Least-squares Mean Difference Research Articles

Acupuncture as a modality of treatment for chemotherapy-induced peripheral neuropathy in breast cancer: A phase 3 randomized controlled trial (ABC-CIPN).

12126 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect in early breast cancer (EBC) and is an unmet need. The study aimed to evaluate the efficacy & safety, of acupuncture on CIPN. Methods: We conducted a prospective, single-center, open-label, phase 3 randomized controlled trial at a tertiary care Indian center. EBC, ≥18 years with ≥grade (gr) 1 CIPN after paclitaxel chemotherapy were block randomized (1:1), & stratified by age (≥/<60 years), to Test (Acupuncture with usual care including pregabalin 75 mg & duloxetine 30 mg, both twice a day per orally, for 4 weeks) & control arm (Usual care alone). Acupuncture was delivered for 12 sessions in gr 1 & 18 sessions in ≥2 CIPN. The primary endpoint was to assess the efficacy of acupuncture in improving QOL as assessed by the sensory score (SS) of QLQ-CIPN20, Pain symptom score (PSS) of QLQ-C30, and total pain score (TPS) by Pain detect scale, and overall QoL by QLQ-C30 at 8 weeks in comparison to baseline (CTRI/2021/01/030480). Results: The median (IQR) age was 50 (43-57) years. Women in test arm in comparison to the control had a significantly higher improvement (decrease) of 26.23 (95% CI 18.52-33.93) versus (Vs) 6.32 (95% CI -1.23 to 13.87) points respectively in CIPN SS at week 8 compared to baseline(least-squares mean difference (LSMD), 19.90 points (95%CI, 11.80-28, P<0.0001). Similarly, patients in test arm had a higher improvement (decrease) of 7.31 (95% CI 5.47-9.13) points Vs 1.12 (95% CI -0.67-2.91) points (LSMD, 6.20 points; 95% CI, 4.30- 8.10; P<0.0001) in TPS of pain detect scale and improvement (decrease) of about 11.56 (95% CI 4.22-18.91) points Vs 3.27 (95% CI -3.93 to 10.47, P=0.0151, in PSS of EORTC QOL-C-30 scale. Additionally, higher improvement (enhanced) in overall QOL, in the test Vs control arm, -7.143(95% CI -13.95 to -0.331) Vs -0.654 (95% CI -7.33 to 6.023); P=0.0020, was noted at week 8. Using the mixed-model approach over the 6 months (secondary end points), average EORTC QLQ-CIPN20 SS was 29.8 (SE, 2.34) in test Vs 38.2 (SE, 2.3) in control arm [difference -8.0 points (95% CI, -14.9 to -1.9; P = 0.0020)]. Average QoL score was 9.71(SE, 0.729) in test Vs 12.21 (SE, 0.716) in control arm [difference 14.3 points (95% CI, 8.2 to 20.5; P = 0.0007)] & average TPS (pain detect) was 18.0 (SE, 2.72) Vs 18.3 (SE, 2.67) [difference -2.5 points (95% CI, -4.5 to -0.5; P=0.0001)] & PSS ( QLQ-C30 scale) was 29.4 (SE, 2.45) Vs 37.2 (SE, 2.41) [ difference -7.8 points (95% CI, -14.6 to -0.9; P=0.0001)] in test Vs control arm respectively. Conclusions: Early breast cancer women with CIPN after (neo) adjuvant taxane therapy experienced a significant and clinically meaningful improvement in taxane induced CIPN related quality of life as a result of an 8 week acupuncture protocol. The results are potentially practice changing and merits consideration as a new standard of care globally in this unmet need. Clinical trial information: CTRI/2021/01/030480.

Patient-reported outcomes (PROs) from a randomized, phase 3 trial of enfortumab vedotin plus pembrolizumab (EV+P) versus platinum-based chemotherapy (PBC) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC).

4502 Background: EV+P nearly doubled median progression-free survival and overall survival vs PBC in patients (pts) with previously untreated la/mUC in the phase 3 EV-302 trial. PROs are reported here. Methods: In EV-302 (NCT04223856) pts were randomized 1:1 to EV+P or PBC (gemcitabine with cisplatin or carboplatin). PRO assessments included the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), and the Brief Pain Inventory Short Form (BPI-SF) completed at baseline, weekly for 12 weeks (wks), then every 3 wks through survival follow-up, inclusive of the time post-progression. Time to pain progression (TTPP) and mean change from baseline in worst pain at wk 26 using the BPI-SF were prespecified analyses statistically tested using a gatekeeping strategy. Mean change from baseline through wk 26 and time to confirmed deterioration (TTCD) of EORTC-QLQ-C30 and BPI-SF domains were prespecified descriptive analyses. TTPP and TTCD were assessed using Kaplan-Meier methods. Results: Of 886 pts randomized, 731 (376 received EV+P; 355 PBC) completed baseline PRO questionnaires. Compliance rates differed between arms and remained >70% through wk 29 for EV+P and through only wk 17 for PBC. Median TTPP was 14.2 months (mos) with EV+P and 10.0 mos with PBC (hazard ratio [HR]=0.92; 95% CI=0.72, 1.17; 2-sided p-value=0.48). The least squares (LS) mean reduction in worst pain at wk 26 was numerically greater with EV+P vs PBC (-0.61 vs -0.03, LS mean difference [95% CI]: -0.58 [-1.05, -0.11] [nominal 2-sided p-value=0.015]). Pts with moderate to severe pain at baseline who were treated with EV+P (n=128, 34%) had a meaningful (>2 pt) improvement from baseline in BPI worst pain from wk 3 through 26. In EORTC QLQ-C30 Global Health Status/Quality of Life [GHS/QoL], EV+P demonstrated a transient worsening at wk 3 (-6.3) that returned to baseline from wks 4 through 26, while patients treated with PBC demonstrated deterioration from wk 1 through wk 17 (range -1.2 to -7.1) when scores returned to baseline. TTCD for EORTC QLQ-C30 GHS/QoL was 5.9 mos with EV+P vs 3.2 mos with PBC (HR = 0.98 [95% CI]: 0.79 – 1.2). Conclusions: Pts treated with EV+P have improved survival compared with PBC without detriment to quality of life and functioning, further supporting the value of EV+P for pts with la/mUC. Compliance, especially after progression, was lower than expected (particularly in the PBC arm) and may have impacted the results. Clinical trial information: NCT04223856 .

Efficacy of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: A Pooled Analysis of Data from Two Phase 3 Randomized Clinical Trials.

New acute pain medications are needed that provide effective analgesia while minimizing side effects and opioid exposure. Clinical trials of co-crystal of tramadol-celecoxib (CTC) have demonstrated an improved benefit/risk profile versus tramadol or celecoxib alone. We pooled data from two phase 3 clinical trials to evaluate the efficacy of CTC 200mg twice daily (BID) in acute moderate-to-severe pain. Efficacy data were pooled from STARDOM1 [acute pain following oral surgery (NCT02982161)] and ESTEVE-SUSA-301 [acute pain following bunionectomy (NCT03108482)]. The primary efficacy outcome was sum of pain intensity difference from 0 to 48 h (SPID0-48). A total of 344 patients received CTC 200mg BID, 342 received tramadol 50 or 100mg four times a day, 181 received celecoxib 100mg BID, and 172 received placebo. The least-squares mean difference in SPID0-48 was -21.8 (p = 0.002) for CTC versus tramadol and -72.8 (p < 0.001) for CTC versus placebo. A similar pattern of SPID0-48 was observed with CTC versus comparator whether patients had moderate or severe pain at baseline. Reduction in pain intensity was faster and reached mild intensity earlier with CTC versus comparators. Patients were significantly (p ≤ 0.005) less likely to receive rescue medication within 4 or 48 h with CTC compared with tramadol or placebo. This pooled analysis reinforces the efficacy profile of CTC versus tramadol and, given that CTC permits lower daily tramadol dosing and thereby reduces unnecessary opioid use, this highlights its improved benefit/risk profile and its potential for the management of moderate-to-severe pain.

Randomized Trial of a Vascular Care Team vs Education for Patients With Peripheral Artery Disease

BackgroundUnderutilization of therapies to reduce ischemic risk in peripheral artery disease (PAD) persists. ObjectivesThe purpose was to conduct an implementation trial of lipid management in vascular disease. MethodsThe OPTIMIZE PAD-1 (Implementation of Vascular Care Team to Improve Medical Management of PAD Patients) trial randomized patients with peripheral artery disease with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL to management via a vascular care team including a clinical pharmacist and an algorithm of intensive lipid management to achieve goal LDL-C in 1 step vs usual care plus provider education. Medications were obtained using commercial insurance. The primary endpoint was percent change in LDL-C at 12 months. ResultsOf 166 enrolled patients, 74.2% did not have an LDL-C level at goal. Among 114 randomized patients (mean age 66 years, 36.0% women, and 15.8% Black), 50.9% received high-intensity statin, and 7.9% received ezetimibe at baseline. The mean 12-month LDL-C change was −49.1% (95% CI: −58.7% to −39.5%) with vascular care team management and −5.4% (95% CI: −15.3% to 4.6%) with usual care; the between-group least-squares mean difference was −43.7% (95% CI: −57.6% to −29.9%; P < 0.0001). Mean LDL-C was reduced in vascular care team patients from 100.6 mg/dL at baseline to 54.8 and 50.1 mg/dL by week 4 and month 12, respectively. At 12 months, vascular care team patients were >3 times as likely to achieve LDL-C <70 mg/dL and 8 times as likely to achieve LDL-C <55 mg/dL (P < 0.0001) than usual care. ConclusionsOPTIMIZE PAD-1 showed that an interprofessional, algorithm-based program can achieve rapid LDL-C lowering in vascular patients using available insurance and therapies, and LDL-C targets can be met in most patients if enabled by optimized systems of care.

Degree of Cyclooxygenase-2 Inhibition Modulates Blood Pressure Response to Celecoxib and Naproxen.

Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI2) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION. Sixteen healthy participants (19-61 years) were treated with celecoxib (100 mg every 12h), naproxen (250 mg every 12h), or placebo administered twice daily for seven days in a double-blind, crossover design randomized by order. On Day 7 when drug levels had reached steady state, the degree of COX inhibition was assessed ex vivo and in vivo. Ambulatory blood pressure was measured throughout the final 12h dosing interval. Both NSAIDs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9±21.7%) than celecoxib (35.7±25.2%; p<0.05). Similarly, naproxen treatment inhibited PGI2 formation in vivo (48.0±24.9%) to a greater degree than celecoxib (26.7±24.6%; p<0.05). Naproxen significantly increased blood pressure compared to celecoxib (differences in least-square means of mean arterial pressure: 2.5 mm Hg (95% CI: 1.5, 3.5); systolic blood pressure: 4.0 mm Hg (95% CI: 2.9, 5.1); diastolic blood pressure: 1.8 mm Hg (95% CI: 0.8, 2.8); p<0.05 for all). The difference in systolic blood pressure relative to placebo was associated with the degree of COX-2 inhibition (p<0.05). Celecoxib 200 mg/day inhibited COX-2 activity to a lesser degree than naproxen 500 mg/day, resulting in a less pronounced blood pressure increase. While the PRECISION trial concluded the non-inferiority of celecoxib regarding cardiovascular risk, this is based on a comparison of doses that are not equipotent.ClinicalTrials.gov identifier: NCT02502006 (https://clinicaltrials.gov/study/NCT02502006).

Once-daily upadacitinib versus placebo in adults with extensive non-segmental vitiligo: a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study

Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6mg (UPA6), upadacitinib 11mg (UPA11), upadacitinib 22mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n=49), UPA11 (n=47), UPA22 (n=43), or PBO (n=46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was-7.60 (95% CI-22.18 to 6.97; p=0.3037) for UPA6,-21.27 (95% CI-36.02 to-6.52; p=0.0051) for UPA11, and-19.60 (95% CI-35.04 to-4.16; p=0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was-7.45 (95% CI-16.86 to 1.96; p=0.1198) for UPA6,-10.84 (95% CI-20.37 to-1.32; p=0.0259) for UPA11 and-14.27 (95% CI-24.24 to-4.30; p=0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n=1)] and non-fatal ischemic stroke [UPA11 (n=1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. AbbVie Inc.

Health-related quality-of-life analysis from KEYNOTE-590: pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer.

In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. NCT03189719.

Repetitive transcranial magnetic stimulation focusing on patients with neuropathic pain in the upper limb: a randomized sham-controlled parallel trial

This study aimed to evaluate the efficacy and safety of navigation-guided repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex in patients with neuropathic pain in the upper limb. This randomized, blinded, sham-controlled, parallel trial included a rTMS protocol (10-Hz, 2000 pulses/session) consisting of five daily sessions, followed by one session per week for the next seven weeks. Pain intensity, as well as pain-related disability, quality of life, and psychological status, were assessed. For the primary outcome, pain intensity was measured daily using a numerical rating scale as a pain diary. Thirty patients were randomly assigned to the active rTMS or sham-stimulation groups. In the primary outcome, the decrease (least square [LS] mean ± standard error) in the weekly average of a pain diary at week 9 compared to the baseline was 0.84 ± 0.31 in the active rTMS group and 0.58 ± 0.29 in the sham group (LS mean difference, 0.26; 95% confidence interval, − 0.60 to 1.13). There was no significant effect on the interaction between the treatment group and time point. Pain-related disability score improved, but other assessments showed no differences. No serious adverse events were observed. This study did not show significant pain relief; however, active rTMS tended to provide better results than sham. rTMS has the potential to improve pain-related disability in addition to pain relief.Clinical Trial Registration number: jRCTs052190110 (20/02/2020).

Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation

BackgroundDupilumab, 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.MethodsIn 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.ResultsA 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 prebronchodilator 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.ConclusionsIn 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.)

Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study

In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P=0.0170), pain (-2.24, 95% CI:-4.30 to-0.17; P=0.0337), fatigue (-2.24, 95% CI:-4.46 to-0.02; P=0.0479), constipation (-3.27, 95% CI-5.49 to-1.05; P=0.0039), QLQ-OES18 pain (-1.77, 95% CI-3.11 to-0.43; P=0.0097), trouble swallowing saliva (-2.09, 95% CI:-3.77 to-0.42; P=0.0146), and choked when swallowing (-3.23, 95% CI:-5.60 to-0.86; P=0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P=0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P<0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. This study was funded by Innovent Biologics and was co-funded by Eli Lilly.

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.

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.

SINGLE-PILL COMBINATION OF THIRD-DOSE TRIPLE ANTIHYPERTENSIVE THERAPY VERSUS STANDARD-DOSE MONOTHERAPY IN PATIENTS WITH MILD TO MODERATE HYPERTENSION

Objective: The study compared the single-pill combination of third-dose triple antihypertensive therapy (amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg) with standard-dose monotherapy (amlodipine 5mg) in reducing systolic blood pressure (SBP) among patients with mild to moderate hypertension. Design and method: This was a multicenter, randomized, double-blind, active-controlled, parallel-group phase III noninferiority trial. Eligible participants aged &gt;=19 years with SBP &gt;=140 to &lt;180 mmHg and diastolic blood pressure (DBP) &lt;110 mmHg after 4 weeks placebo run-in period were randomized to either 8 weeks of combination therapy (ALC) or monotherapy (A5). The primary efficacy endpoint, noninferiority in SBP reduction, was assessed using the upper limit of the one-sided 97.5% confidence interval (97.5%CI) for the difference in SBP reduction between treatments at week 8, with a noninferiority margin of 3 mmHg. Results: The efficacy endpoint analysis included 167 and 166 in the ALC and A5 groups. After 8 weeks, the ALC and A5 groups showed SBP reductions of -18.3±11.9 and -19.4±12.5, respectively, and DBP reductions of -8.5±7.3 and -9.8±7.0 mmHg, respectively (p&gt;0.025 for both). The unadjusted least-square mean (LSM) difference in SBP reduction was 1.15 mmHg, with a 97.5%CI upper limit of 3.51 mmHg. More female patients were allocated to the A5 than the ALC groups (47.6% vs. 34.1%, p=0.012). Both treatments exhibited greater SBP reduction in women than men (-21.4 vs. -16.8 mmHg, p=0.009 in the ALC group; -21.9 vs -17.1 mmHg, p&lt;0.001 in the A5 group). The sex-adjusted LSM difference in SBP reduction was 0.46 mmHg, with a 97.5%CI upper limit of 2.79 mmHg. The response rates (achieving SBP &lt;140 mmHg and DBP &lt;90 mmHg and/or reduction of SBP &gt;=20 mmHg and/or DBP &gt;=10 mmHg from baseline) were 73.1% for ALC and 75.3% for A5 groups (p=0.633). Adverse drug reactions (ADRs) occurred in 3 patients receiving ALC and 5 patients receiving A5, all being mild. Conclusions: The study demonstrated that the single-pill third-dose triple antihypertensive therapy is comparable to standard-dose monotherapy in reducing SBP over 8 weeks without increasing ADRs, providing further support for the low-dose combination antihypertensive drugs in the initial treatment of hypertension. (NCT05362110)

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 function assessment 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 12 months between July 2017 and December 2020; 50 (28 females and 22 males; 54.5 ± 18.7 years) with normal body mass index (BMI) (18.5–25 kg/m2) and 50 (21 females and 29 males; 47.2 ± 13.3 years) with severe obesity (BMI ≥ 40 kg/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 ± 1.7 kg/m2 and 50.3 ± 5.9 kg/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.

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.

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 spesolimabin patients with moderate-to-severe hidradenitis suppurativa: a randomized double-blind placebo-controlled clinical trial.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin 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 (PoCC) study was conducted at 25 centres across 12 countries from 3 May 2021 to 21 April 2022. Patients had moderate-to-severe HS for ≥ 1 year before enrolment. 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 weeks 4 to 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 the 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 0, absolute change from baseline in the 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. In this completed trial, randomized patients (n = 52) received spesolimab (n = 35) or placebo (n = 17). The difference vs. placebo in least squares mean is reported. At week 12, the percentage change in total AN count was similar between treatment arms: -4.1% [95% confidence interval (CI) -31.7 to 23.4]. There was greater numerical improvement in the spesolimab arm, as measured by IHS4 (13.9, 95% CI -25.6 to -2.3); percentage change from baseline in dT count (-96.6%, 95% CI -154.5 to -38.8); and the proportion of patients achieving a dT count of 0 (18.3%, 95% CI -7.9 to 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 vs. placebo. Spesolimab demonstrated a favourable safety profile, similar to that observed in trials in other diseases. This exploratory PoCC study supports the development of spesolimab as a new therapeutic option in HS.

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.