12-week Treatment Research Articles

Abstract TP108: Virtual Reality Smart Glove May Improve Hand and Arm Function After Stroke

Introduction: Upper extremity impairment is common after stroke. The Neofect Smart Glove is a novel virtual reality-based portable rehabilitation system that may help restore hand and arm function. Objective: To assess the effect of the Smart Glove on functional recovery and total dose of rehabilitation among subacute and chronic stroke patients with upper extremity impairment. Design: Multi-center, prospective, randomized, open-label, blinded-endpoint (PROBE) phase 2 trial consisting of a 12-week active treatment period followed by a 12-week follow-up period. Methods/Interventions: Patients in the intervention group were instructed to use the Smart Glove for at least one session per day for at least 5 days per week in addition to their usual care during the 12-week active treatment period. Patients in the control group received their usual care only. Outcomes: The change from baseline to week 12 in the Jebsen-Taylor Hand Function Test (JTHFT) was the primary efficacy outcome and the change in the Upper Extremity Fugl-Meyer Assessment (UE-FMA) was secondary. Feasibility was assessed by determining the total dose of rehabilitation. Statistics: Differences between treatment arms were compared using analysis of covariance (ANCOVA) in the overall population and, separately, in the subset of patients with mild to moderate upper extremity impairment (baseline JTHFT ≤ 500). Results: During the 12-week active treatment period, there were no differences between the intervention (n = 18) and control (n = 24) groups in the change in the JTHFT (median -64 vs. -69 sec, P = 0.88), the change in the UE-FMA (median 8 vs. 8 points, P = 0.61), or the total dose of rehabilitation (median 1434 vs. 584 min, P = 0.18) (Figure 1). Among the subset of patients with mild to moderate symptoms (baseline JTHFT ≤ 500, n = 31), Smart Glove assignment was associated with a greater improvement in the JTHFT (median -72 vs. -40 sec, P = 0.01) and a greater dose of rehabilitation (median 1739 vs. 510 min, P = 0.04) during the active treatment period (Figure 2). There was a trend toward a greater improvement in the UE-FMA (median 10 vs. 8 points, P = 0.15). Conclusion: While the trial did not show a benefit in the overall study population, Smart Glove use was associated with enhanced recovery of hand and arm function and a higher dose of rehabilitation among patients with mild to moderate upper extremity impairment, suggesting that the Smart Glove may be an effective treatment in this population.

Effectiveness and safety of transcutaneous auricular vagus nerve stimulation for depression in patients with epilepsy.

Our study aimed to evaluate the effectiveness and safety of transcutaneous auricular vagus nerve stimulation (taVNS) for treating mild to moderate depression in patients with epilepsy (PWE). A single-arm, prospective, multi-center, pre-post controlled study was conducted in Eastern China. After a four-week baseline period, PWE with mild to moderate depression began treatment with taVNS, administered for 30min, three times daily, over a 12-week period. The primary outcome measure was the change in 24-item Hamilton Depression Rating Scale (HAMD) scores from baseline to week 12. Secondary outcomes included the response and remission rates for depression at week 12, as well as changes in the 14-item Hamilton Anxiety Rating Scale (HAMA), the Pittsburgh Sleep Quality Index (PSQI), and the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) scores, and seizure frequency at weeks 4 and 12 compared to baseline. Adverse events (AEs) were recorded to assess the safety of taVNS. Both modified Intention-To-Treat (mITT) and Per-Protocol (PP) analyses were employed. Sixty-nine participants were enrolled in this study. Of these, 61 (88.4%) completed the 4-week treatment phase, and 50 (72.5%) finished the 12-week treatment phase. In the mITT analysis, HAMD scores significantly decreased by 4.54±7.44 (p<0.001) from baseline to week 12, with clinical response in 16 (26.2%) and remission in 15 (24.6%) patients. HAMA scores also decreased significantly by week 4 (3.23±5.18, p<0.001) and week 12 (4.95±6.78, p<0.001). PSQI scores and seizure frequency showed non-significant changes at week 4, but seizure frequency decreased significantly by week 12 (0.03±10.47, p=0.038). In the PP analysis, similar improvements were observed. After 12weeks of taVNS compared to baseline, HAMD scores decreased significantly by 5.32±8.98 (p<0.001), with 32% of patients achieving a clinical response and 24% achieving clinical remission. And HAMA scores also decreased by 5.66±7.54 (p<0.001), seizure frequency by 0.14±11.03 (p=0.018), and PSQI scores by 1.06±4.14 (p=0.076).There was a significant increase in QOLIE-31 scores by 5.17±14.71 (p=0.020). Ten (14.5%) patients experienced non-serious adverse events, the most common of which was ear pain (n=4); one patient withdrew due to tinnitus enhancement; all resolved after reducing the stimulation intensity or stopping the treatment. Our study suggests that taVNS may effectively improve depressive symptoms in PWE. This may be an efficacious and safe treatment for mild to moderate depression in PWE.

Dupilumab for chronic obstructive pulmonary disease with type 2 inflammation: a pooled analysis of two phase 3, randomised, double-blind, placebo-controlled trials.

Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, which are key drivers of type 2 inflammation. We aimed to characterise the efficacy and safety of dupilumab in patients with COPD and type 2 inflammation. For this pooled analysis, we pooled and analysed data from all patients in the intention-to-treat populations of the phase 3, randomised, double-blind, placebo-controlled BOREAS and NOTUS trials, which comprised 206 hospitals and clinics in BOREAS and 217 in NOTUS in 38 countries across Europe, Asia, North America, South America, Africa, and Australia. Eligible patients were current or former smokers with 10 pack-years or more of smoking history, were aged 40-85 years, had physician-diagnosed COPD for at least 12 months before randomisation, had a post-bronchodilator FEV1/forced vital capacity (FVC) ratio of less than 0·7, had a post-bronchodilator percentage predicted FEV1 of 30-70%, had documented evidence of two moderate or one severe exacerbations of COPD in the previous year (at least one exacerbation had to have occurred on triple therapy), and had blood eosinophil counts 300 cells per μL or more during screening. Patients had to have symptomatic COPD and a reported chronic productive cough for at least 3 months in the previous year. Key exclusion criteria were history of asthma, pulmonary disease other than COPD, or other diagnosed pulmonary or systemic disease associated with elevated blood eosinophil. In both trials, eligible patients were randomly assigned (1:1) via block randomisation with block size 4 to receive subcutaneous dupilumab 300 mg or matching placebo once every 2 weeks for 52 weeks, alongside established background therapy with inhaled corticosteroids, a long-acting β2-agonist, and a long-acting muscarinic antagonist. The primary endpoint was the annualised rate of moderate or severe exacerbations over 52 weeks. 1874 patients were randomly assigned in BOREAS and NOTUS from May 9, 2019, to May 23, 2023; 938 (50·1%) were randomly assigned to the dupilumab groups and 936 (49·9%) were randomly assigned to the placebo groups. Mean age across both groups was 65·1 years (SD 8·2). 622 (33·2%) of 1874 patients were female and 1252 (66·8%) were male. 1628 (86·9%) patients were White, 719 (38·4%) were from Eastern Europe, and 1316 (70·2%) were former smokers. During the 52-week treatment period, 559 moderate or severe exacerbations were reported in 338 (36·0%) of 938 patients in the dupilumab group and 774 exacerbations were reported in 394 (42·1%) of 936 patients in the placebo group. There was a reduction in the annualised rate of moderate or severe exacerbations compared with placebo (annualised exacerbation rate 0·794 in the dupilumab group and 1·156 in the placebo group; incidence rate ratio 0·687, 95% CI 0·595-0·793; p<0·0001). In the dupilumab group, the time to first severe exacerbation was longer than in the placebo group (0·611, 0·409-0·912; p=0·016). However, there was no reduction in the annualised rate of severe exacerbations (annualised exacerbation rate 0·084 in the dupilumab group and 0·124 in the placebo group; 0·674, 0·438-1·037; p=0·073). Treatment-emergent adverse events, serious adverse events, adverse events that led to permanent treatment discontinuation, and adverse events that led to death were similar between the two groups. Dupilumab, as an add-on to standard triple therapy, reduced the annualised rate of moderate or severe exacerbations compared with placebo, highlighting its potential for personalised treatment approaches in patients with COPD with specific clinical endotypes. Sanofi and Regeneron Pharmaceuticals.

Early Improvements With Atogepant for the Preventive Treatment of Migraine: Results From 3 Randomized Phase 3 Trials.

Three phase 3 trials demonstrated the efficacy and safety of atogepant in episodic migraine (EM) and chronic migraine (CM) across 12-week treatment periods. This analysis evaluates improvements in efficacy and functional outcomes in the first 4 weeks of treatment with the oral calcitonin gene-related peptide receptor antagonist, atogepant, for the preventive treatment of migraine. ADVANCE, ELEVATE, and PROGRESS were phase 3, multicenter, randomized, double-blind, placebo-controlled 12-week trials. ADVANCE and ELEVATE included participants aged 18-80 years with >1 year history of EM and 4-14 monthly migraine days (MMDs). ELEVATE required previous treatment failures to 2-4 classes of oral preventives. PROGRESS included participants aged 18-80 years with >1 year history of CM, ≥15 monthly headache days, and ≥8 MMDs. This analysis reports the atogepant 60 mg once daily (QD) and placebo treatment arms. Outcomes included efficacy endpoints (reporting a migraine day on day 1, change from baseline in weekly migraine days [WMDs] at weeks 1-4, and in MMDs in the first 4 weeks) and functional endpoints evaluated by the Activity Impairment in Migraine-Diary (AIM-D) at weeks 1-4 and the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) at weeks 1-2 and 4. The modified intent-to-treat population included the ADVANCE (atogepant, n = 222; placebo, n = 214), ELEVATE (atogepant, n = 151; placebo, n = 154), and PROGRESS (atogepant, n = 256; placebo, n = 246) studies. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1. The odds ratio compared with placebo was 0.39 (95% CI 0.23-0.67; p = 0.0006) in ADVANCE, 0.53 (95% CI 0.29-0.94, p = 0.031) in ELEVATE, and 0.63 (95% CI 0.43-0.93, p = 0.021) in PROGRESS. Atogepant treatment reduced WMDs at weeks 1-4 and MMDs in the first 4 weeks, and improved AIM-D and EQ-5D-5L at all assessed timepoints for weeks 1-4 compared with placebo. Atogepant 60 mg QD demonstrated superiority to placebo in efficacy and functional measures in the first 4 weeks of treatment across 3 preventive studies, 2 in EM and 1 in CM. ClinicalTrials.gov NCT03777059; NCT04740827; NCT03855137. Submitted: 12/13/2018; 02/02/2021; 02/25/2019. First patient enrolled: 12/14/2018; 03/05/2021; 03/11/2019 clinicaltrials.gov/ct2/show/NCT03777059. clinicaltrials.gov/ct2/show/NCT04740827 clinicaltrials.gov/ct2/show/NCT03855137. This study provides Class II evidence that atogepant 60 mg QD reduces migraine frequency and improves functional outcomes within 4 weeks of initiation in patients with EM and patients with CM.

Stopping of adalimumab in juvenile idiopathic arthritis-associated uveitis (ADJUST): a multicentre, double-masked, randomised controlled trial.

Adalimumab is an effective treatment for juvenile idiopathic arthritis-associated uveitis. Data are scarce on the effects of discontinuing adalimumab after control of the disease had been reached. We aimed to assess efficacy and safety of discontinuing treatment in patients with juvenile idiopathic arthritis-associated uveitis. We conducted a multicentre, double-masked, randomised, placebo-controlled trial at 20 ophthalmology and rheumatology clinics across the USA, the UK, and Australia. Patients aged at least 2 years who had controlled arthritis and uveitis for at least 1 year on adalimumab were randomly assigned in a 1:1 ratio using a web-based system to receive adalimumab or placebo, administered subcutaneously every 2 weeks until the 48-week visit or treatment failure. The primary outcome was the time to treatment failure, defined by recurrence of uveitis or arthritis; all participants were included in the primary and safety analysis. Unmasking occurred at treatment failure, and patients were offered open-label adalimumab through 48 weeks of follow-up. This trial was registered with ClinicalTrials.gov (NCT03816397). 87 patients were enrolled from March 3, 2020, to Feb 14, 2024, whereafter the prespecified interim stopping criteria were met and enrolment was stopped. One patient in each group dropped out but data were included in analyses. Six (14%) of 43 patients in the adalimumab group and 30 (68%) of 44 patients in the placebo group had treatment failure (hazard ratio 8·7, 95% CI 3·6-21·2; p<0·0001). The median time to treatment failure in the placebo group was 119 days (IQR 84-243). The median time to re-establishing sustained control of inflammation in the placebo group after restarting adalimumab was 105 days (63-196). 226 non-serious adverse events occurred in the adalimumab group (7·5 events per person-year, 95% CI 6·5-8·5), and 115 non-serious adverse events occurred in the placebo group (6·8 events per person-year, 5·6-8·1). Four serious adverse events were reported, all in the adalimumab group. Discontinuing adalimumab led to higher rates of recurrence of uveitis, arthritis, or both in patients with previously controlled juvenile idiopathic arthritis-associated uveitis. However, all patients who had treatment failure successfully regained control of inflammation by the end of the 48-week study period after restarting adalimumab. US National Institutes of Health (National Eye Institute).

Longitudinal integrated proteomic and metabolomic skin changes in atopic dermatitis patients treated with dupilumab.

Inhibition of IL-4/IL-13 driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD). To assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment. Skin tape strip (STS) were collected from lesional/non-lesional skin of 20 AD patients during 16-week dupilumab treatment and from 20 healthy volunteers (HV) followed for 16-weeks. STS extracts were examined by LC-MS proteomic analysis and targeted metabolomics. Approximately 2,500 individual proteins were identified in STS extracts. 490 proteins were present in ≥80% of AD and HV skin samples and differentially expressed in AD skin. 249 proteins were significantly reduced (cluster 1) and 136 were significantly increased (cluster 2) in AD skin (both p<0.0001 compared to HV). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes and actin filament proteins. Significant increase in cluster 1 and significant inhibition in cluster 2 proteins expression was achieved in AD skin by 16-weeks of dupilumab treatment (p<0.0001 for both, compared to baseline) and approached HV skin levels. These improvements were also revealed in differential metabolite changes in STS extracts, including amino acids, nucleotide breakdown products and antioxidants. Longitudinal integrated assessment of the skin proteome and metabolome in AD patients treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. Identified changes were linked to improvements in clinical AD skin assessments, including TEWL and disease severity. Mass spectrometry analysis identifies molecular improvements in skin protein and metabolite composition in AD patients and their relationship to targeted suppression of IL-4/IL-13 signaling by dupilumab treatment and clinical response. The study performed longitudinal sampling and analysis of skin samples of AD patients treated by dupilumab and provided evaluation of structural and inflammatory protein components of skin barrier, skin metabolites and their changes on treatment.

P0580 Efficacy and safety results of tulisokibart re-induction treatment in participants with ulcerative colitis in the Phase 2 ARTEMIS-UC clinical trial

Abstract Background Tulisokibart is a monoclonal antibody that targets tumor necrosis factor-like cytokine 1A (TL1A), a regulator of inflammation and fibrosis in inflammatory bowel disorders such as ulcerative colitis (UC). The Phase 2 ARTEMIS-UC study demonstrated a significantly higher proportion of tulisokibart vs. placebo participants achieving clinical remission after 12 weeks of treatment1. This analysis evaluates the effects of re-induction treatment in participants who were non-responders during the initial 12-week induction period of the study. Methods Participants (≥18 years) of moderate to severe active UC, with conventional or advanced treatment failure, were randomized (1:1 ratio) to placebo or the 12-week induction treatment (intravenous tulisokibart 1000 mg, Day 1 and 500 mg, Weeks 2, 6, and 10). The study population consisted of 2 cohorts based on a genetic diagnostic test (Dx) assessing likelihood for responding to anti-TL1A treatment. Cohort 1 included participants stratified by Dx results while Cohort 2 included only Dx positive participants. Cohort 1 is the population used in these post-hoc analyses evaluating induction non-responders. Induction non-responders in either the tulisokibart or placebo groups were assigned to an open label 12-week re-induction with aforementioned induction dosing regimen (non-responders are defined as participants who did not achieve reduction of ≥2 points and ≥30% in modified Mayo score from baseline, accompanied by a reduction ≥1 in rectal bleeding sub score or absolute rectal bleeding sub score ≤1 at week 12). Efficacy and safety were assessed following the re-induction treatment at Week 26. Results In Cohort 1, 67 and 68 participants were randomized to receive placebo or tulisokibart induction treatment, respectively. At Week 14, 41 (placebo) and 21 (tulisokibart) induction non-responders entered re-induction and received 12-week open label tulisokibart treatment. At Week 26, 48% and 63% of participants who received initial 12-week of tulisokibart treatment (total 24-week tulisokibart treatment) and 63% and 76% of participants who received initial 12-week placebo treatment (total 12-week tulisokibart treatment) achieved symptomatic improvement and symptomatic response, respectively (Table). Re-induction with tulisokibart was well tolerated with no serious AEs or discontinuations due to AEs and no new safety signals (Table). Conclusion Re-induction treatment with tulisokibart is effective in participants who did not respond to initial induction treatment. Additionally, up to two tulisokibart induction regimens totaling 24 weeks is well tolerated with no new safety signals identified.

Efficacy of complement inhibition with pegcetacoplan in children with C3 glomerulopathy.

C3 glomerulopathy (C3G) is a rare kidney disease due to a dysregulation of the alternative complement pathway, orphan of specific treatment. Pegcetacoplan is an inhibitor of the third complement component C3, currently on a phase III registration protocol in C3G. Here we describe our experience with the off-label use of pegcetacoplan in pediatric patients with C3G. This retrospective, observational study evaluated the efficacy and safety of pegcetacoplan in five pediatric patients, not eligible in the registration protocol, over a 12-week treatment period. The drug was given subcutaneously, twice a week for the first month, then weekly. The change in urinary protein-to-urinary creatinine ratio (mean of three samples) was the primary endpoint. We also evaluated the changes in serum C3, albumin, sC5-b9, creatinine, and urinary erythrocytes (number/µL). At baseline, median proteinuria/creatininuria ratio (mean of three samples) was 4.97mg/mg (3.53-7.69), and after 12weeks of treatment with pegcetacoplan, it decreased to less than 30% of baseline (p = 0.043) as did erythrocyturia (p = 0.043). C3 levels increased more than 600% of baseline (p = 0.043), whereas the levels of sC5-b9 decreased to normal range (p = 0.043). Three of four patients with impaired kidney function showed an improvement in eGFR. No adverse event was recorded. In C3G patients, pegcetacoplan therapy improves clinical and laboratory features during a 12-week treatment. The present study, although small and with a limited follow-up, supports the use of complement-targeted therapy in C3G. Further studies with a larger number of patients and longer follow-up are needed.

P1188 Real-world quality of life experience of subcutaneous infliximab use in children with Inflammatory Bowel Disease (IBD) at a tertiary paediatric centre

Abstract Background Subcutaneous infliximab (SC-IFX) use offers relative pharmacokinetic stability and efficacy and safety profiles comparable to intravenous-infliximab (IV-IFX) in adult patients with IBD (1-4). Regular hospital admissions for infusions have an impact Quality of Life (QoL), impacting work and school commitments as well as increasing financial burden. Aim to assess tolerability and QoL in patients switched from IV to SC infliximab collected 12 weeks after the switch. Methods A prospectively identified cohort of 33 children with IBD commenced 120mg fortnightly SC-IFX dosing between February to July 2024 in an Australian tertiary paediatric IBD service. QoL and medication tolerability questionnaires (SIAQ and Costs For Patient’s questionnaire) included assessment of tolerability, convenience, satisfaction along with data about travel time and costs were completed at week 12. Assessment of disease activity, inflammatory biomarkers and therapeutic drug monitoring occurred 4 weekly for the first 12 weeks. Results 31(94%) patients completed the 12-week study treatment period. 21 patients (68%) responded to the QOL questionnaires. Satisfaction with SC treatment was 20 (95%) across respondents, only 1 patient reporting ‘somewhat dissatisfied’ experience. 18 (85%) described ease of administration, with 3 (14%) finding injections "not easy". Respondents described financial impacts to be greatest, followed by time-commitment for attendance, loss of school and work time for attendance for infusions. Nearly 2/3 caregivers required formal leave from employment to facilitate infusion attendance, and 1/3 of patients required full day off school. 100% described a definite or probable willingness to continue SC injections beyond the 12-week period. Conclusion We describe the largest cohort of children with IBD prescribed SC-IFX with short-term follow-up. There was high treatment persistence with the drug. QOL data demonstrates high patient satisfaction, with positive impacts on patient quality-of-life with treatment described. Our real-world experience of paediatric SC-IFX use suggests this well tolerated and preferable alternative to IV-IFX dosing in children in with IBD. Further large-cohort and long-term paediatric data is required. References 1)Schreiber S, Ben-Horin S, Leszczyszyn J et al. Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease. Gastroenterology 2021; 160: 2340-53. 2)Buisson A, Nachury M, Bazoge M et al. Long-term effectiveness and acceptability of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel disease treated with intensified doses: The REMSWITCH-LT study. Aliment Pharmacol Ther 2024; 59: 526-34. 3)Gianolio L, Armstrong K, Swann E et al. Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy. J Pediatr Gastroenterol Nutr 2023; 77: 235-9. 4)Gianolio L, Armstrong K, Swann E et al. OC5 Effectiveness and safety of switching to subcutaneous infliximab in paediatric inflammatory bowel disease patients on established intravenous biosimilar infliximab maintenance therapy: real world data from a regional cohort. Frontline Gastroenterology 2024; 15: A4-A.

PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial.

Recurrent respiratory papillomatosis (RRP) is a rare debilitating condition caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Papillomas develop in the aerodigestive tract, leading to significant voice disturbance and airway obstruction. No systemic treatment currently exists. We aimed to assess the safety and clinical activity of PRGN-2012 in adult patients with RRP treated at the recommended phase 2 dose. This was a single-centre, single-arm, phase 1/2 trial. Adult patients aged 18 years or older with RRP who required three or more interventions in the 1 year before treatment received adjuvant PRGN-2012 on day 1 following surgical debulking of disease, and on days 15, 43, and 85. Primary outcome measure was complete response rate, defined as the percentage of patients who did not require an intervention to control RRP in the 12 months after treatment. Safety outcomes included treatment-related adverse events. This study is registered ClinicalTrials.gov (NCT04724980). From March 16, 2021, to June 1, 2023, 38 patients were enrolled and received the 12-week treatment course. Among the 35 patients treated at the recommended phase 2 dose of 5×1011 particle units, 18 (51%) of 35 patients had a complete response (95% CI 34-69) with the median duration of complete response yet to be reached. Adverse events were mild and included grades 1-2 injection site reaction (34 [97%] of 35), fatigue (28 [80%] of 35), chills (25 [71%] of 35), and fever (24 [69%] of 35). PRGN-2012 treatment resulted in complete response in 51% of the patients treated and was safe. Based on these positive pivotal study results, a biologics license application to the US Food and Drug Administration (FDA) is planned, positioning PRGN-2012 to be an FDA-approved medical treatment for adult patients with RRP. National Institutes of Health.

Patient factors associated with treatment completion in a 12-week inpatient dual diagnosis treatment program.

To identify whether mental health wellbeing, age, gender or recent substance use pattern affected completion rates of a dual diagnosis inpatient program. This retrospective cohort study reviewed medical records of patients admitted between October 2018 and December 2021 of Westside Lodge, a dual diagnosis inpatient program. Demographic information, mental health screening tool results (BASIS-24) and self-reported substance use data were accessed from the patients' electronic medical records. 181 admissions were included in the study, of which the majority were male (53.6%). Recently used common substances were alcohol (52%), cannabis (40%) and methamphetamine (43%). None of the factors studied demonstrated any statistically significant effect on the likelihood of program completion. This study found that age, gender, mental health wellbeing and recent substances used were not associated with the likelihood of completing inpatient dual diagnosis treatment though further high-powered studies are required to validate these claims.

Sovleplenib in patients with primary or secondary warm autoimmune haemolytic anaemia: results from phase 2 of a randomised, double-blind, placebo-controlled, phase 2/3 study.

Spleen tyrosine kinase inhibitors are potential treatment options for warm autoimmune haemolytic anaemia. This study aimed to assess the preliminary efficacy and safety of sovleplenib-an oral spleen tyrosine kinase inhibitor-in patients with warm autoimmune haemolytic anaemia in China. Here we report on the phase 2 results. This randomised, double-blind, placebo-controlled, phase 2 part from the phase 2/3 study was conducted at 13 centres in China. Eligible patients, aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of no more than 2, had primary or secondary warm autoimmune haemolytic anaemia (stable underlying disease not requiring drug intervention) with no response to previous glucocorticoid treatment, haemoglobin of less than 100 g/L with active haemolysis, and a positive direct antiglobulin test. The study comprised two periods; patients were randomly assigned (3:1) to receive sovleplenib or placebo at 300 mg orally once a day in the 8-week double-blind period. Upon completion, all patients entered an open-label treatment period for at least 16 weeks and received sovleplenib 300 mg once a day until 24 weeks after the last patient was randomly assigned. The primary endpoint for phase 2 of the trial was overall haemoglobin response rate (haemoglobin ≥100 g/L with an increase of ≥20 g/L from baseline at least once, and haemoglobin not affected by rescue therapy, such as red blood cell transfusions, intravenous immunoglobulin, and glucocorticoids) by week 24. Efficacy analyses in the 0-8 week double-blind period included all patients who were randomly assigned, analysed by intention-to-treat. Safety analysis in the double-blind period included patients in the intention-to-treat population who received at least one dose of the study medication. This phase 2/3 study is registered with ClinicalTrials.gov, NCT05535933, and the phase 3 part is ongoing. Between Sept 26, 2022, and May 9, 2023, 34 patients were screened and 21 patients (four [19%] male and 17 [81%] female) were enrolled in the study and randomly assigned to receive either sovleplenib (n=16) or placebo (n=5). All 21 patients completed the 0-8-week double-blind treatment and entered the open-label treatment period. The overall haemoglobin response rate was 67% (14 of 21 patients) by week 24, and durable haemoglobin response rate was 48% (ten of 21 patients) by week 24. During the 0-8-week double-blind treatment, 13 (81%) of 16 patients in the sovleplenib group versus five (100%) of five patients taking placebo reported treatment-emergent adverse events (TEAEs), and four (25%) of 16 patients versus four (80%) of five patients reported grade 3 adverse events. Although all 21 patients had a TEAE during the 24-week treatment with sovleplenib, only seven (33%) patients had grade 3 events. The most common grade 3 TEAE was anaemia (four [19%] patients), which was not related to treatment. There were no grade 4 or 5 TEAEs. Sovleplenib treatment achieved an encouraging overall haemoglobin response in Chinese patients with warm autoimmune haemolytic anaemia and was well tolerated. The phase 3 part of the study (ESLIM-02) is currently ongoing to further substantiate the efficacy and safety of sovleplenib in this setting. HUTCHMED.

Lebrikizumab decreases type 2 inflammatory biomarker levels in patients with asthma: data from randomized phase 3 trials (LAVOLTA I and II).

Lebrikizumab is an interleukin (IL)-13 inhibitor that specifically blocks IL-13 signaling. Here, we report the effects of lebrikizumab on asthma serum biomarkers in 2 phase 3 clinical studies. LAVOLTA I and LAVOLTA II are replicate, double-blind, placebo-controlled trials with 52-week placebo-controlled treatment periods that evaluated lebrikizumab 37.5- and 125-mg doses every 4 weeks. Patients were aged 18-75 years with uncontrolled asthma on stable background therapy. Biomarkers assessed included immunoglobulin E (IgE), periostin, CC motif chemokine ligand (CCL)13, and CCL17. Statistical significance was assessed for difference in fold-change for lebrikizumab versus placebo using a mixed-effects model for repeated measures. At early time points in LAVOLTA I and II (weeks 1 and 4), decreases in periostin and CCL13 were statistically significant versus placebo (all p < 0.001) for both lebrikizumab doses. For the 125-mg lebrikizumab dose at week 1 in LAVOLTA I, the decrease in CCL17 was statistically significant (p = 0.001). Reductions in periostin, CCL13, and CCL17 were maintained throughout the trial duration. Significant decreases versus placebo (p ≤ 0.001) were seen in IgE by weeks 12 and 24 in LAVOLTA I and LAVOLTA II, respectively. Significant reductions in relevant inflammatory biomarkers were observed in the LAVOLTA I and LAVOLTA II studies.

Risankizumab and guselkumab for psoriasis: a 1-year real-world practice indirect comparison.

Psoriasis is a chronic inflammatory skin disease with a genetic predisposition and autoimmune component, often treated with immunomodulators such as biologic therapies. In this study, the authors evaluated the effectiveness and safety of two of these over a 52-week treatment period. A double-center retrospective cohort study was conducted, enrolling patients with moderate to severe psoriasis who received either guselkumab or risankizumab at dermatology clinics for a minimum of 52-weeks. Out of the 90 patients enrolled in the study, 49 (54.4%) received guselkumab, while 41 (45.6%) received risankizumab. Regarding therapy efficiency, there was no statistically significant difference in PASI90 and PASI100 at week 4 between the two groups (p = 0.428, p = 0.750, respectively). By week 16, PASI90 responses were higher in the guselkumab group (p = 0.039). However, there was no difference in PASI100 response at week 16 (p = 0.957). At weeks 24 and 52, PASI90 and PASI100 responses were similar in both groups. Our results demonstrated that both guselkumab and risankizumab were effective in patients who had previously failed other biologics. Clinical outcomes in both the guselkumab and risankizumab groups had remained unaffected during prior biologic treatments, including anti-TNF, anti-IL17, and/or anti-IL12/23. Treatments yielded consistent outcomes regardless of factors such as obesity, gender, and comorbidities. The small sample size. Our results demonstrated that both guselkumab and risankizumab were effective in patients who had previously failed other biologics. Clinical outcomes in both the guselkumab and risankizumab groups had remained unaffected during prior biologic treatments, including anti-TNF, anti-IL17, and/or anti-IL12/23. Treatments yielded consistent outcomes regardless of factors such as obesity, gender, and comorbidities.

CT-P39 Compared With Reference Omalizumab in Chronic Spontaneous Urticaria: Results From a Double-Blind, Randomized, Active-Controlled, Phase 3 Study.

This study compared the therapeutic equivalence of CT-P39 (an omalizumab biosimilar) and EU-approved reference omalizumab (ref-OMA) in patients with chronic spontaneous urticaria. This double-blind, randomized, active-controlled Phase 3 study (NCT04426890) included two 12-week treatment periods (TPs). In TP1, patients received CT-P39 300 mg, ref-OMA 300 mg, CT-P39 150 mg, or ref-OMA 150 mg. In TP2, patients treated with ref-OMA 300 mg were rerandomized to CT-P39 300 mg or ref-OMA 300 mg; patients initially randomized to CT-P39 300 mg continued this regimen; and patients initially randomized to CT-P39 or ref-OMA 150 mg received 300 mg dosing with the same drug. The primary endpoint for the assessment of therapeutic equivalence of CT-P39 300 mg and ref-OMA 300 mg was changefrom baseline in weekly itch severity score (ISS7) at week 12. In TP1, 619 patients were randomized (CT-P39 300 mg, n = 204; ref-OMA 300 mg, n = 205; CT-P39 150 mg, n = 107; ref-OMA 150 mg, n = 103). Equivalence was demonstrated between CT-P39 300 mg and ref-OMA 300 mg for mean change from baseline in ISS7 at week 12; confidence intervals (CIs) were within predefined equivalence margins: global analysis: treatment difference 0.77, 95% CI -0.37 to 1.90; US analysis: treatment difference 0.70, 90% CI -0.22 to 1.63. The proportion of patients experiencing ≥ 1 treatment-related adverse event was comparable across groups. Secondary efficacy, quality of life, pharmacokinetic, safety, and immunogenicity outcomes were comparable between groups at a given dose level, with no evident impact of switching. Equivalent efficacy was observed between CT-P39 and ref-OMA, with comparable safety also evident.

Fertility-sparing treatment outcomes using immune checkpoint inhibitors in endometrial cancer patients with Lynch syndrome.

To evaluate the efficacy of immune checkpoint inhibitors (ICIs) for fertility-sparing treatment in Lynch syndrome-associated endometrial cancer (LS-EC). Four LS-EC cases received programmed cell death protein 1 (PD-1) inhibitors for fertility preservation at the Obstetrics and Gynecology Hospital of Fudan University from 2017 to 2023. The clinical data and long-term outcomes were retrospectively reviewed. Case 1, carrying germline MLH1 mutation, was diagnosed with Stage IIAmMMRd (International Federation of Gynecology and Obstetrics 2023) endometrial cancer (EC) at 38 years old. She received PD-1 inhibitor treatment and achieved a pathological complete response (CR) at 42 weeks. Case 2, carrying MLH1 mutation, underwent colorectal cancer surgery at 22 years and was diagnosed with EC and synchronous ovarian cancer at 39 years. After 24-week PD-1 treatment, CR of EC and ovarian cancer was achieved. Case 3, carrying MSH2 mutation, was diagnosed with endometrial atypical hyperplasia (EAH) at 35 years. After receiving 7-month progestin, she had the progressed disease with Stage IA2mMMRd EC and colon cancer was found soon after. She received PD-1 treatment for 18 weeks and achieved a CR of EC. She conceived naturally with full term delivery. Case 4, carrying MSH2 mutation, had a recurrence of Stage IBmMMRd EC 15 months after CR from EAH treated with progestin at 40 years. She received PD-1 treatment for 18 weeks and achieved CR. No recurrence was found in all cases after 3-41 months of follow-up after CR. ICIs might be an effective choice for LS-EC patients desiring fertility preservation.

Pegloticase and Methotrexate Cotherapy in Patients With Uncontrolled Gout With Prior Pegloticase Monotherapy Failure: Findings of an Open-Label Trial.

Patients with uncontrolled gout have few treatment options. Pegloticase lowers serum urate (SU) levels, but antidrug antibodies limit SU-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) cotherapy increases pegloticase response rates and lowers IR risk in pegloticase-naïve patients. Therefore, the question of re-treating patients with previous pegloticase monotherapy failure has arisen. The ADVANCE open-label trial examined pegloticase plus MTX cotherapy efficacy and safety following pegloticase monotherapy failure. Patients with uncontrolled gout (SU levels ≥6 mg/dL, oral urate-lowering therapy failure or intolerance, and ≥1 gout sign or symptom) who previously lost SU-lowering response to pegloticase monotherapy were included. Key exclusion criteria were moderate-to-severe IR or anaphylaxis to pegloticase, MTX contraindication, immunosuppressant administration, glucose-6-phosphate dehydrogenase deficiency, and estimated glomerular filtration rate <30 mL/min/1.73m2. After a 6-week subcutaneous MTX run-in (at 25 mg/wk), patients entered 24-week pegloticase (at 8 mg biweekly) plus MTX treatment. The primary end point was SU-lowering response rate during month 6 (SU levels <6 mg/dL for ≥80% of weeks 20-24). Safety was assessed via adverse events (AEs) and laboratory monitoring. Eleven patients began pegloticase plus MTX treatment (91% male patients, mean age 58.6 ± 11.3 years, mean ± SD SU levels 8.5 ± 3.2 mg/dL, 91% tophaceous). Previous pegloticase course was 2 to 27 infusions, with the last infusion admins being a mean ± SD of 3.7 ± 2.4 years before. One patient (9%) maintained response during month 6; 10 patients prematurely discontinued treatment (loss of SU lowering [n = 8], IR [n = 2]). Eight patients (73%) experienced ≥1 AE, most commonly gout flare. All AEs were mild or moderate. Pegloticase plus MTX response rate following failed monotherapy was lower (9% vs 71%) and IR rate was higher (18% vs 4%) than in pegloticase-naïve patients. These findings demonstrate the challenge of overcoming established antipegloticase antibodies and emphasize the importance of initiating immunomodulation before the first pegloticase exposure.

Lerodalcibep and evolocumab for the treatment of homozygous familial hypercholesterolaemia with PCSK9 inhibition (LIBerate-HoFH): a phase 3, randomised, open-label, crossover, non-inferiority trial.

Lerodalcibep, a small binding anti-PCSK9 protein (adnectin), showed effective LDL cholesterol reduction in heterozygous familial hypercholesterolaemia. We aimed to assess the safety and efficacy of lerodalcibep and evolocumab in a globally diverse homozygous familial hypercholesterolaemia population. This phase 3, randomised, open-label, crossover, non-inferiority study consisted of two 24-week treatment periods separated by an 8-week washout. The study was conducted in 12 lipid clinics in six countries (India, Israel, Norway, South Africa, Türkiye, and the USA). Patients aged 10 years or older with genetically confirmed homozygous familial hypercholesterolaemia were randomly assigned by computer-generated randomisation scheme performed centrally via interactive response technology to either monthly lerodalcibep 300 mg (1·2 mL subcutaneous injection) or monthly evolocumab 420 mg (subcutaneous 9 min infusion of 3·5 mL) for 24 weeks (period A) followed by an 8-week washout and then crossed over to the alternate therapy for the next 24 weeks (period B). The trial was open label, but all efficacy parameters were masked to patients, study staff, and the sponsor from randomisation. The primary efficacy endpoint was the percent change from baseline (day 1 of period A) in LDL cholesterol concentration to week 24 for period A and B. The intention-to-treat (ITT) population, defined as all randomly assigned patients, was used for the primary analysis. The safety population included all patients who received any study medication. The margin used to establish non-inferiority was 6%. The trial is registered with ClinicalTrials.gov (NCT04034485) and EudraCT (2019-003611-62), and has now finished. Patients were enrolled from Nov 11, 2019, to July 2, 2021, and the final study visit took place on Aug 8, 2022. Of 82 patients screened, 66 entered period A (ITT population). The mean age was 28·7 years (SD 15·2); 20 (30%) of 66 were paediatric patients; 36 (55%) of 66 were female and 30 (45%) of 66 were male; and the mean baseline LDL cholesterol was 10·59 mmol/L (SD 4·37). Mean LDL cholesterol reduction by ITT analysis at week 24 was -4·9% (SE 3·5) on lerodalcibep compared with -10·3% (3·5) on evolocumab; the mean difference between treatments was 5·4% (95% CI -0·2 to 11·1), which did not show non-inferiority at the prespecified 6% margin. LDL cholesterol response varied considerably across the patient population but was generally similar in the same patients with both lerodalcibep and evolocumab. When averaged across all monthly visits, LDL cholesterol response was -9·1% (SE 3·2) on lerodalcibep and -10·8% (3·2) on evolocumab. Importantly, genotyping and free PCSK9 suppression were not predictive of response. Both drugs were well tolerated, with no treatment-related serious adverse events. Injection site reactions were reported in one (2%) of 65 patients on lerodalcibep and 15 (24%) of 62 patients on evolocumab. The LDL cholesterol response was highly variable, but generally similar in patients treated with both lerodalcibep and evolocumab. Importantly, the study showed the inability to predict response based on genotyping, reinforcing the rationale for PCSK9 inhibition in all patients with homozygous familial hypercholesterolemia and continuing its use in responders. LIB Therapeutics.

Phase 1/2 trial of brogidirsen: Dual-targeting antisense oligonucleotides for exon 44 skipping in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe muscle disorder caused by mutations in the DMD gene, leading to dystrophin deficiency. Antisense oligonucleotide (ASO)-mediated exon skipping offers potential by partially restoring dystrophin, though current therapies remain mutation specific with limited efficacy. To overcome those limitations, we developed brogidirsen, a dual-targeting ASO composed of two directly connected 12-mer sequences targeting exon 44 using phosphorodiamidate morpholino oligomers. An open-label, dose-escalation, phase 1/2 trial assessed the safety, pharmacokinetics, and efficacy of brogidirsen in six ambulant patients with DMD amenable to exon 44 skipping. Following dose escalation, extended 24-week treatment with 40mg/kg and 80mg/kg yielded dose-dependent increases in dystrophin (16.63% and 24.47% of normal). Functional assessments indicated motor stabilization, and plasma proteomics revealed reductions in peptidyl arginine deiminase 2 (PADI2), titin (TTN), and myomesin 2 (MYOM2), highlighting potential biomarkers. Brogidirsen's efficacy was supported invitro using urine-derived cells from patients with DMD. These promising results warrant a subsequent trial for DMD. This study was registered at ClinicalTrials.gov (NCT04129294).

Effects of B Vitamins on Symptoms and Cognitive Functions in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Objective: Schizophrenia which is a chronic disabling burdensome psychotic disorder has been treated with different antipsychotic medications. Some studies have reported a possible correlation between deficiency in minerals, nutrients and vitamins — mainly group B vitamins — and the development of schizophrenia. In the present study, we aimed to examine the effect of the B vitamin group as an adjuvant treatment to antipsychotics in individuals with chronic schizophrenia. Method: In a randomized, double-blind clinical trial study, involving two groups of 25 patients with chronic schizophrenia, we compared the effects of a 12-week adjuvant treatment with a combination of B vitamins — B1 (15mg), B2 (15mg), B6 (10mg), B12 (10µg) and nicotinamide (50 mg) — with a placebo. The impact on negative, positive and cognitive symptoms of schizophrenia was assessed for both groups before the intervention (T0) and at 4, 8 and 12 weeks after the intervention (T1, T2, and T3, respectively). Results: Following the treatment, negative symptoms scores decreased in the treatment group at 12 weeks following the beginning of the treatment (F (4, 45) = 464.7, P &lt; 0.0001). Although a trend toward improvement in positive symptoms and cognitive scores was seen, these changes were not significant. Conclusion: Our results suggest that selecting the group B vitamins as an adjuvant treatment to the antipsychotics may have beneficial effects on improving negative symptoms of patients with chronic schizophrenia.