS mean difference -3.8 [95% CI: -4.9, -2.6], P&amp;lt;0.0001), with improvement sustained through Week 52 in the dupilumab HE group (figure). Similar improvements were observed for EREFS inflammation subscore. Assessment of changes in remodelling was limited by low prevalence of fibrostenotic features in young children. Conclusion Dupilumab HE led to significant improvement in EREFS total score at Week 16 versus placebo, which was sustained through Week 52. Dupilumab HE also improved EREFS inflammation subscore.

Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy.

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). A primary end-point event occurred in 163 patients in the vutrisiran group and in 202 in the placebo group. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

High-Adherence Dichoptic Treatment Versus Patching in Anisometropic and Small Angle Strabismus Amblyopia: A Randomized Controlled Trial

PurposeTo compare the effectiveness and safety of a novel binocular eye-tracking-based-home-treatment (CureSight) to patching for the treatment of amblyopia. DesignProspective, masked, randomized controlled noninferiority trial. SettingMulticenter, multinational, home treatment. ParticipantsOne hundred forty-nine children 4 to < 9 years with anisometropic, small-angle strabismic, or mixed-mechanism amblyopia were randomized to either binocular treatment (n=75) or patching (n=74). InterventionsThe binocular treatment group used the CureSight system for 90 min/day, 5 days/week for 16 weeks (120 hours). The patching group received 2-hour patching 7 days/week (224 hours). Main outcome measuresThe primary outcome was the mean improvement from baseline in amblyopic eye visual acuity (VA) to week 16 in both study groups (non-inferiority of ≤0.10 logarithm of the minimum angle of resolution [logMAR]). Other outcomes included changes in stereoacuity and binocular VA from baseline to week 16. ResultsThe mean improvement from baseline at week 16 in the binocular treatment group was noninferior to patching group improvement in the modified intent-to-treat (mITT) dataset (LS mean difference between groups in improvement from baseline: 0.034 logMAR (95% CI -0.009 to 0.076)). In the per-protocol (PP) dataset, the mean improvement from baseline at week 16 in the binocular treatment group was superior to patching group improvement (LS mean difference between groups in improvement from baseline: 0.05 logMAR ([95% CI; 0.007 to 0.097]). At week 16, both groups showed significant median improvement in stereoacuity, with no significant between-group difference in the magnitude of improvement in both the mITT and the PP datasets. Binocular VA was also improved in both groups (p<0.0001). Median adherence in the mITT binocular treatment group (94.0%) was also significantly higher than in the patching group (83.9%; p=0.0038). ConclusionsBinocular, eye-tracking-based amblyopia home treatment is at least as effective as patching.