Loading Dose Research Articles

Long-term safety and efficacy of ritlecitinib in adults and adolescents with alopecia areata and at least 25% scalp hair loss: Results from the ALLEGRO-LT phase 3, open-label study.

ALLEGRO-LT is an ongoing, long-term, open-label, multicentre, phase 3 study of ritlecitinib in adults and adolescents with alopecia areata (AA). To evaluate ritlecitinib safety and efficacy through Month 24 in patients with AA and ≥25% scalp hair loss. ALLEGRO-LT enrolled rollover patients who previously received study intervention in either ALLEGRO phase 2a or 2b/3 studies and de novo patients who had not received treatment in either study. The de novo cohort results are reported here. Patients aged ≥12 years with AA and ≥25% scalp hair loss received a daily, 4-week 200-mg ritlecitinib loading dose, followed by daily 50-mg ritlecitinib. Analyses are based on data up to the cut-off (December 2022). Efficacy outcomes included proportions of patients achieving Severity of Alopecia Tool (SALT) scores ≤20 and ≤10, Patient Global Impression of Change (PGI-C) score of 'moderately improved' or 'greatly improved' and eyebrow assessment (EBA) and eyelash assessment (ELA) response (≥2-grade improvement from baseline or normal score in patients with abnormal baseline EBA/ELA). Mean (SD) ritlecitinib exposure among the 449 de novo patients enrolled was 728.7 (273.81) days. At Month 24 (as observed), 73.5% and 66.4% of patients achieved SALT score ≤20 and ≤10; 82.4% had PGI-C response; 60.8% and 65.7% had EBA and ELA response. 86.1% of patients reported treatment-emergent adverse events (AEs); most were mild or moderate in severity, with the most frequent being positive SARS-CoV-2 test (24.2%), headache (20.8%) and pyrexia (13.0%). Rates of serious AEs, severe AEs and treatment discontinuations were 4.9%, 6.0% and 6.5%, respectively. Herpes zoster infection occurred in six patients, serious infections in four, malignancies (excluding nonmelanoma skin cancer) in three and major adverse cardiovascular events in three. In patients with AA and ≥25% scalp hair loss, ritlecitinib demonstrated clinical efficacy and had an acceptable safety profile with long-term treatment. ClinicalTrials.gov NCT04006457.

P0834 Mucosal improvement and histologic healing with amiselimod for active Ulcerative Colitis: a phase 2, randomised, placebo-controlled trial

Abstract Background Amiselimod is an investigational oral, sphingosine 1-phosphate (S1P) receptor modulator (highest affinity for S1P1, followed by S1P5) whose immunomodulatory mechanism of action includes decreasing circulating peripheral lymphocytes. The study objective was to assess the endoscopic/histologic outcomes of 2 dose regimens of amiselimod for mild to moderate UC. Methods Patients (age, 18-75 y) with mild to moderate UC (modified Mayo Score [MMS], 3-8) with an endoscopic subscore of ≥2 and active disease extending ≥15 cm from anal verge were enrolled in a phase 2, randomised, double-blind, placebo-controlled trial. Patients were randomly assigned to: (1) amiselimod 0.4 mg once daily (QD) for 2 weeks (loading dose), then 0.2 mg QD for 10 weeks (group A); (2) amiselimod 0.8 mg QD for 2 weeks (loading dose), then 0.4 mg QD for 10 weeks (group B); or (3) placebo QD. Stable maintained doses of oral/rectal 5-aminosalicylate or oral corticosteroids (≤20 mg/day prednisolone dose equivalent) were permitted. Endpoints included change from baseline in MMS (primary), and percentage of patients with endoscopic improvement (Mayo endoscopic subscore ≤1 [secondary]), histologic remission (Geboes index score of <2.0 [original Geboes Score; exploratory]), or mucosal healing (Mayo endoscopic subscore ≤1 and Geboes index score of <2.0; exploratory) at Week 12. Results A total of 321 patients were included (107 per group). For groups A, B, and placebo, the mean (SD) age was 40.6 (14.5) y, 41.6 (12.4) y, and 40.5 (12.4) y, respectively; 41.1%, 40.2%, and 43.0% were female, respectively. Most patients had moderate UC (80.4%, 79.4%, and 79.4%, respectively) and the baseline median (range) MMS score was 6 (3-8) for each group. For the primary endpoint, a significant improvement in mean MMS from baseline at Week 12 was observed for Group A (-2.3) and Group B (-2.3) vs placebo (-1.6; P<0.01 for both vs placebo). Both amiselimod groups had a significantly larger percentage of patients with endoscopic improvement vs placebo at Week 12 (P<0.01 for both vs placebo; Figure). Significantly higher rates of histologic remission were achieved in patients in both amiselimod groups vs placebo at Week 12 (P≤0.03 for both vs placebo; Figure). As well, significantly more patients in Group A (15.0%) and Group B (15.9%) vs placebo (5.6%) had mucosal healing at Week 12 (P=0.02 for both vs placebo).The most common haematologic adverse events with amiselimod (group A, group B) vs placebo were leucopenia (8.4%, 15.9% vs 0%), anaemia (5.6%, 3.7% vs 3.7%), and neutropenia (1.9%, 5.6% vs 0%). Conclusion Both 12-week dosing regimens of amiselimod for UC were superior to placebo for inducing mucosal improvement and histologic healing with a favourable safety profile.

OP41 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active ulcerative colitis: Results from a phase 2b, randomised, double-blind, placebo-controlled, dose-ranging, basket trial (RELIEVE UCCD)

Abstract Background Duvakitug is a human IgG1 monoclonal antibody that inhibits TL1A binding to DR3, a key driver of inflammation and fibrosis. In comparison, it has less binding selectivity for DcR3, which regulates excess TL1A, maintaining homeostasis. Duvakitug has demonstrated reduced inflammation and fibrosis in colitis animal models.1 The efficacy and safety of duvakitug in adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease was assessed in a phase 2b basket trial (NCT05499130).2 Methods RELIEVE UCCD was a randomised, placebo (PBO)-controlled, double-blind induction study. The UC cohort comprised of adults with moderately to severely active disease with inadequate response, loss of response or intolerance to previous conventional and/or advanced therapies (ATs). Eligible patients were randomised to receive subcutaneously a 2250 mg loading dose of duvakitug or PBO, followed by either duvakitug 450 mg, 900 mg or PBO (1:1:1; stratified by prior AT) every 2 weeks.2 The primary endpoint was clinical remission (per modified Mayo score) at week 14. Safety was assessed by adverse event (AE) reporting and laboratory monitoring. Results In total, 137 patients were randomised, treated and included in the UC cohort analysis (450 mg: n=47; 900 mg: n=46; PBO: n=44). Demographics and baseline characteristics were generally similar across arms (Table 1). Both duvakitug doses successfully achieved the week 14 primary endpoint of clinical remission (36% [450 mg], 48% [900 mg] versus 20% [PBO]; PBO-adjusted rates: 16% [450 mg], 27% [900 mg]). The results were statistically significant based on the prespecified Bayesian analysis, with a >0.90 posterior probability that each duvakitug dose is superior to PBO. Duvakitug treatment effect was observed in both AT-experienced and -naïve patients (Table 2). AE incidence was lower for duvakitug (49% [450 mg], 43% [900 mg]) versus PBO (52%), as was incidence of AEs leading to discontinuation (0% [450 mg], 2% [900 mg] versus 5% [PBO]). Conclusion Duvakitug demonstrated statistically significant and clinically meaningful treatment responses compared to PBO in patients with UC; it was well tolerated with no emergent safety signals observed. These induction study results support further development of duvakitug as a potential treatment option for patients with moderately to severely active UC. Funding Duvakitug is being developed in partnership by Teva and Sanofi.

OP40 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active Crohn’s disease: results from a phase 2b, randomised, double-blind, placebo-controlled dose-ranging, basket trial (RELIEVE UCCD)

Abstract Background Duvakitug is a human IgG1 monoclonal antibody that inhibits TL1A binding to DR3, a key driver of inflammation and fibrosis. In comparison, it has less binding selectivity for DcR3, which regulates excess TL1A, maintaining homeostasis. Duvakitug has demonstrated reduced inflammation and fibrosis in colitis animal models.1 Few data are available for the potential of anti-TL1A therapies in Crohn’s disease (CD). A phase 2b induction basket trial (NCT05499130)2 assessed the efficacy, safety and tolerability of duvakitug in adults with moderately to severely active ulcerative colitis and CD. Methods RELIEVE UCCD was a randomised, placebo (PBO)-controlled, double-blind induction study. The CD cohort comprised of adults with moderately to severely active disease with documented inadequate response, loss of response or intolerance to conventional and/or advanced therapies (ATs). Patients were randomised to receive subcutaneously a 2250 mg loading dose of duvakitug or PBO, followed by either duvakitug 450 mg, 900 mg or PBO (1:1:1; stratified by prior AT) every 2 weeks.2 Primary endpoint was endoscopic response (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) at week 14. Safety and tolerability were assessed by adverse event (AE) reporting and laboratory monitoring. Results In total, 138 patients with CD were randomised, treated and included in the analysis (n=46 per arm). Demographics and baseline characteristics were similar across arms (Table 1). Both duvakitug doses achieved the primary endpoint (26% [450 mg], 48% [900 mg] versus 13% [PBO]; PBO-adjusted rates: 13% [450 mg], 35% [900 mg]) with statistically significant endoscopic responses based on the prespecified Bayesian analysis, with a >0.90 posterior probability that each duvakitug dose is superior to PBO. Duvakitug treatment effect was observed in both AT-experienced and -naïve patients (Table 2). AE incidence was similar for duvakitug 900 mg (43%) and PBO (48%), and lower than duvakitug 450 mg (67%). Incidences of AEs leading to discontinuation were 2% each for duvakitug 900 mg and PBO, and 9% for duvakitug 450 mg. Conclusion These are the first data reported for a double-blind, randomised, PBO-controlled induction study of an anti-TL1A antibody in patients with CD. Duvakitug demonstrated statistically significant and clinically meaningful endoscopic response versus PBO with no emergent safety signals observed. These results support further development of duvakitug as a treatment option for patients with moderately to severely active CD. Funding Duvakitug is being developed in partnership between Teva and Sanofi.

Intraoperative Tranexamic Acid Infusion Reduces Perioperative Blood Loss in Pediatric Limb-Salvage Surgeries: A Double-Blinded Randomized Placebo-Controlled Trial.

Limb-salvage surgery for malignant bone tumors can be associated with considerable perioperative blood loss. The aim of this randomized controlled trial was to assess the safety and efficacy of the intraoperative infusion of tranexamic acid (TXA) in children and adolescents undergoing limb-salvage surgery. All participants were <18 years of age at the time of surgery and diagnosed with a malignant bone tumor of the femur that was treated with resection and reconstruction with a megaprosthesis. Exclusion criteria included anatomic locations other than the femur, reconstruction with a vascularized fibular graft, and a previous history of deep venous thrombosis, coagulopathy, or renal dysfunction. Participants were randomly allocated to either the TXA group (a preoperative loading dose infusion of 10 mg/kg of TXA followed by a continuous infusion of 5 mg/kg/hr until the end of surgery) or the placebo group (the same dosage but with TXA substituted with an infusion of normal saline solution). Intraoperative and perioperative blood loss were calculated with use of the hemoglobin balance method. Perioperative blood loss at postoperative day 1 and at discharge from the hospital were calculated. The total volumes of blood transfused intraoperatively and postoperatively were recorded. A statistical comparison between the groups was performed for blood loss and blood transfusion as well as for possible independent variables other than TXA, including age, body mass index, histopathologic diagnosis, tumor volume, preoperative hemoglobin level, type of resection, and the duration of surgery. A total of 48 participants, with a mean age of 12.5 ± 3.44 years (range, 5 to 18 years) and a male-to-female ratio of 1.18, were included. All participants were Egyptians by race and ethnicity. There were no minor or major drug-related adverse events. There was no significant difference between the groups with respect to intraoperative blood loss (p = 0.0616) or transfusion requirements (p = 0.812), but there was a significant difference in perioperative blood loss at postoperative day 1 (p = 0.0144) and at discharge from the hospital (p = 0.0106) and in perioperative blood transfusion (p = 0.023). TXA can be safely infused intraoperatively in children and adolescents undergoing limb-salvage surgery, and it contributes significantly to the reduction of perioperative blood loss and transfusion requirements. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Identifying the Optimal Sampling Strategy for the Bayesian Estimation of Vancomycin AUC0-24 in Adult Hematologic Cancer Patients.

The latest consensus recommends using the ratio between the area under the curve over 24 h (AUC0-24) and minimal inhibitory concentration (MIC) as the therapeutic target for vancomycin in clinical practice, with a Bayesian approach and population pharmacokinetic (popPK) model being particularly recommended. While using both post-dose peak concentration (Cpeak) and pre-dose concentration (Ctrough) is more accurate than Ctrough alone, the optimal sampling strategy for estimating AUC0-24 is still unclear. The objective of this study was to determine the best sampling time(s) to estimate AUC0-24 using the Bayesian approach in these specific adult hematologic cancer patients. A virtual population (n = 7000) was simulated based on the distribution of the significant covariates (ideal body weight and estimated glomerular filtration rate) from the population used to develop the previous pharmacokinetic model. The dosing regimens from the Le Blanc et al. nomogram were used to generate, with NONMEM® (v.7.5), simulated pharmacokinetic (PK) profiles of one loading dose followed by three maintenance doses (steady state). Strategies involving two samples taken during earlier maintenance doses and one sample taken at steady state were tested using the Bayesian approach to predict PK parameters. These strategies were then evaluated for their ability to predict AUC0-24 at steady state (AUC0-24,ss) RESULTS: For single-sample strategies, a sample taken anytime from 4 h post-dose can estimate AUC0-24,ss with precision similar to Ctrough (R2 ≈ 0.75), regardless of renal function (R2 ≈ 0.73-0.77). For two-sample strategies, taking samples at least midway through the dosing interval provides the highest precision for estimating AUC0-24,ss during the first two maintenance doses (R2 ≈ 0.75-0.77). In both strategies, using Cpeak did not yield as precise results as sampling midway through the dosing interval or at Ctrough. This study is the first to test multiple limited sampling strategies using a dosing nomogram stratified by renal function. The results show that vancomycin sampling can extend beyond traditional Cpeak and Ctrough without compromising the accuracy of maximum a posteriori Bayesian estimation of AUC0-24,ss, thereby providing an opportunity to investigate these limited sampling strategies combined with model-informed precision dosing in a clinical setting.

Generative deep learning approach to predict posttreatment optical coherence tomography images of age-related macular degeneration after 12 months.

Predicting long-term anatomical responses in neovascular age-related macular degeneration (nAMD) patients is critical for patient-specific management. This study validates a generative deep learning (DL) model to predict 12-month posttreatment optical coherence tomography (OCT) images and evaluates the impact of incorporating clinical data on predictive performance. A total of 533 eyes from 513 treatment-naïve nAMD patients were analyzed. A conditional generative adversarial network (cGAN) served as the baseline model, generating 12-month OCT images using pretreatment OCT, fluorescein angiography (FA), and indocyanine green angiography (ICGA). We then sequentially added OCT after three loading doses, baseline visual acuity (VA), treatment regimen (pro re nata or treat-and-extend), drug type, and switching events. The generated and patient OCT images were compared for intraretinal fluid, subretinal fluid, pigment epithelial detachment, and subretinal hyperreflective material, both qualitatively and quantitatively. The baseline model achieved acceptable accuracy for four macular fluid compartments (range 0.74-0.96). Incorporating OCT after loading doses and other clinical parameters improved accuracy (range 0.91-0.98). With all the clinical inputs, the model achieved 92% accuracy in distinguishing wet macular status from dry macular status. The segmented fluid compartments in the generated images correlated positively with those in the patient images. Integrating clinical and treatment data, particularly OCT data after loading doses, significantly enhanced the 12-month predictive performance of cGANs. This approach can help clinicians anticipate anatomical outcomes and guide personalized, long-term nAMD treatment strategies.

Auranofin-loaded PLGA Nanoparticles for Neuroprotection against Aluminium-induced Alzheimer's Disease.

The aim of the current study was to explore nano-formulation for effective neuroprotection by auranofin. Currently, the treatment options for various CNS disorders, particularly neurodegenerative disorders, are greatly constrained. A significant obstacle in this pursuit is the blood-brain barrier, a shielding covering that hinders the route of numerous biochemical treatments into the brain. To overcome this problem, nanoformulation- based approaches are gaining interest, increasing the compound's BBB penetrability. The objective of this study was to evaluate whether nanoparticles fabricated from poly(lactic-co-glycolic acid) encapsulated with auranofin could oppose aluminium chloride-induced Alzheimer's disease. Auranofin-encapsulated PLGA nanoparticles were prepared, and their particle size, Entrapment Efficiency (EE), distribution of particles, morphological surface charge, and structural characteristics were characterized. During the in vivo study, rats were orally administered AlCl3 at 100 mg/kg for 21 days. Meanwhile, auranofin and auranofin nanoparticles were orally administered at doses of 5 and 10 mg/kg and 2.5 and 5 mg/kg, respectively, within 2 weeks. After the course therapy, the rats were decapitated, and the hippocampus was collected for the estimated biochemical and neuroinflammatory markers. The auranofin nanoparticles were characterized, revealing % entrapment efficiency (98%) and % loading dose (76%). The nanoparticles exhibited a morphological surface charge of 27.5 ± 5.10 mV, a polydispersity index of 0.438 ± 0.12, and a mean particle size of 101.5 ± 10.3 nm. In the in vivo study, administering a gold compound (auranofin) and formulation (auranofin nanoparticles) resulted in a significant improvement in cognitive deficits, changes in biochemical parameters, and markers of neuroinflammation triggered with aluminium chloride. The results have suggested that auranofin nanoparticles demonstrate abilities to protect neurons compared to auranofin alone. The noticed therapeutic benefits of the auranofin-encapsulated PLGA nanoparticles can be attributed to modulation in particle size with antioxidative and anti-inflammatory impacts of auranofin. Consequently, the outcome of the research has revealed that gold compound nanoparticles hold the potential to be a promising option for altering the therapeutic course of Alzheimer's disease.

Efficacy and Safety of Intravitreal Dexamethasone Implant in Treatment-Resistant Diabetic Macular Edema: Six-month Results.

To investigate the efficacy and safety of intravitreal Dexamethasone implant (DEX-I) therapy in the treatment of diabetic macular edema (DME) refractory to intravitreal bevacizumab (IVB). This retrospective and cross-sectional study included 37 eyes of 37 patients who received 3 loading doses of IVB injections for DME with no response and underwent DEX-Iimplant. Best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurements and central foveal thickness (CFT) measured by spectral domain optical coherence tomography (SD-OCT) were recorded and compared before DEX-I, at the first week, first, second, third and sixth months. Duration of DME, glycated hemoglobin (HbA1c) levels, DME types and lens status (phakic, pseudophakic) were also recorded. The mean age of the patients was 61.14 ±8.69 years (59.5% male, 40.5% female). 35.1% of the patients had cystoid macular edema, 64.9% had diffuse macular edema and 73 % were phakic and 27% were pseudophakic. BCVA, CFT and IOP values before DEX-Iinjection were 0.78 ±0.16 LogMAR, 493.73 ±107.6 µm and 13.05 ±2.59 mmHg, respectively. At 6 months after DEX-I, BCVA, CFT and IOP values were 0.64 ±0.11 LogMAR, 397.35 ±59.72µm and 16.3 ±2.51 mmHg, respectively. In all follow-ups, there was asignificant improvement in BCVA, asignificant decrease in CFT and asignificant increase in IOP compared to pre-injection. Ocular hypertension was observed in 0.8 % of patients and progression of cataract progression in 1% of patients after treatment. DEX-Itherapy is an effective and safe treatment option for DME refractory to IVB treatment.

Population exposure-response analysis of the effect of ritlecitinib on eyebrow assessment and eyelash assessment in patients with alopecia areata.

Ritlecitinib is an orally bioavailable, small molecule that has been approved by the U.S. Food and Drug Administration (FDA) as a once-daily oral treatment option for people 12 years of age and older with severe alopecia areata. This article assessed the exposure-response (ER) relationship of eyebrow and eyelash assessment (EBA/ELA) scores on ritlecitinib and compared them to the Severity of Alopecia Tool (SALT) score (primary endpoint) ER relationship on ritlecitinib. EBA and ELA both are numeric rating scales (NRS) with four levels (0 the most severe, 3 the normal). Longitudinal ER modeling with ordinal regression was conducted to describe ritlecitinib efficacy regarding the hair regrowth in eyebrows and eyelashes separately. The average concentration in the time interval between two adjacent EBA/ELA records was used as the exposure metric. The developed models described the longitudinal EBA/ELA profile and the responder rates adequately. The ER models and the model-based simulations implied that the tested doses in the phase IIb/III clinical trial are in the ascending region, but the magnitude of loading dose effect on earlier efficacy is different across the efficacy endpoints of EBA, ELA, and SALT scores (which could be explained by the estimated [concentration at half maximum effect]). The established longitudinal ER relationships supported the selection of 50 mg dose for overall Alopecia areata (AA) patients with impaired eyebrow and eyelash hairs. The presented analysis using the ordinal regression model can be utilized in any ER analysis where PD response is an ordinal categorical variable.

The effect of an additional pre-extubational loading dose of caffeine citrate on mechanically ventilated preterm infants (NEOKOFF trial): Study protocol for a multicenter randomized clinical trial.

Minimizing the duration of mechanical ventilation is one of the most important therapeutic goals during the care of preterm infants at neonatal intensive care units (NICUs). The rate of extubation failure among preterm infants is between 16% and 40% worldwide. Numerous studies have been conducted on the assessment of extubation suitability, the optimal choice of respiratory support around extubation, and the effectiveness of medical interventions. Since the Caffeine Therapy for Apnea of Prematurity (CAP) trial, caffeine has become one of the essential drugs at NICUs. However, the optimal dosage and timing for adequate effectiveness still need to be more conclusive. Previous studies suggest that higher doses of caffeine treatment increase the success rate of extubation. Therefore, we aim to determine whether using a single additional loading dose of caffeine citrate one hour prior to extubation impacts the success rate of extubation. The study is an open-label, multicenter randomized clinical trial testing the effectiveness and safety of pre-extubational loading dose of caffeine citrate. Inclusion criteria will be infants born before the 32nd gestational week, before the first extubation attempt after at least 48 hours of mechanical ventilation, and a signed parental informed consent. A total of 226 patients will be randomly allocated to either the experimental or control group. The randomization will be stratified by gestational age and antenatal steroid prophylaxis. Preterm infants in the experimental group will receive an additional intravenous (IV) loading dose (20 mg/kg) of caffeine citrate one hour before the first planned extubation, in addition to the standard dosing regimen (20 mg/kg caffeine citrate IV on the first day of life and 5 to 10 mg/kg IV or orally caffeine citrate each consecutive day). Preterm infants in the control group will receive the standard dosing regimen. The primary outcome will be reintubation within 48 hours. A pre-extubational loading dose of caffeine citrate can reduce extubation failure. Obtaining evidence on this feature has the potential to contribute to finding the optimal dosing regimen. The study protocol was approved by the Hungarian Ethics Committee for Clinical Pharmacology of the Medical Research Council and National Institute of Pharmacy and Nutrition (OGYÉI/6838-11/2023). ClinicalTrials.gov identifier NCT06401083 Registered 06. May 2024.; EudraCT number: 2022-003202-77.

The Effect of Different Loading Doses of Tranexamic Acid with the Same Maintenance Dose on Total Blood Loss in the Operative Management of Adolescent Idiopathic Scoliosis

The Effect of Different Loading Doses of Tranexamic Acid with the Same Maintenance Dose on Total Blood Loss in the Operative Management of Adolescent Idiopathic Scoliosis

Lebrikizumab Improves Atopic Dermatitis in Adult and Adolescent Patients With Skin of Color: 16-Week Results From the ADmirable Study

Introduction: Lebrikizumab is a novel monoclonal antibody that binds with high affinity and a slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL13 with high potency. ADmirable (NCT05372419) is an ongoing, open-label, Phase 3b clinical trial of lebrikizumab in patients with moderate-to-severe atopic dermatitis (AD) and skin of color (SoC). These are the first primary results of any Phase 3 clinical trial studying patients with AD and SoC, a historically underrepresented patient population. Methods: At baseline and Week 2, patients received 500-mg lebrikizumab loading doses followed by 250-mg every 2 weeks through Week 16. Concomitant topical therapy was allowed. Patients receiving protocol-defined rescue therapy were discontinued. Key eligibility criteria included: ≥12 years of age, self-reported race other than White, Fitzpatrick Phototype IV-VI, and moderate-to-severe AD. This study includes new objective measures of pigment such as PDCA-Derm™. Endpoints are summarized as observed (primary analysis) and using non-responder imputation/multiple imputation (NRI/MI; supporting analysis). Results: At baseline (N=90), patients had a mean (SD) age of 40.7 (19.6) years, AD disease duration of 19.7 (16.1) years, Eczema Area and Severity Index (EASI) of 26.4 (12.2), and Pruritus Numeric Rating Scale (NRS) of 7.0 (2.2). Forty-three percent of patients were female and 16% were adolescent. Most patients had an Investigator’s Global Assessment (IGA) of 3 (69%). Patients self-reported their race as Black/African American (78%), Asian (11%), American Indian/Alaskan Native (7%), and Native Hawaiian or Other Pacific Islander (4%). Patients had Fitzpatrick Phototypes of IV (43%), V (24%), and VI (32%). At Week 16, 69.2% (54/78) of patients achieved a 75% improvement in EASI (NRI/MI, 66.9%), 44.9% (35/78) achieved a 90% improvement in EASI (NRI/MI, 42.5%), 44.9% (35/78) achieved an IGA 0/1 with ≥2-point improvement (NRI/MI, 44.1%), and 58.1% (36/62) reported ≥4-point Pruritus NRS improvement (NRI/MI, 55.4%). Approximately 50% of patients reported itch improvement within 6 weeks. Using PDCA-Derm™, hypopigmentation and hyperpigmentation improved in 33.3% (4/12) and 63.0% (29/46) of patients, respectively (as observed). Most treatment emergent adverse events (TEAE) were mild-to-moderate in severity. No TEAEs lead to discontinuation and no cases of treatment-related conjunctivitis were reported. No serious adverse events were observed. Conclusion: Lebrikizumab improved signs and symptoms of disease, including post-inflammatory pigment discoloration, in patients with AD and SoC and demonstrated a favorable safety profile.

Lebrikizumab Improves Atopic Dermatitis and ​Quality of Life in Patients With Moderate-to-Severe Atopic Dermatitis Previously Treated With Dupilumab: ​ Results From the ADapt Trial

ADapt (NCT05369403), an open-label, Phase 3b, 24-week study, evaluated the efficacy and safety of lebrikizumab (LEB) in patients with moderate-to-severe atopic dermatitis (AD) previously treated with dupilumab (DUPI). Patients must have discontinued DUPI due to inadequate response (non-response, partial response, or loss of response), intolerance or an adverse event (AE), or other reasons. Four or more weeks after discontinuing DUPI, patients received a 500-mg LEB loading dose at Baseline and at Week 2 followed by 250 mg every 2 weeks through Week 16 (Q2W). At Week 16, responders (IGA 0 or 1 with ≥2-point improvement (IGA0,1) or EASI75 [primary endpoint]) received LEB 250 mg once every 4 weeks (Q4W); other patients continued with 250 mg Q2W. Q2W and Q4W data were pooled and analyzed as-observed and with nonresponder/multiple imputation (NRI/MI). Among 86 enrolled patients, 56% discontinued DUPI due to inadequate response, 16% due to intolerance/AEs to DUPI, and 28% for other reasons. For all patients, at Weeks 16 and 24, respectively, proportions of patients achieving: 1) EASI75: 57.4% and 60.0%, as-observed; 50.7% and 52.8% NRI/MI; 2) IGA0,1: 38.7% and 38.2%, as-observed; 35.6% and 36.8%, NRI/MI; 3) Face-IGA 0: 42% and 49%, as-observed; 4) Pruritus NRS ≥4-point improvement 53.2% and 61.5% as-observed; 48.8% and 47.9% NRI/MI; and 5) DLQI ≥4-point improvement 83.0% and 83.0% as-observed. The safety profile was consistent with other LEB Phase 3 trials. Four patients who discontinued DUPI due to conjunctivitis did not report conjunctivitis with LEB. 3.5% of patients reported treatment-emergent conjunctivitis. In DUPI-experienced patients, treatment of moderate-to-severe AD with LEB resulted in meaningful improvements in skin clearance, itch, and quality of life.

Faricimab efficacy in type 1 macular neovascularization: AI-assisted quantification of pigment epithelium detachment (PED) volume reduction over 12 months in Naïve and switch eyes

BackgroundThis study evaluates the efficacy of intravitreal Faricimab in reducing pigment epithelium detachment (PED) and fluid volumes in both treatment-naïve eyes and eyes unresponsive to anti-VEGF mono-therapies, all diagnosed with type 1 macular neovascularization (T1 MNV) over a period of 12-month.MethodsA retrospective, single-center cohort study was conducted at the Jules Gonin Eye Hospital, Lausanne, Switzerland. Clinical records of treatment-naïve and non-responder switch patients presenting T1 MNV secondary to neovascular age-related macular degeneration (nAMD) from September 2022 to March 2023 were reviewed. Patients received a loading dose of three monthly Faricimab injections followed by a treat-and-extend (T&E) regimen. Multimodal imaging, including structural OCT and AI-assisted analysis, was used to quantify PED volumes and related fluid biomarkers at baseline, 3-month, 6-month, and 12-month follow-up. Statistical analyses included linear mixed models to evaluate differences and trends in intraretinal (IRF), subretinal fluid (SRF) and PED volumes.Results65 eyes of 65 patients were enrolled (female: 70.7%; mean age = 80.7yrs, SD = 6.9yrs). 80% had received anti-VEGF treatment (Switch group) and 20% were treatment-Naïve at baseline. At 12 months, intravitreal treatments were more frequent in the Switch group (mean number = 8.3 vs. 6.0; p = 0.009). BCVA improved at the 12-month follow-up in Naïve eyes (+ 6.9 ETDRS letters from baseline, p = 0.053) and was maintained in Switch eyes. No cases of intraocular inflammation were observed. Significant reduction in SRF and IRF volumes were noted in both groups. A significant reduction in PED volume was observed over the follow-up period in both groups (mean slope = -206 nL, 95%CL = -273/-138; p-value < 0.001).ConclusionsIntravitreal Faricimab significantly reduced PED volumes in both treatment-Naïve and non-responder Switch patients over 12 months. The study highlights Faricimab’s potential as an effective treatment option for T1 MNV in nAMD, offering significant improvements in PED volume and related fluid biomarkers.

Maintenance therapy with a P2Y12 receptor inhibitor after cangrelor in patients with acute coronary syndrome. The ELECTRA-SIRIO 2 investigators' viewpoint.

According to the ESC guidelines, cangrelor may be considered in P2Y12-inhibitor-naïve acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). The aim of this review is to summarize available evidence on the optimal maintenance therapy with P2Y12 receptor inhibitor after cangrelor. Transitioning from cangrelor to a thienopyridine, but not ticagrelor, can be associated with a drug-drug interaction (DDI); therefore, a ticagrelor loading dose (LD) can be given any time before, during, or at the end of a cangrelor infusion, while a LD of clopidogrel or prasugrel should be administered at the time the infusion of cangrelor ends or within 30 minutes before the end of infusion in the case of a LD of prasugrel. Administration of any oral antiplatelet agent at the end of a cangrelor infusion will also result in a transient period of increased platelet reactivity. The inter-individual variability of this period is difficult to predict because it depends on many factors related to the patient and the treatment. In addition, experimental studies indicate that cangrelor may exert a cardioprotective effect beyond the blockade of platelet aggregation. Considering the available data, the potential use of cangrelor in ACS patients goes well beyond the current indications. Furthermore, we believe that it might be prudent to avoid use of thienopyridines during and soon after a cangrelor infusion until conclusive data on the effect of the DDI on the clinical outcome are available. On the other hand, ticagrelor seems to be an optimal oral agent for continuation of P2Y12 inhibition in patients receiving cangrelor infusion.

Investigation of Teicoplanin Trough Concentrations and Safety Following High-Dose Loading in a Pediatric Population.

Therapeutic drug monitoring-informed teicoplanin dosage adjustments are recommended for safe and effective use. The authors' group previously reported that only half of children reached the recommended blood concentration range at the standard teicoplanin loading dose. It has been suggested that higher loading doses are necessary; however, the usefulness and safety of high-dose loading in pediatric patients in clinical practice are unknown. This retrospective cohort study was conducted between January 2018 and June 2021 using electronic medical records. The analysis included 2- to 16-year-old patients treated with teicoplanin who met the eligibility criteria. We assessed the trough concentration of teicoplanin and its safety after high-dose loading in pediatric patients. Overall, 86 patients received a high-dose loading regimen (15 mg/kg every 12 hours for 3 doses, followed by 10 mg/kg once daily). Notably, 55 of the 86 patients (64%) achieved the target trough concentration (>15 mg/L) at significantly higher rates without increasing the incidence of organ damage compared with the standard loading regimen. Multivariate analysis revealed significant differences in age and renal function as factors that inhibited the attainment of the target trough concentration. Simulation analysis using a nomogram stratified by age and renal function revealed that the predicted teicoplanin trough levels were within the target trough values in 73% of patients. High-dose teicoplanin loading safely increases trough blood concentrations in the pediatric population. For further optimization, the dose selection should be stratified according to age and renal function.

Intravenous fosphenytoin therapy for the rescue of acute trigeminal neuralgia crisis in pre- and post-neurosurgical patients: a retrospective observational study.

There is no established treatment for the acute exacerbation of trigeminal neuralgia. We aimed to investigate the efficacy and safety of intravenous fosphenytoin for this disease. We conducted a retrospective observational study of data from 41 patients with trigeminal neuralgia who received intravenous fosphenytoin therapy. Fosphenytoin diluted with physiological saline was administered intravenously at a loading dose of 9.8-20.7 mg/kg or at a dose of 7.5-9.5 mg/kg when maintenance therapy was needed. Pain was evaluated using a numerical rating scale (NRS), assessed immediately before administration (baseline) and at 2, 12, and 24 h after administration. The mean (± standard deviation) NRS score was 9.85 ± 0.69, 0.49 ± 1.47, 1.60 ± 2.19, and 3.46 ± 3.19 at baseline, 2, 12, and 24 h after administration, respectively (p < 0.001). Intravenous fosphenytoin therapy was effective for the acute exacerbation of trigeminal neuralgia regardless of whether it was administered during the perioperative period of microvascular decompression (MVD) or the type of drugs used concomitantly. Fosphenytoin was effective when re-administered (n = 14) or at a maintenance dose (n = 2). The adverse drug reactions observed were mild dizziness in six patients, abnormal auditory perception and thirst in three patients each, and somnolence, decreased SpO2, and drug eruption in one patient each, all of which were transient. Intravenous fosphenytoin therapy can immediately eliminate pain during acute exacerbation of trigeminal neuralgia and can be a useful therapeutic drug in emergency response or until elective treatment, such as MVD, is performed.

Comparison of postoperative analgesia between dezocine plus flurbiprofen axetil and sufentanil in patients with CRC undergoing tumor resection: A prospective, observational study.

Flurbiprofen axetil is a nonsteroidal anti-inflammatory drug used for analgesia. Its combination with dezocine has previously shown a superior postoperative analgesic effect compared with that of opioids. The present study compared the analgesic effect between dezocine plus flurbiprofen axetil (DFA) and sufentanil in patients with colorectal cancer (CRC) following resection of the tumor. The study was performed as a prospective, observational study. It included 107 patients who were treated using a patient-controlled analgesia (PCA) pump following the resection of CRC. Patients in the DFA group were given a loading dose of 5 mg dezocine and 50 mg flurbiprofen axetil, followed by PCA with a combination comprising 30 mg dezocine, 200 mg flurbiprofen axetil and 8 mg ondansetron. Patients in the control group were treated with sufentanil at a loading dose of 5-10 µg followed by PCA with a combination of 100 µg sufentanil and 8 mg ondansetron. The DFA group reported lower pain numerical rating scale scores at 2 h (2.4±1.2 vs. 2.9±1.2) and 12 h (2.0±1.0 vs. 2.5±1.2) and reduced rates of moderate-to-severe pain at 12 h (6.7 vs. 21.0%) compared with those in the control group. In addition, the number of PCA boluses in the DFA group was lower than that in the control group [median (interquartile range), 6.0 (4.5-8.5) vs. 8.5 (5.0-11.0)]. The total satisfaction rate was increased, albeit not significantly, in the DFA group compared with that in the control group (80.0 vs. 62.9%). The levels of tumor necrosis factor-α at 24 and 48 h, and of interleukin-6 at 24 h were decreased in the DFA group compared with those in the control group. The incidences of adverse events did not differ between the groups. These findings indicate that DFA provides more effective analgesia, improves patient satisfaction and reduces the levels of pro-inflammatory cytokines with similar adverse effects compared with those of sufentanil in patients after CRC resection.

Dialysate and plasma meropenem concentrations in continuous intraperitoneal regimen during peritoneal-dialysis-related peritonitis

Background A single dose of intraperitoneal (IP) meropenem is recommended for peritoneal-dialysis (PD)-related peritonitis stemming from extended-spectrum β-lactamase-producing organisms. However, data on IP meropenem is limited. Methods This prospective, descriptive study was conducted to examine plasma and dialysate meropenem levels during continuous IP meropenem administration in five patients with PD-related peritonitis. All patients received an IP meropenem loading dose of 500 mg, followed by IP meropenem at 125 mg/L, with four exchanges daily. The plasma and dialysate meropenem concentrations were measured at specified intervals for a 24-hour period utilizing a high-performance, liquid chromatography method. Results Five patients with PD related peritonitis were studied. The mean-maximum dialysate and plasma meropenem levels were 158.1 mg/L (standard deviation [SD] ± 62.9) and 29.4 mg/L (SD ± 15.9), respectively. The mean dialysate meropenem level was at its minimum of 32.6 mg/L (SD ± 19.1) at 24 hours. Throughout the period, the dialysate meropenem levels exceeded the minimal inhibitory concentration of the pathogenic resistance organism (&gt; 8 mg/L). Four patients responded to the treatment, whereas one developed treatment failure from fungal peritonitis. Conclusion An IP meropenem loading of 500 mg, followed by 125 mg/L every 6 hours, provided an adequate dialysate meropenem concentration and is an effective treatment for PD related peritonitis. Trial registration Thai Clinical Trials Registry (TCTR20191121002) with date of first registration at 21/11/2019 (retrospectively registered).