Least-squares Mean Difference Research Articles

Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation.

Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear. In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52. A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchiodilator FEV1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab. In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.).

PSIII-13 Putative metabolites for sow lifetime opportunity and production traits

Abstract Identifying females with favorable lifetime born alive (opportunity) and weaned (wn; production) traits requires extended observation. Estimate of lifetime (4 parities) difference in the economic margin over genetic cost between a high producing female (48 pigs weaned; wn) and a low producing female (31 wn) is approximately $1,000. Determining metabolic compounds present from females with favorable or unfavorable longevity traits may provide profiles that could be assessed in younger females prior to entry within the breeding system to indicate their potential productivity. Females within the USMARC breeding system were retained through four parities then harvested between 12 to 15 d following their post-weaning estrus. Liver, skeletal muscle, and subcutaneous adipose tissues were collected and stored at -80° C for later analyses. Females were categorically identified by the level of opportunity (born alive; ba) and production (wn) over their lifetime. Females with consistent opportunity and production traits at each parity were categorized as high (H; 61 ba), medium (M; 50 ba), or low (L; 39 ba) opportunity and H (50 wn), M (42 wn), or L (34 wn) production resulting in six categories (HH, HL, MH, ML, LH, LL). Tissue extracts were subjected to positive mode UPLC-MS and numerous features were detected. Using Progenesis Q software features were annotated and those with a fold-change ≥ 2.0 and P &amp;lt; 0.05 by category were then tested using a mixed model in SAS to determine LS Mean differences of raw abundances among the six categories. Of those compounds tested in SAS, a significance threshold was set at P &amp;lt; 0.01 as a false discovery adjustment. Within liver 877 compounds were analyzed with 152 yielding a significant (P &amp;lt; 0.01) categorical effect. Of those, 43 compounds predominantly identified either HH or LL from other categories. Within skeletal muscle 359 compounds were subjected to mixed models, 221 compounds had significance for a category effect, and 105 compounds were predominantly different for HH or LL from all other categories. Within adipose tissue, 406 compounds were submitted to mixed model testing, 186 compounds had a categorical effect with 44 compounds predominantly different for HH or LL categories. Annotation of these compounds suggest differences in metabolites associated with, but not limited to, bacteria by-products (pradmicin, adifolin, lactobacillic acid), alkyloids, sapogenins, amino acids (lysine, tyrosine), minerals (calcium, copper), lipids (sphingomyelin), and fatty acids (mono-, di-, tri-acylglycerol). Future confirmation and evaluation of these metabolites in young pre-breeding females will need to be done. Establishing a metabolic profile panel that could discern young pre-breeding gilts with a likelihood of becoming a LL female will improve economic productivity and animal welfare concerns.

Efficacy and safety of dupilumab with concomitant topical corticosteroids in Japanese pediatric patients with moderate-to-severe atopic dermatitis: A randomized, double-blind, placebo-controlled phase 3 study

BackgroundWe investigated the efficacy and safety of dupilumab in Japanese patients aged ≥6 months to <18 years old with moderate-to-severe atopic dermatitis not adequately controlled with existing therapies. MethodsIn this randomized, double-blind, phase 3 study, patients received dupilumab (n = 30) or placebo (n = 32) with concomitant topical corticosteroids for 16 weeks, then all patients received dupilumab from 16 to 52 weeks. The primary endpoint was the proportion of patients with ≥75% improvement in Eczema Area and Severity Index (EASI) score from baseline (EASI-75) to Week 16. Key secondary endpoints included changes in EASI score, proportion of patients with investigator global assessment (IGA) scores of 0/1, and changes in worst daily itch numerical rating scale (NRS) scores (evaluated in patients aged ≥6 to <12 years [n = 35]). ResultsAt Week 16, more patients achieved EASI-75 with dupilumab than placebo (43.3% vs 18.8%; P = 0.0304), and the least squares mean (LSM) difference in percent change in EASI scores at Week 16 of dupilumab vs placebo was –39.4% (P = 0.0003). However, no significant difference in the proportion of patients achieving IGA scores of 0/1 at Week 16 with dupilumab versus placebo were seen (10.0% vs 9.4%; P = 0.8476). The percent change in worst daily itch NRS scores at Week 16 was higher with dupilumab (LSM difference: –33.3%; nominal P = 0.0117). Dupilumab was well tolerated; no new safety signals were identified. ConclusionsDupilumab showed consistent efficacy and was well tolerated in Japanese patients aged ≥6 months to <18 years with moderate-to-severe atopic dermatitis previously insufficiently controlled with existing therapies.

P127 Comparison of the Efficacy, Safety and Immunogenicity of a Proposed Biosimilar MSB11456 with Tocilizumab Reference Product in Moderate-to-Severe Rheumatoid Arthritis: Results of a Randomized Double-Blind Study

Abstract Background/Aims Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody indicated for treating rheumatoid arthritis (RA) and other inflammatory diseases. MSB11456 is a proposed biosimilar to US-licensed tocilizumab and EU-approved tocilizumab. It has already shown equivalent pharmacokinetic, pharmacodynamic safety, tolerability, and immunogenicity profiles to these products given subcutaneously (SC) as a single dose in healthy volunteers. This Phase III, multi-centre, randomised, double-blind, multiple fixed-dose, parallel group study compared efficacy, safety and immunogenicity of MSB11456 and EU-approved tocilizumab administered SC in moderate-to-severe RA patients. Methods Patients were randomised to 162mg MSB11456 or EU-approved tocilizumab for 24 weeks (W). At W24, patients receiving EU-approved tocilizumab were re-randomised to continue treatment or switch to MSB11456 for up to W52. Safety evaluations were conducted up to W63. A change from baseline in Disease Activity Score-28 Joint Count-ESR (DAS28-ESR) at W24 was analysed, as the primary efficacy endpoint, using analysis of covariance to determine the least squares mean (LSM) difference between MSB11456 and EU-approved tocilizumab; equivalence was considered if the 90% confidence interval (CI) was entirely within the FDA equivalence interval -0.6 to 0.5. Secondary endpoints were 20% improvement in ACR core set measures at W24 and DAS28-ESR at W12. Additional endpoints included ACR50/70, change in DAS28-CRP, Simplified and Clinical Disease Activity Indexes, evaluation of immunogenicity up to W55 and safety up to W63. Results Clinically relevant LSM decreases from baseline in DAS28-ESR were observed from W2 up to W24 with both treatments. The 90% CI for LSM difference in the change from baseline in DAS28-ESR between treatments was fully included within the predefined equivalence interval, which demonstrated therapeutic equivalence of MSB11456 and EU-approved tocilizumab (Table 1). Other efficacy endpoint analyses supported this conclusion. No discernible patterns in the nature or frequency of treatment-emergent adverse events (TEAEs) were identified to suggest a difference between drugs. Anti-drug antibodies incidence was similar among treatment arms. Switching from EU-approved tocilizumab to MSB11456 had no clinically relevant impact on efficacy or safety. Conclusion Equivalent efficacy, immunogenicity and safety profiles of MSB11456 and EU-approved tocilizumab were demonstrated in moderate-to-severe RA patients, confirming equivalence between MSB11456 and the EU-approved tocilizumab. Disclosure A. Zubrzycka-Sienkiewicz: None. M. Misterska-Skora: None. M. Socik-Pojawa: None. K. Klama: None. M. Ullman: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. C. Petit-Frere: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. A. Illes: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. P. Baker: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Monnet: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Morais: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Brzezicki: None.

Baseline Characteristics and mNAPSI Change from Baseline Scores Through Month12 for Patients with Moderate-to-Severe Plaque Psoriasis and Concomitant Nail Psoriasis Treated with Biologics from PSoHO.

Nail psoriasis is highly prevalent among patients with psoriasis yet remains one of the most challenging areas to treat. To better understand the treatment landscape for psoriatic nail disease, more studies are needed that compare the effectiveness of different biologics for patients with nail psoriasis. This study contributes to this objective by directly comparing the effectiveness of approved biologics in improving nail psoriasis for patients up to month12 in a real-world setting. Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. This study assessed the change in modified Nail Psoriasis Severity Index (mNAPSI) score from baseline to months3, 6 and 12 for 763 patients and compared the effectiveness of anti-interleukin (IL)-17A biologics versus other approved biologics, as well as ixekizumab versus secukinumab, guselkumab, risankizumab and adalimumab. Comparative adjusted analyses used frequentist model averaging (FMA). Least square mean difference (LSMD) in mNAPSI scores are presented as observed. Irrespective of the severity of nail psoriasis at baseline, the anti-IL-17A cohort had greater mean mNAPSI reductions from baseline compared to the other biologics cohort through month12, reaching significance at months3 and 6 in the adjusted analysis. For patients with moderate-to-severe nail psoriasis, ixekizumab showed numerically higher mean reductions in mNAPSI scores compared to all other studied biologics, reaching significance versus guselkumab at all timepoints and risankizumab at month6. This real-world study showed that patients with moderate-to-severe psoriasis and any severity of concomitant nail involvement had significantly faster and more substantial improvements in nail psoriasis up to month6 in the anti-IL-17A cohort compared to the other biologics cohort. Of the individual biologics studied, ixekizumab showed the highest numerical improvements in nail psoriasis at month12. EUPAS24207.

The impact of severe obesity on image quality and ventricular function assessment in echocardiography and cardiac MRI.

This study sought to evaluate the impact of severe obesity on image quality and ventricular functionassessment in cardiovascular magnetic resonance (MRI) and trans-thoracic echocardiography (TTE). We studied 100 consecutive patients who underwent clinically indicated cardiac MRI and TTE studies within 12months between July 2017 and December 2020; 50 (28 females and 22 males; 54.5 ± 18.7years) with normal body mass index (BMI) (18.5-25kg/m2) and 50 (21 females and 29 males; 47.2 ± 13.3years) with severe obesity (BMI ≥ 40kg/m2). MRI and TTE image quality scores were compared within and across cohorts using a linear mixed model. Categorical left (LVF) and right (RVF) ventricular function were compared using Cohens Kappa statistic. Mean BMI for normal weight and obese cohorts were 22.2 ± 1.7kg/m2 and 50.3 ± 5.9kg/m2, respectively. Out of a possible 93 points, mean MRI image quality score was 91.5 ± 2.5 for patients with normal BMI, and 88.4 ± 5.5 for patients with severe obesity; least square (LS) mean difference 3.1, p = 0.460. TTE scores were 64.2 ± 13.6 for patients with normal BMI and 46.0 ± 12.9 for patients with severe obesity, LS mean difference 18.2, p < 0.001. Ventricular function agreement between modalities was worse in the obese cohort for both LVF (72% vs 80% agreement; kappa 0.53 vs 0.70, obese vs. normal BMI), and RVF (58% vs 72% agreement, kappa 0.18 vs 0.34, obese vs. normal BMI). Severe obesity had limited impact on cardiac MRI image quality, while obesity significantly degraded TTE image quality and ventricular function agreement with MRI.

Cognitive–behavioral therapy for patients with somatoform disorders: A pilot preliminary randomized controlled trial

Background and objective: Cognitive–behavioral therapy (CBT) for somatoform disorders (SFDs) is understudied in China. Western findings may not be applicable to Chinese culture. This preliminary study evaluated the efficacy of CBT for patients in China, relative to treatment-as-usual (TAU). Methods: Seventy patients with SFDs randomly received either combined CBT and TAU (CBT + TAU), or TAU alone between January 2018 to May 2019. The CBT + TAU group received 12 weekly individual 50-minute CBT sessions. Participants were blindly assessed at 4 timepoints (baseline, week 6, end of treatment: week 12; 12 weeks post-treatment: week 24) using the following outcome measures: SQSS (Self-screening Questionnaire for Somatic Symptoms); PHQ-15 (Patient-Health-Questionnaire-15) and the WI (Whiteley Index); GAD-7 (General Anxiety Disorder-7); HAMD-17 (Hamilton Depression Rating Scale-17); Family Burden Interview Schedule (FBIS); Sheehan Disability Scale (SDS); and the Short Form of Quality-of-Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF). The primary endpoint was the difference between the SQSS total score at week 24 and the baseline. A mixed model for repeated measures was used to analyze inter- and intra-group changes from the baseline. Results: At week 24, The least-squares mean (LSM) change of the total score on the SQSS was −18.87 points and −9.69 points, respectively in the CBT + TAU group and in the TAU group (LSM difference, −9.18 points; 95% confidence interval, −15.72 to −2.64; P = 0.0068). At week 24, the LSM changes from baseline in the WI, HAMD, PHQ15, FBIS and SDS total scores were significantly different between the two groups, however, there was no significant difference in the Q-LES-Q-SF. The SQSS of group effect sizes were 0.63 at 24 weeks. The dropout rates of the CBT + TAU and TAU groups were comparable (22.9% and 19.3%). Conclusions: These preliminary findings suggest that CBT may be helpful for improving the symptoms of patients with SFDs in China.

Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa: A randomized, double-blind, placebo-controlled clinical trial.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies. To explore the effects of spesolimab treatment in patients with HS. This randomized, double-blind, placebo-controlled, proof-of-clinical-concept study was conducted at 25 centers across 12 countries from May 3, 2021, to April 21, 2022. Patients had moderate-to-severe HS for ≥1 year before enrollment. Patients were randomized (2:1) to receive a loading dose of 3600 mg intravenous spesolimab (1200 mg at Weeks 0, 1, and 2) or matching placebo, followed by maintenance with either 1200 mg subcutaneous spesolimab every 2 weeks from Week 4-10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at Week 12. Secondary endpoints were the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of zero, absolute change from baseline in revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥1 flare (all at Week 12), and patient-reported outcomes (PROs). In this completed trial, randomized patients (N=52) received spesolimab (n=35) or placebo (n=17). The difference (95% confidence interval) versus placebo in least squares mean are reported. At Week 12, the percentage change in total AN count was similar between treatment arms: -4.1% (-31.7, 23.4). There was greater numerical improvement in the spesolimab arm, as measured by IHS4: -13.9 (-25.6, -2.3); percentage change from baseline in dT count: -96.6% (-154.5, -38.8); and the proportion of patients achieving a dT count of zero: 18.3% (-7.9, 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 versus placebo. Spesolimab demonstrated a favorable safety profile, similar to that observed in trials in other diseases. This exploratory proof-of-clinical-concept study supports the development of spesolimab as a new therapeutic option in HS. ClinicalTrials.gov identifier: NCT04762277.

Effect of loperamide on heart rhythm: Randomized, double-blind, controlled study in healthy adults

BackgroundExcessively high doses of loperamide (of up to 792 mg/day) have recently been associated with reports of cardiac events. However, no data currently demonstrate a direct effect of high doses of loperamide on the occurrence of cardiovascular abnormalities. ObjectivesThis study aimed to assess the effects of loperamide on QT/corrected QT (QTc) intervals, electrocardiogram (ECG) morphology, and overall safety and tolerability at therapeutic and supratherapeutic exposures in healthy adults. MethodsThis randomized, double-blind, 4-way-crossover study enrolled 65 healthy adults to receive loperamide 8 mg (therapeutic dose), loperamide 48 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), and placebo. Least square (LS) mean difference in change from baseline in Fridericia-corrected QT (ΔQTcF) intervals between loperamide (8 mg and 48 mg) and placebo with the 2-sided 90% CI was calculated for each time point. A noninferiority criterion of mean difference in ΔQTcF of 10 ms evaluated whether loperamide was noninferior to placebo. Treatment safety was assessed throughout the study. ResultsMost participants were female (66.2%) and white (95.4%). The age was 36.4 years (SD 9.77). The highest upper limit of the 2-sided 90% CI for LS mean difference in ΔQTcF between loperamide and placebo was 3.39 ms for the therapeutic dose and 9.28 ms for the supratherapeutic dose of loperamide, which were below the 10 ms threshold, thereby demonstrating noninferiority of loperamide to placebo. There were no statistically significant morphologic ECG changes after loperamide administration. There were no deaths, serious adverse events, or severe treatment-emergent adverse events. ConclusionSingle-dose loperamide at therapeutic (8 mg) and supratherapeutic (48 mg) doses do not show evidence of QTc prolongation of clinical concern in healthy participants. No new safety findings were identified.

Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy

BackgroundIn nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. ObjectivesThis study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. MethodsPatients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. ResultsA total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of −2.1 (95% CI: −3.6 to −0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: −2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). ConclusionsIn symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.

Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial

A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. Regeneron Pharmaceuticals and Bayer.

Therapeutic Potential of Buprenorphine in Depression: A Meta-Analysis of Current Evidence.

Emerging research indicates buprenorphine, used in management of opioid use disorder, has attracted interest for its potential in treating a variety of psychiatric conditions. This meta-analysis aimed to determine the efficacy of buprenorphine in treating symptoms of depression. Using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a search was conducted of several databases until April 25, 2022, for English language articles related to buprenorphine and its use in treating various mental health conditions. Standardized mean differences (SMDs) and its 95% confidence intervals (CIs) were reported for the Hamilton Rating Scale for Depression (HAM-D) and the Montgomery-Asberg Depression Rating Scale (MADRS) scores. Statistical analyses were performed using Cochrane RevMan 5. Of the 1,347 identified studies, six clinical trials were included. MADRS-10 least square mean difference (LSMD) inter-group assessment favored buprenorphine over placebo, but it lacked statistical significance. Similarly, MADRS scores as well as HAM-D inter-group assessment were in favor of buprenorphine, however, were not statistically significant. These findings suggest a potential therapeutic role for buprenorphine in treating depression, albeit with caution due to the observed lack of statistical significance and the potential for confounding factors. Preliminary evidence suggests potential efficacy of buprenorphine at lower doses in improving improving outcomes specifically related to depression. However, due to limitations in statistical significance and possible confounding factors, entail cautious interpretation. Further rigorous research is needed to investigate the long-term effects, optimal dosing, and determine the role of adjuvant drug therapy.

Safety and Efficacy of Switching SAR341402 Insulin Aspart and Originator Insulin Aspart vs Continuous Use of Originator Insulin Aspart in Adults With Type 1 Diabetes: The GEMELLI X Trial.

SAR341402 insulin aspart (SAR-Asp) is a rapid-acting insulin analog developed as an interchangeable biosimilar to the marketed insulin aspart reference product (NovoLog; NN-Asp). GEMELLI X was a randomized controlled trial to assess outcomes with a biosimilar in line with the US Food and Drug Administration requirements for designation as an interchangeable biosimilar. This report assessed whether multiple switches between SAR-Asp and NN-Asp lead to equivalent safety and efficacy compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D) treated with multiple daily injections, using once-daily insulin glargine U100 (Lantus) as the basal insulin. This open-label randomized (1:1), parallel-group, phase 3 trial compared four × four weeks of alternating use of individually titrated SAR-Asp and NN-Asp (NN-Asp for first four weeks, SAR-Asp in last four weeks; switching group) vs 16 weeks of continuous use of NN-Asp (nonswitching group). End points included pharmacokinetics, immunogenicity, adverse events, hypoglycemia, insulin dose, and change in efficacy parameters. Of the 210 patients randomized, 200 (95.5%) completed the trial. Patients assigned to switching group (n = 104) and nonswitching group (n = 106) showed similar safety and tolerability, including anti-insulin aspart antibody responses, adverse events, and hypoglycemia. At week 16, there was no relevant difference between switching vs nonswitching groups in the change from baseline in glycated hemoglobin (least square [LS] mean difference = 0.05% [95% confidence interval [CI] = -0.13, 0.22]; 0.50 mmol/mol [-1.40, 2.39]), fasting plasma glucose (LS mean difference = 0.23 mmol/L [95% CI = -1.08, 1.53]; 4.12 mg/dL [-19.38, 27.62]), and changes in insulin dosages. Alternating doses of SAR-Asp and NN-Asp compared with continuous use of NN-Asp showed similar safety, immunogenicity, and clinical efficacy in adults with T1D. This study supports interchangeability between SAR-Asp and NN-Asp in T1D management.

Varenicline solution nasal spray for dry eye disease in Chinese patients: a randomized phase 3 trial

Dry eye disease has a high prevalence and exerts a significant negative effect on quality of life. In China, there are currently no available nasal sprays to promote natural tear production in patients with dry eye disease. We therefore evaluated the efficacy and safety of OC-01 (varenicline solution) nasal spray versus vehicle in Chinese patients with dry eye disease. This was a randomized, multicenter, double-masked, vehicle-controlled, phase 3 clinical trial conducted at ophthalmology departments in 20 hospitals across China (NCT05378945). Eligible patients had a diagnosis of dry eye disease based on patient symptoms, Eye Dryness Score (EDS), Schirmer's Test (with topical anesthesia) Score (STS), and corneal fluorescein staining (CFS) score. Participants were randomly assigned 1:1 using an Interactive Web Response System (IWRS) to receive OC-01 0.6mg/mL twice daily (BID) or vehicle nasal spray. Participants, investigators, and sponsor were all masked to treatment assignment. The primary endpoint was the percentage of subjects in the intention-to-treat population achieving ≥10mm improvement in STS from baseline at week4. In total, 340 patients were randomized from 21 July 2022 to 04 April 2023, 78.8% were female. Patients in the OC-01 group (n=176) had significantly higher achievement of ≥10mm improvement in STS (35.8% [n=63] versus 17.7% [n=29], stratified odds ratio: 2.67, 95% CI: 1.570-4.533, p=0.0002) and a significantly greater increase from baseline STS (least-squares mean difference [SE]: 3.87 [0.794], p<0.0001) at week 4 versus the vehicle group (n=164). In addition, OC-01 led to a numerically greater reduction in mean EDS from baseline at week 4 compared to the vehicle group (LS mean [SE] difference:-1.3 [2.20]; 95% CI:-5.64 to 2.99, p=0.5467). The most common adverse event was mild, transient sneezing (78% of OC-01 administrations). No serious adverse events related to nasal administration occurred. OC-01 (varenicline solution) nasal spray BID has clinically meaningful efficacy for reducing the signs (as measured by STS) and may improve the symptoms (as measured by EDS) of dry eye disease, with an excellent safety and tolerability profile, in the Chinese population. Jixing Pharmaceutical Co. Ltd.

Efficacy of ravulizumab in patients with generalized myasthenia gravis by time from diagnosis: A post hoc subgroup analysis of the CHAMPION MG study.

The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis. Changes from baseline to week 26 in MG-ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least-squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures. In ravulizumab-treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2-years subgroup versus the >2-years subgroup for MG-ADL (-4.3 [0.70] vs. -2.9 [0.37]; p = .0511) or QMG (-4.3 [0.94] vs. -2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG-ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2-years and >2-years subgroups was not statistically significant. No clinically meaningful between-subgroup differences in treatment-emergent adverse events were observed in ravulizumab-treated patients. Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation.

A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis

BackgroundEffective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator–activated receptor delta agonist, has potential benefits.MethodsIn this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).ResultsOf the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, −3.2 vs. −1.7; least-squares mean difference, −1.5; 95% CI, −2.5 to −0.5, P=0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.ConclusionsIn this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.)

Benralizumab does not elicit therapeutic effect in patients with chronic spontaneous urticaria: results from the phase 2b multinational, randomised, double-blind, placebo-controlled ARROYO trial.

Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils. To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment. The 24-week, randomised, double-blind, placebo-controlled, phase 2b portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomised to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in ISS7 at Week 12. The key secondary endpoint was change from baseline in UAS7 at Week 12. Additional secondary endpoints included other metrics to assess CSU at Week 24; blood eosinophil levels; and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups. Of 155 patients, 59 were randomised to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at Week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% confidence interval -4.09 to 0.50) nor in change from baseline in UAS7 score at Week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.4016; benralizumab 60 mg vs. placebo, P = 0.0819). Depletion of blood eosinophil levels was observed at Week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab. Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo.

RNA Interference With Zilebesiran for Mild to Moderate Hypertension

Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. ClinicalTrials.gov Identifier: NCT04936035.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial

There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300mg QW (n=31), stapokibart 600-300mg Q2W (n=30), or placebo QW (n=31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were-1.0 (-2.3, 0.2) in stapokibart Q2W group (p=0.065) and-0.2 (-1.5, 1.0) in stapokibart QW group (p=0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference-12.9%, 95% CI-25.3%,-0.4%, p=0.043), as well as AM iTNSS over 2 weeks (LS mean difference-17.4%, 95% CI-31.0%,-3.8%, p=0.013) and 4 weeks (LS mean difference-15.4%, 95% CI-29.0%,-1.9%, p=0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference-0.4, 95% CI-0.7,-0.1, p=0.014) and 4-week (LS mean difference-0.4, 95% CI-0.7,-0.04, p=0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

Trial of N-Acetyl-l-Leucine in Niemann–Pick Disease Type C

BackgroundNiemann–Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann–Pick disease type C.MethodsIn this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann–Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.ResultsA total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was −1.97±2.43 points after 12 weeks of receiving NALL and −0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.ConclusionsAmong patients with Niemann–Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann–Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.)