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PubMed2026

Extended Reality Interventions for Osteoarthritis of the Knee and Recovery After Total Knee Arthroplasty: Systematic Review and Meta-Analyses.

BACKGROUND: Nonpharmacologic interventions are important for treating knee pain due to osteoarthritis or after total knee arthroplasty (TKA), and extended reality (XR) technology may enhance treatments for these indications. OBJECTIVE: This systematic review aimed to evaluate XR interventions for pain due to knee osteoarthritis (KOA) or for recovery after TKA. METHODS: Databases were searched through May 2023 and updated in December 2025. Eligible trials evaluated XR interventions to treat KOA pain or after TKA. We classified interventions by depth of immersion and clinical mechanism. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria to determine the certainty of evidence for prioritized outcomes. Meta-analyses were performed when ≥3 studies evaluated similar comparisons, outcomes, and time points. RESULTS: Eligible trials addressed KOA (k=12) or recovery after TKA (k=9). Sample sizes ranged from 36 to 306 participants, and most studies had a follow-up of ≤3 months. Nineteen studies assessed pain-related functioning and pain intensity, and 5 assessed adverse events (AEs). For KOA, 10 studies examined interactive digital rehabilitation (IDR), and 2 examined virtual reality (VR)-digitally augmented exercise (DAE). IDR for KOA may result in better pain-related functioning (low certainty of evidence [COE]; pooled standardized mean difference [SMD] -0.59, 95% CI -1.11 to -0.06; prediction interval [PI] -1.72 to 0.55; k=5) and lower pain intensity at 6-8 weeks (low COE; pooled SMD -0.46, 95% CI -0.92 to 0.00; PI -1.39 to 0.47; k=4). VR-DAE for KOA (k=2) produced inconsistent results (very low COE). For post-TKA studies, 5 examined IDR, 2 examined VR-DAE, 1 examined VR-distraction, and 1 examined VR-psychoeducation. Post-TKA IDR may result in better pain-related functioning (low [k=4] and moderate COE [k=1]) but little to no difference in pain intensity (low-moderate COE; pooled SMD at 3-4 months -0.12, 95% CI -0.75 to 0.52; PI -1.63 to 1.27; k=3). VR-psychoeducation probably results in lower pain at 4 weeks (moderate COE; k=1), and VR-distraction may result in 6 months (low COE; k=1), whereas VR-DAE produced mixed findings (k=2; very low COE). IDR was not associated with AEs, and VR may not be associated with AEs for KOA (high and low COE), though AE reporting was uncommon (k=5) and evidence was very uncertain for post-TKA. CONCLUSIONS: IDR may augment treatment for KOA and post-TKA recovery, and VR may benefit post-TKA rehabilitation. This review is the first to stratify by level of immersion, clinical mechanism, and follow-up duration and to systematically evaluate AEs. IDR may be ready for integration into KOA care, while use after TKA needs more evidence. Randomized controlled trials with implementation outcomes could determine how XR interventions can be used for KOA, whereas trials evaluating efficacy and AEs are needed before their use for post-TKA.

Humans↗

PubMed2026

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING: Sanofi.

Humans↗

PubMed2026

The efficacy of modified psychodynamic psychotherapy for patients with schizophrenia-spectrum disorders in Germany: a prospective, single-centre, assessor-blinded, parallel-group, randomised controlled trial.

BACKGROUND: People with schizophrenia-spectrum disorders have difficulties in interpersonal functioning that remain insufficiently addressed by standard care. Despite long-standing clinical use, psychodynamic psychotherapy has little empirical support compared with other psychosocial treatments for people with schizophrenia-spectrum disorders. We evaluated the efficacy of Modified Psychodynamic Psychotherapy for Schizophrenia (MPP-S), a manualised treatment tailored to the interpersonal vulnerability characteristic of this population, plus treatment as usual (TAU), compared with TAU alone. METHODS: This prospective, single-centre, assessor-blinded, parallel-group, randomised controlled trial was conducted at the Psychiatric University Hospital of the Charité at St Hedwig Hospital in Berlin, Germany. Participants were outpatients aged 18-64 years who were diagnosed with schizophrenia or schizoaffective disorder and exclusion criteria included organic brain disorder, somatic illness affecting cerebral function, and current or past alcohol or illicit drug misuse requiring addiction-specific treatment. Participants were randomly assigned 1:1 in blocks of ten to MPP-S (minimum 30 sessions) plus TAU or TAU alone. Outcome assessors were masked, but participants and therapists were not. The primary outcome was psychosocial functioning, measured using the Mini International Classification of Functioning, Disability and Health Rating for Limitations of Activities and Participation in Psychological Disorders (Mini-ICF-APP) and evaluated at baseline and prespecified post-treatment (24 months) and follow-up (36 months) assessments. Analyses followed the intention-to-treat principle. Linear mixed models were used to analyse incomplete longitudinal data under a missing-at-random assumption. People with lived experience were not formally involved in the design, conduct, or reporting of this study. This trial was preregistered at ClinicalTrials.gov (NCT02576613) and is complete. FINDINGS: From Oct 12, 2015, to Dec 7, 2021, 130 participants (57 [44%] female and 73 [56%] male) were randomly assigned to either MPP-S plus TAU (n=65) or TAU alone (n=64). One participant withdrew consent to data analysis. Regarding the primary outcome of psychosocial functioning, linear mixed models showed significant group-by-time interactions favouring the intervention: estimated marginal means indicated adjusted between-group differences in Mini-ICF-APP scores of -3·45 (95% CI -5·51 to -1·40; p=0·0011) at 24 months and -4·07 (-6·19 to -1·94; p=0·0002) at 36 months. The frequency of adverse events was similar between groups. There were three serious adverse events: two participants died by suicide (one in the MPP-S plus TAU group who did not start psychotherapy and one in the TAU alone group) and one participant in the MPP-S plus TAU group was admitted to a forensic hospital. INTERPRETATION: MPP-S added to TAU could improve psychosocial functioning compared with TAU alone. Our findings suggest efficacy and possible long-term benefits of psychodynamic psychotherapy for schizophrenia-spectrum disorders and indicate its potential role alongside other psychotherapeutic and psychosocial treatments. FUNDING: Berlin Institute of Health, Deutsche Gesellschaft für Psychoanalyse, Psychotherapie, Psychosomatik und Tiefenpsychologie, International Psychoanalytic University Berlin, and Köhler-Stiftung.

Humans↗

PubMed2026

A Multimethod Evaluation to Assess Feasibility, Acceptability, and Preliminary Efficacy of HPVVaxFacts, a Tailored Mobile Web App, for Parents With Unvaccinated Children: Pilot 2-Arm Randomized Controlled Trial.

BACKGROUND: Mobile health (mHealth) interventions may improve provider-parent communication on human papillomavirus (HPV) vaccination to reduce concerns, and increase intention and uptake. HPVVaxFacts (233 Analytics) is a novel, mobile web app delivering tailored education based on the Health Belief Model and Theory of Reasoned Action, addressing parental concerns preclinic visit. OBJECTIVE: This study aimed to assess the feasibility, acceptability, and preliminary efficacy of HPVVaxFacts among parents of adolescents aged 9-17 years. METHODS: We conducted a pilot, randomized controlled trial in 2 urban Tennessee clinics from June to September 2023 comparing 2 groups: tailored education via HPVVaxFacts mobile web app (intervention, n=27), and nutrition education (attention control, n=30). Eligible parents had or were caregivers to a child aged 9 to 17 years unvaccinated against HPV, had a mobile phone, had an upcoming clinic visit, and spoke English. The recruitment strategy was patient intake software-Phreesia (Phreesia, Inc) and eClinicalWorks (eClinicalWorks). Although unblinded, parents could deduce their study arm assignment. Providers were blinded. Feasibility, acceptability, and preliminary efficacy (HPV vaccine knowledge, concerns, intentions, and vaccination rates) were assessed using multimethod evaluation. Parents were assessed at baseline and immediately post intervention via surveys. Vaccination rates were assessed at 12 months post intervention via electronic health records. Nineteen parent interviews were conducted up to 9 months post intervention. A clinic staff consultation (n=6) was 1 month post intervention. RESULTS: Of 57 enrolled parents, most were female (52/57, 91%), non-Hispanic White (44/57, 77%), had ≤US $80,000 household income (32/57, 56%), and had some college or less (27/57, 47%). In total, 81% (29/36) of parents viewed HPVVaxFacts. Post intervention, HPV vaccine initiation was higher in the intervention group compared to the attention control group (48% vs 17%; difference 0.24; 95% CI 0.03-0.46; P=.01). Parents in the HPVVaxFacts arm demonstrated a greater reduction in knowledge (ie, knowledge increase; mean change: -0.6 vs 0.1) and concern scores (mean change: -3.4 vs -1.4) than those in the nutrition education arm. However, between-arm differences were not statistically significant (P=.13 and P=.14, respectively). The majority found the study protocol and HPVVaxFacts acceptable. Benefits of HPVVaxFacts include confirming their decision to vaccinate, supporting parent-child discussion on the vaccine, and answering questions preclinic visit or offering questions for the provider. Study protocol delivery and mobile web app instructions were suggested areas for improvement. Barriers for HPVVaxFacts use include content in English only and digital format. CONCLUSIONS: Our study suggests HPVVaxFacts was feasible and acceptable among parents to provide previsit, tailored information on HPV vaccination. Outcomes offer a positive trajectory but need more exploration. Next steps include a well-powered efficacy trial to determine the impact of HPVVaxFacts on initiation vaccine rates and parental hesitancy factors, as well as to explore an interaction, effect modification, and mediation among different variables.

Humans↗

PubMed2026

Could creatine supplementation combined with physical rehabilitation accelerate return to play in athletes with patellar tendinopathy?

BACKGROUND: Several dietary supplements have been proposed to positively influence the rehabilitation process following injury. However, to date, no studies have specifically examined the effects of scientifically supported ergogenic aids on recovery outcomes when combined with physical performance interventions. Therefore, the aim of this study was to analyze the ergogenic effects of creatine supplementation on neuromuscular performance, tendon thickness, pain, and body composition in athletes diagnosed with patellar tendinopathy (PT). METHODS: Using a triple-blind experimental design, 20 federated athletes (age: 33.7 ± 9.84 years) with PT were randomly assigned to either a creatine supplementation group (CR; n = 9) or a placebo group (PLA; n = 11). All participants followed a physical rehabilitation intervention that included daily eccentric training combined with stretching exercises, along with one session every 10 days of extracorporeal shock wave therapy (ESWT) and manual therapy targeting the tendon and surrounding muscle tissue. At the end of each eccentric training session, the participants ingested 3 capsules of creatine monohydrate - Creapure® (CR) or sucrose (PLA). At the beginning (PRE), after 4 weeks (MID), and after 8 weeks (POST), the pain level (Victorian Institute for Sports Assessment-Patella, VISA-P), tendon thickness (echography), body composition (bioelectrical impedance system), and neuromuscular performance using a countermovement jump test (CMJ) and a strength test (5-RM) of knee extension in the injured leg. RESULTS: A significant main effect of time was observed for VISA-P scores (p < 0.001; η2 p = 0.626), indicating a reduction in pain over time in both the creatine (CR) and placebo (PLA) groups. At POST, both groups showed significant improvements compared to PRE (CR: 78.0 points [69.2-86.8] vs. 60.6 points [53.4-67.7]; p = 0.002; PLA: 75.2 points [66.3-84.0] vs. 60.0 points [52.5-67.5]; p = 0.003). However, only the CR group showed a statistically significant improvement in the MID compared to PRE (MID: 70.2 points [60.0-80.5]; p = 0.027). A significant main effect of time was observed for both tendon thickness (p < 0.001; η2 p = 0.629) and the 5-RM leg extension test (p < 0.001; η2 p = 0.739), with both groups showing progressive improvements over time. Nevertheless, as trend toward a statistically significant time·supplementation interaction was observed (p = 0.099; η2p = 0.126), with an increase in performance only in CMJ in MID vs PRE (36.8  cm (33.8-39.7) vs 34.3  cm (30.8-37.7); p = 0.019) and POST vs MID (POST: 37.6  cm (33.5-41.8); p = 0.015). CONCLUSIONS: A physical rehabilitation program involving eccentric training, stretching, and ESWT is effective in reducing tendon thickness and increasing muscle strength. However. It seems that the addition of CR induces an earlier reduction of pain and a positive effect on CMJ performance. Therefore, CR could be considered as an ergogenic recovery aid in athletes with PT.

Humans↗

PubMed2026

Manual, digital, and AI tumour-infiltrating lymphocyte scoring: a secondary analysis of the APHINITY randomised trial.

BACKGROUND: Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS: In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74·1 months (IQR 68·3-75·4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS: Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0·84 [95% CI 0·79-0·88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11·6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0·41-0·93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0·36-0·48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (≥70·0%; mean absolute improvement 12·1 percentage points [SD 2·8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0·010). INTERPRETATION: Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING: None.

Humans↗

PubMed2026

Efficacy and safety of mitapivat in adults with transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE-T): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: The absence of disease-modifying therapies for patients with α-thalassaemia and oral disease-modifying therapies for patients with β-thalassaemia has been a substantial unmet need in these patients. We assessed the efficacy and safety of mitapivat, an oral allosteric activator of pyruvate kinase, in adults with transfusion-dependent thalassaemia. METHODS: ENERGIZE-T is a global, double-blind, randomised, placebo-controlled, phase 3 trial, conducted across 19 countries in North America, Europe, Asia-Pacific, South America, and the Middle East. Patients aged 18 years or older with transfusion-dependent α-thalassaemia or β-thalassaemia were randomly allocated (2:1) with a central interactive response technology system, stratified by geographical region and thalassaemia genotype, to receive 100 mg mitapivat or placebo orally twice a day for 48 weeks. The primary endpoint was transfusion reduction response (TRR), defined as a reduction of at least 50% in transfused red blood cell units with a reduction of at least two units in any consecutive 12-week period until week 48 compared with baseline. Efficacy was analysed in the full analysis set, comprising all randomly allocated patients. Type, severity, and relationship of adverse events and serious adverse events were assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT04770779) and is active but not recruiting. FINDINGS: Between Nov 30, 2021 and May 2, 2023, 305 patients were screened, of whom 258 were randomly allocated (median age 33·5 years [IQR 27·0-44·0]; 136 [53%] female and 122 [47%] male participants). Of 258 patients allocated, 238 (92%) completed the double-blind treatment period. All patients were required to have a safety follow-up approximately 4 weeks after the final dose of study drug, regardless of completion of the double-blind period or continuation into the open-label extension period. In the full analysis set, TRRs occurred in 52 (30%) of 171 patients in the mitapivat group and 11 (13%) of 87 in the placebo group (adjusted difference 18 percentage points [95% CI 8-27]; two-sided p=0·0003). The safety analysis set comprised 172 patients in the mitapivat group (including one patient allocated to the placebo group who received one dose of mitapivat in error) and 85 in the placebo group. Adverse events were reported in 155 (90%) patients treated with mitapivat and 71 (84%) treated with placebo; the most common events with mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhoea, and fatigue. Serious adverse events were reported in 19 (11%) patients treated with mitapivat and 13 (15%) treated with placebo. Ten (6%) patients who received mitapivat and one (1%) who received placebo discontinued study treatment due to adverse events. No deaths were reported. INTERPRETATION: Mitapivat significantly reduced the transfusion burden and was generally well tolerated, showing a favourable benefit-risk profile. These findings support mitapivat as the first oral disease-modifying therapy for adults with transfusion-dependent α-thalassaemia or β-thalassaemia, providing a new treatment option to reduce transfusion burden in this patient population. FUNDING: Agios Pharmaceuticals, Inc.

Adult↗

PubMed2026

Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.

Humans↗

PubMed2026

Effects of six weeks of guanidinoacetic acid supplementation with and without creatine monohydrate on cognitive function and markers of health in healthy adults.

BACKGROUND: Guanidinoacetic acid (GAA) supplementation has been reported to increase brain creatine content more effectively than creatine monohydrate (CrM). However, the effects on cognitive function are unclear. PURPOSE: The purpose of this proof-of-concept exploratory clinical trial was to determine whether GAA supplementation with and without CrM affects cognitive function and/or markers of health. METHODS: In a double-blind, randomized, and counterbalanced manner, 58 healthy and active adults (33 females, 35.5 ± 14 years, 76.2 ± 14 kg) ingested a PLA (PLA, 2 × 6 g/d maltodextrin), GAA (2 × 1 g/d) + PLA (2 × 5 g/d), or GAA (2 × 1 g/d) + CrM (2 × 5 g/d) for six weeks. The participants donated fasting blood samples and completed a battery of tests and questionnaires assessing various aspects of function, mood, stress, sleep quality, and markers of health at baseline and after six weeks of supplementation. Data were analyzed using General Linear Model (GLM) multivariate and univariate with repeated measures, and mean changes from baseline with 95% confidence intervals, and Chi-squared analysis, and considered significant when the probability of error was 0.05 or less, and approaching significance (p > 0.05-p < 0.10). RESULTS: GAA supplementation tended to improve overall reaction time (-241.8 ms [-533, 50], p = 0.10) while significant interaction effects were observed in overall reaction time (p = 0.031-330 ms [-629, -31]) and YES reaction time (-290 ms [-484, -96], p = 0.004) while recalled correct reaction time (-178 ms [-374, 21], p = 0.078) and recalled correct YES (7.4 % [-1, 15.8], p = 0.084) approached significance compared to PLA. Limited to no effects were observed on the Delayed Picture Recognition Task Test, Digit Vigilance Task Test, Corsi Block Task Test, or Stroop Color-Word Task Test. The amount of time engaged in moderate physical activity was significantly greater (p < 0.05) in the GAA group compared to PLA. Participants in the GAA group reported a lower frequency of controlling irritations (p = 0.036), and feeling like difficulties are mounting (p = 0.053) on the Perceived Stress Scale. Some positive and potentially undesirable effects were observed in sleep quality assessments. The quality of life assessment revealed that participants in the GAA group reported less frequent feelings of being worn out (p = 0.068) and that their health was excellent (p = 0.092) while those in the GAA + CrM group reported more frequent limitations when bending, kneeling, or stooping (p = 0.053), more often feeling full of life (p = 0.081), and less frequency in feeling downhearted and depressed (p = 0.066). No clinically meaningful changes were observed in blood markers or self-reported side effects among the groups. CONCLUSION: Dietary supplementation with GAA (2 g/d) and the combination of CrM (10 g/d + GAA 2 g/d) for six weeks improved delayed verbal episodic recognition memory and retrieval speed and some measures of perceived stress, sleep quality, and quality of life. However, most cognitive tests were not affected, particularly when comparing the GAA to the PLA group; there were some inconsistencies in the findings, and several differences only approached significance. Additional research is needed before conclusions can be drawn. Clinical trial registration: ISRCTN68542582.

Humans↗

PubMed2026

The glucagon and GLP-1 receptor dual agonist DD01 for metabolic dysfunction-associated steatotic liver disease and steatohepatitis (DD01-DN-02): 12-week results from a randomised, double-blind, multicentre, placebo-controlled, phase 2 trial.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a major public health problem arising in the context of metabolic syndrome and obesity. DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects. METHODS: DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA. Adults aged 18-70 years with obesity or who were overweight (BMI ≥25 kg/m2) were included in the study. Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4. Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system. The randomisation sequence was computer-generated by an independent statistician. Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo. Safety analyses included all participants who received at least one dose of study drug. Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption. This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants. FINDINGS: Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo. The mean age of participants was 48·4 years (SD 10·6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH. At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28·8 [95% CI 7·2-115·2]; adjusted relative risk 6·3 [95% CI 2·5-15·9]; p<0·0001). Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo. The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34). Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group. Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group. No deaths occurred. INTERPRETATION: In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies. FUNDING: D&D Pharmatech, Neuraly.

Humans↗

PubMed2026

Neurological effects of encapsulated dexamethasone sodium phosphate in children aged 6-9 years with ataxia telangiectasia (NEAT): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.

Humans↗

PubMed2026

[Effect of electroacupuncture combined with suspension exercise therapy on lower limb motor function in elderly patients with post-stroke spastic hemiplegia].

OBJECTIVE: To observe the efficacy of electroacupuncture (EA) combined with suspension exercise therapy in elderly patients with post-stroke spastic hemiplegia and its effect on lower limb motor function. METHODS: A total of 120 elderly patients with post-stroke spastic hemiplegia were enrolled. Using a 2×2 factorial design, all the patients were assigned to a group A (conventional treatment), a group B (conventional treatment combined with suspension exercise therapy), a group C (conventional treatment combined with EA at Jiaji [EX-B2] and limb acupoints), and a group D(conventional treatment combined with suspension exercise therapy and EA at Jiaji [EX-B2] and limb acupoints), with 30 patients in each group. The main acupoints were bilateral Jiaji (EX-B2) points at the C2-C7, T2-T12, L1-L5, and S1 segments. The adjunct acupoints included Jianyu (LI15), Binao (LI14), Huantiao (GB30), Chengfu (BL36), etc. on the affected side.Continuous wave was applied at a frequency of 100 Hz with a current intensity of 1.5-3.0 mA, and needles were retained for 30 min, once daily for 4 weeks. Before treatment and after 2 and 4 weeks of treatment, the modified Ashworth scale (MAS),Fugl-Meyer assessment (FMA), Berg balance scale (BBS), and Barthel index scores were evaluated in the four groups. Root mean square (RMS) values of surface electromyography (sEMG) of the erector spinae and rectus abdominis muscles on the affected side, as well as balance function indexes, including the mean pressure symmetry index (SI), contact area SI, ellipse area, and displacement distances of the center of pressure in the anteroposterior (AP) and mediolateral (ML) directions, were measured. Clinical efficacy was also compared among the four groups. RESULTS: After 2 and 4 weeks of treatment, MAS scores in all groups were lower than those before treatment (P<0.05), whereas FMA, BBS, and Barthel index scores were higher than those before treatment (P<0.05). After 4 weeks of treatment, MAS scores were lower than those after 2 weeks of treatment (P<0.05), whereas FMA, BBS, and Barthel index scores were higher than those after 2 weeks of treatment (P<0.05) in the four groups. At both 2 and 4 weeks after treatment, group D had lower MAS scores (P<0.05) and higher FMA,BBS, and Barthel index scores (P<0.05) than the other three groups. After 2 and 4 weeks of treatment, RMS values of sEMG of the erector spinae and rectus abdominis muscles on the affected side at all tested angles were higher than those before treatment in all groups (P<0.05), and the values after 4 weeks of treatment were higher than those after 2 weeks of treatment(P<0.05). At both 2 and 4 weeks after treatment, all these indexes in the group D were higher than those in the other three groups (P<0.05). After 2 and 4 weeks of treatment, the mean pressure SI, contact area SI and ellipse area of each group were lower than those before treatment (P<0.05). After 4 weeks of treatment, the mean pressure SI, contact area SI and ellipse area of each group were lower than those after 2 weeks of treatment (P<0.05). After 2 and 4 weeks of treatment, the AP displacement distances of groups A, C and D were lower than those before treatment (P<0.05), and after 4 weeks of treatment, the AP displacement distances of groups A, C and D were lower than those after 2 weeks of treatment (P<0.05);after 2 weeks of treatment, there was no statistically significant difference in AP displacement distance in the group B compared with before treatment (P>0.05), and after 4 weeks of treatment, the AP displacement distance of group B was lower than that before treatment (P<0.05). After 2 weeks of treatment, there was no statistically significant difference in ML displacement distance in group A compared with before treatment (P>0.05); after 4 weeks of treatment, the ML displacement distance of group A was lower than that before treatment (P<0.05). After 2 and 4 weeks of treatment, there was no statistically significant difference in ML displacement distance in the group B compared with that before treatment (P>0.05).After 2 and 4 weeks of treatment, the ML displacement distances of groups C and D were lower than those before treatment(P<0.05), and after 4 weeks of treatment, the ML displacement distances of groups C and D were lower than those after 2 weeks of treatment (P<0.05). At both 2 and 4 weeks after treatment, mean pressure SI, contact area SI, ellipse area, and AP and ML displacement distances in the group D were lower than those in the other three groups (P<0.05). Factorial analysis of variance showed that EA had the strongest main effect on FMA score (F=6.243, P<0.05), suspension exercise therapy had the strongest main effect on BBS score (F=6.292, P<0.05), and the interaction effect was most significant for MAS score (F=5.941, P<0.05), indicating that the combined therapy produced a greater synergistic effect on reducing muscle tone than on the other outcome measures. The total effective rate in the group D was 93.3% (28/30), which was higher than those in the group A (53.3% [16/30]), group B (56.7% [17/30]), and group C (66.7% [20/30], P<0.05). CONCLUSION: EA combined with suspension exercise therapy could effectively promote the recovery of lower limb function in elderly patients with post-stroke spastic hemiplegia, improve motor and balance functions, and enhance activities of daily living.

Humans↗

PubMed2026

Durvalumab and tremelimumab, with or without lenvatinib, combined with transarterial chemoembolisation in participants with embolisation-eligible hepatocellular carcinoma (EMERALD-3): a global, randomised, open-label, sponsor-blinded, phase 3 study.

BACKGROUND: Transarterial chemoembolisation (TACE), a standard treatment for embolisation-eligible hepatocellular carcinoma (HCC), induces tumour immune responses. Single tremelimumab regular interval durvalumab (STRIDE) is a standard treatment in advanced HCC. In this phase 3 trial, we assessed the efficacy and safety of STRIDE, with or without lenvatinib, plus TACE, in participants with embolisation-eligible HCC. METHODS: EMERALD-3 is a phase 3, randomised, open-label, sponsor-blinded study, conducted at 177 medical sites in 21 countries. Eligible participants were 18 years or older (aged ≥21 years in Egypt or Singapore) at screening and had confirmed HCC (by imaging or histopathologically from biopsy specimen, surgery, or both) not amenable to curative surgery, curative ablation, or transplantation but amenable to TACE. Participants had Child-Pugh class A liver function, an Eastern Cooperative Oncology Group performance status of 0-1, and at least one measurable target intrahepatic lesion per modified Response Evaluation Criteria in Solid Tumours. Participants were randomly allocated in a 1:1:1 ratio to receive STRIDE plus lenvatinib plus TACE, STRIDE plus TACE, or TACE until each group reached its preplanned enrolment target of 175 participants. After the STRIDE plus TACE group reached its enrolment target, randomisation was adjusted to continue in a 1:1 ratio between the STRIDE plus lenvatinib plus TACE group and TACE group until approximately 275 participants were enrolled in each of these two groups. Randomisation used a centrally assigned interactive response technology system, stratified by region, baseline tumour burden, and previous palliative embolisation. In the STRIDE plus lenvatinib plus TACE group, on the first day, participants were given 300 mg tremelimumab intravenously, followed by 1500 mg durvalumab plus oral lenvatinib (8 mg for <60 kg bodyweight or 12 mg for ≥60 kg bodyweight); participants then received 1500 mg durvalumab every 4 weeks plus once-daily lenvatinib for up to 36 cycles. In the STRIDE plus TACE group, participants were given 300 mg tremelimumab and 1500 mg durvalumab intravenously on the first day, followed by 1500 mg durvalumab every 4 weeks. The technique and number of TACE procedures were at the investigators' discretion, with the first procedure administered at least 7 days after the first dose of durvalumab in the two investigation treatment groups and within 7 days of random allocation in the TACE group. The primary endpoint was progression-free survival for STRIDE plus lenvatinib plus TACE versus TACE. Key secondary endpoints were overall survival for STRIDE plus lenvatinib plus TACE versus TACE and progression-free survival and overall survival for STRIDE plus TACE versus TACE. This study was registered with ClinicalTrials.gov (NCT05301842), with enrolment completed. FINDINGS: From March 28, 2022, to Nov 20, 2024, 1124 participants were screened. The full analysis set comprised 760 participants, who were randomly allocated to STRIDE plus lenvatinib plus TACE (n=293), STRIDE plus TACE (n=175), or TACE (n=292). 633 (83%) participants were male and 127 (17%) were female; 548 (72%) were Asian. At the first data cutoff (Sept 2, 2025); the overall median follow-up for progression-free survival was 10·0 months (IQR 4·6-17·2); median follow-up for progression-free survival was 11·0 months (IQR 4·8-18·4) for STRIDE plus lenvatinib plus TACE and 8·3 months (4·1-15·5) for TACE. Median progression-free survival was 13·0 months (95% CI 12·2-16·7) for STRIDE plus lenvatinib plus TACE versus 9·8 months (8·0-11·4) for TACE (HR 0·70 [95% CI 0·57-0·86]; p=0·0007). At the second data cutoff (Feb 23, 2026) and a median follow-up for overall survival of 24·6 months (IQR 16·5-31·5) for STRIDE plus lenvatinib plus TACE and 22·9 months (14·9-30·2) for TACE, median overall survival was 39·5 months (95% CI 34·1-not reached) for STRIDE plus lenvatinib plus TACE and 34·7 months (28·8-not reached) for TACE (HR 0·84 [95% CI 0·65-1·09]; p=0·18). At this data cutoff, median progression-free survival was 12·9 months (95% CI 10·2-15·9) for STRIDE plus TACE and 8·1 months (6·5-10·2) for the first 175 participants randomised to TACE (HR 0·71 [95% CI 0·56-0·91]), with median follow-up of 10·3 months (IQR 4·6-23·7) for STRIDE plus TACE and 7·7 months (3·0-18·5) for the first 175 participants randomly allocated to TACE. The most common adverse events of maximum grade 3 or 4 were hypertension (34 [12%] of 287) for STRIDE plus lenvatinib plus TACE, post-embolisation syndrome and anaemia (ten [6%] of 175 each) for STRIDE plus TACE, and post-embolisation (17 [6%] of 290) for TACE. 184 (64%) participants receiving STRIDE plus lenvatinib plus TACE, 89 (51%) receiving STRIDE plus TACE, and 68 (23%) receiving TACE had serious adverse events. Treatment-related adverse events with an outcome of death during the treatment-emergent period occurred in seven (2%) of 287 participants who received STRIDE plus lenvatinib plus TACE (two for myocarditis; and one each for hepatic failure, haemophagocytic lymphohistiocytosis, septic shock, cardiac failure, and unknown cause), none of 175 participants who received STRIDE plus TACE, and two (1%) of 290 participants who received TACE (one each for acute myocardial infarction and unknown cause). INTERPRETATION: STRIDE plus lenvatinib plus TACE showed a statistically significant progression-free survival improvement versus TACE. These findings support a STRIDE-based regimen as a potential new treatment option for people with embolisation-eligible HCC; additional follow-up is being conducted for final analysis of overall survival across treatment groups. FUNDING: AstraZeneca.

Adult↗