Treatment Period Research Articles

Metabolic dynamics in chronic gastritis: Examining urinary profiles post Helicobacter pylori eradication

Chronic gastritis is the persistent and insidious inflammation of the gastric lining. Helicobacter pylori (H. pylori ) has been identified as the most common cause of chronic gastritis and consequently elimination of H. pylori can lead to its cure. This editorial explores the use of urinary metabolic profiles before and after eradication to identify biomarkers that can aid in prognosis and treatment. Despite providing promising insights, there are limitations such as a small sample size (17 patients), a narrow treatment period of 2 wk, and treatment heterogeneity, which raise concerns. Nevertheless, these findings have opened a gateway to enhancing the treatment and prognosis of chronic gastritis through urinary metabolomics.

Clinical management of iron deficiency anemia in Japan: iron prescription patterns, treatment effectiveness, and assessments.

Iron deficiency anemia is one of the most common types of anemia, but real-world clinical management practices in Japan are unclear. This study retrospectively explored iron prescription patterns, treatment effectiveness, and assessments. Patients with at least one treatment period between September 2020 and September 2022 were included and classified into three groups (ferric carboxymaltose [FCM]: 7437 patients, saccharated ferric oxide [SFO]: 98,648 patients, and oral iron: 359,547 patients). Iron-related laboratory values over time and testing proportions were evaluated. Median baseline hemoglobin levels were lowest with FCM (FCM: 8.10g/dL, SFO: 8.70g/dL, oral iron: 9.70g/dL), but changes in hemoglobin levels by 12weeks were greatest with FCM (FCM: 3.20g/dL, SFO: 2.60g/dL, oral iron: 1.70g/dL). The median serum ferritin level at 8weeks after FCM treatment was 43.70ng/mL for ≤500mg, versus 123.30ng/mL for >500 to ≤1500mg. All groups had a low proportion of serum ferritin and transferrin saturation (TSAT) testing at diagnosis (<38%), which decreased further for post-treatment assessment (<24%). This study suggests the importance of prescribing an appropriate total iron cumulative dose per the package insert, along with diagnosis and assessments based on serum ferritin/TSAT.

Effects of flexor reflex stimulation on gait aspects in stroke patients: randomized clinical trial.

Gait deficits are very common after stroke and therefore an important aspect in poststroke rehabilitation. A currently little used method in gait rehabilitation after stroke is the activation of the flexor reflex (FR) by electrical stimulation of the sole of foot while walking. The aim of this study wasto investigate the effect of FR stimulation on gait performance and gait parameters in participants with stroke within a single session of flexor reflex stimulation using Incedo™. Twenty-five participants with subacute (n = 14) and chronic (n = 11) stroke were enrolled in the study. Motor functions were tested with a 10-m walk test (10mWT), a 2-min walk test (2minWT), and a gait analysis. These tests were performed with and without Incedo™ within a single session in randomized order. In the 10mWT, a significant difference was found between walking with Incedo™ (15.0 ± 8.5s) versus without Incedo™ (17.0 ± 11.4s, p = 0.01). Similarly, the 2minWT showed a significant improvement with Incedo™ use (90.0 ± 36.4m) compared to without Incedo™ (86.3 ± 36.8m, p = 0.03). These results indicate that while the improvements are statistically significant, they are modest and should be considered in the context of their clinical relevance. The gait parameters remained unchanged except for the step length. A subgroup analysis indicated that participants with subacute and chronic stroke responded similarly to the stimulation. There was a correlation between the degree of response to electrostimulation while walking and degree of improvement in 2minWT (r = 0.50, p = 0.01). This study is the first to examine FR activation effects in chronic stroke patients and suggests that stimulation effects are independent of the time since stroke. A larger controlled clinical trial is warranted that addresses issues as the necessary number of therapeutical sessions and for how long stimulation-induced improvements outlast the treatment period. The trial was retrospectively registered in German Clinical Trials Register. DRKS00021457. Date of registration: 29 June 2020.

Effect of Avenciguat on Albuminuria in Patients with CKD: Two Randomized Placebo-Controlled Trials.

Avenciguat is a novel, potent soluble guanylate cyclase activator in development for CKD. Two trials investigated avenciguat in diabetic (NCT04750577) and non-diabetic (NCT04736628) CKD. A prespecified pooled analysis of two randomized, double-blind, placebo-controlled trials of identical design. Adults with CKD (eGFR ≥20 and <90 mL/min/1.73 m2, urine albumin-to-creatinine ratio [UACR] ≥200 and <3500 mg/g) were randomized to 20 weeks of placebo or avenciguat 1, 2, or 3 mg three times daily (TID; adjunctive to angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker. Primary endpoint: change from baseline in UACR in 10-hour urine at week 20, analyzed per protocol. Secondary endpoint: UACR change from baseline in first morning void urine at week 20. Safety was monitored throughout. Overall 500 patients (mean age 62 years [SD 13]; mean eGFR 44 mL/min/1.73 m2 [SD 18] and median 10-hour UACR 719 [interquartile range 379-1285] mg/g ) received placebo (n=122) or avenciguat 1 mg (n=125), 2 mg (n=126), or 3 mg (n=127) TID. All 243 patients in study one and 27/261 patients in study two had diabetes. Avenciguat 1, 2, and 3 mg TID reduced UACR in 10-hour and first morning void urine versus placebo throughout the treatment period. At week 20, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UACR in 10-hour urine with avenciguat 1, 2, and 3 mg TID were -15.5% (-26.4, -3.0), -13.2% (-24.6, -0.1), and -21.5% (-31.7, -9.8), respectively, analyzed per protocol. Corresponding changes in first morning void urine were -19.4% (-30.0, -7.3), -15.5% (-26.9, -2.5), and -23.4% (-33.5, -11.8), respectively. Avenciguat was well tolerated, overall frequency of adverse events was low and similar to placebo. The number of patients who discontinued study drug due to adverse events with avenciguat 1, 2, and 3 mg TID were 5 (4%), 11 (9%), and 11 (9%), respectively, compared with 4 (3%) in the placebo group. Avenciguat lowered albuminuria, and was well tolerated in patients with CKD.

Ramosetron as an add-on therapy for refractory fibromyalgia: A randomized, double-blind, placebo-controlled trial.

This study aimed to assess the efficacy and safety of intravenous ramosetron for pain relief in patients with fibromyalgia (FM) unresponsive to conventional treatments. . In this prospective, double-blind, placebo-controlled trial, 80 FM patients were randomly allocated to receive either placebo (n = 40) or ramosetron (n = 40) at a dosage of 0.3 mg/day intravenously for five consecutive days. The primary outcome was the reduction in pain intensity at the end of the treatment period, evaluated using a visual analogue scale (VAS). Secondary outcome measures included the FM Impact Questionnaire, Beck Depression Inventory (BDI), Multi-Dimensional Health Assessment Questionnaire (MDHAQ), EQ-5D, and State-Trait Anxiety Inventory on days 5 (end of treatment), 7, 10, and 28. Safety was continuously monitored throughout the study. . At the end of the treatment phase, the ramosetron group demonstrated a significantly greater reduction in VAS pain scores compared with the placebo group (1.18 ± 1.60 vs 0.54 ± 1.59, p< 0.05). Additionally, the ramosetron group exhibited significant improvements in BDI (4.42 ± 5.18 vs 1.33 ± 4.87, p< 0.05) and MDHAQ pain scale (0.37 ± 0.74 vs 0.04 ± 0.52, p< 0.05) scores. However, these improvements in pain VAS and BDI scores were not sustained through day 28. The safety profile of ramosetron was favorable, with gastrointestinal symptoms, particularly constipation, being the most commonly reported adverse events. . Intravenous administration of ramosetron provided safe and effective short-term relief of pain intensity in FM patients with inadequate response to standard treatments.

Phenylbutyrate Treatment in a Boy with MCT8 Deficiency: Improvement of Thyroid Function Tests and Possible Livertoxicity.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations. The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G > T (p.V235L). During a treatment period of 13 months, PB led to a significant decrease of elevated TSH and T3 serum concentrations, while fT4 increased. Weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate (PAA) in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity. In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies towards body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation.

Effect of complex decongestive therapy on frailty and quality of life in women with breast cancer-related lymphedema: the before-and-after treatment study

ObjectiveTo investigate the impact of Complex Decongestive Therapy (CDT) on the severity of frailty and quality of life in individuals suffering from postmastectomy lymphedema syndrome.MethodsParticipants who met the inclusion criteria were informed about CDT and informed consent was obtained. Edmonton Frailty Scale (EFS), extremity volüme (EV), lymphedema stage(LS), EQ-5D General Quality of Life Scale (EQ-5D-5L), and Quick Disabilities of Arm, Shoulder, and Hand (DASH) scores were evaluated by the same physician before and after treatment. A total of 15 sessions of CDT were performed for 3 weeks, five days a week. During the treatment period, hospitalized patients received guidance from a nurse on protecting the affected arm in their daily routine.ResultsEighty patients with breast cancer-related lymphedema who met the inclusion criteria were included in the study. Following a period of 3 weeks of practice and training, the specialist physician conducted the final evaluation and assessments. All patients showed a statistically significant reduction in EV, and regression in LS, EFS, and Quick DASH score (p&amp;lt;0.001). Statistically significant improvement was also observed in quality of life and general health status. (p&amp;lt;0.001).ConclusionThe application of 15 sessions of CDT and educational interventions to women with postmastectomy lymphedema syndrome due to breast cancer yielded positive outcomes. This approach led to an enhancement in patients’ functional capacity, improving their quality of life and a subsequent reduction in the severity of frailty.

P.020 Shifts in daytime functioning items on the insomnia severity scale with lemborexant after 6 months of treatment

Background: Improvements in daytime functioning ideally accompany improvements in insomnia. Scores on the Insomnia Severity Index (ISI) daytime-related items were analyzed following treatment with lemborexant (LEM), a dual orexin receptor antagonist, or placebo (PBO), based on baseline severity. Methods: Participants (≥18 y) with insomnia disorder in E2006-G000-303, a 12-month, randomized, double-blind, PBO-controlled study (first 6 months: Treatment Period 1 [TP1]), were randomized to PBO or LEM 5 mg (LEM5) or 10 mg (LEM10) for 6 months. ISI items are rated 0 (no problem) to 4 (very severe problem); daytime-related ISI items have a maximum score of 16. Results: Of 949 participants, 749 (78.9%) completed the ISI at baseline and end of TP1. Baseline daytime ISI total score distributions were similar between groups. More participants with baseline scores of 9-12 and 13-16 shifted to 0-4 with LEM5 (49.7% and 39.1%, respectively) and LEM10 (46.2% and 46.3%) versus PBO (26.6% and 29.6%). Overall shift distributions were significantly different, favoring both LEM groups (P&lt;0.01). LEM was well tolerated. Conclusions: More LEM-treated participants had improved daytime functioning, evidenced by the significantly larger number of participants whose scores moved into lower categories (ie, better sleep) versus PBO-treated participants, demonstrating additional value beyond improved sleep parameters.

A phase 1 study to assess the absolute bioavailability, mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib, an oral inhibitor of EGFR exon 20 insertion mutations, in healthy participants.

Mobocertinib (TAK-788) is a first-in-class oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that received accelerated approval for the treatment of patients with non-small cell lung cancer with EGFR exon 20 insertion mutations previously treated with platinum-based chemotherapy. This phase 1, 2-period, study was conducted to assess the absolute bioavailability of mobocertinib (Period 1), as well as mass balance, pharmacokinetics, metabolism, and excretion of [14C]-mobocertinib (Period 2) in healthy adult males. In Period 1, participants received a single oral capsule dose of 160mg mobocertinib, followed by a 15-minute intravenous infusion of 50µg (~ 2 µCi) [14C]-mobocertinib administered from 3.75 to 4h after the capsule dose. In Period 2, a single oral dose of 160mg (~ 100 µCi) [14C]-mobocertinib was administered as an oral solution. The geometric mean absolute bioavailability of mobocertinib was determined to be 36.7%. After oral administration of [14C]-mobocertinib, mobocertinib and its active metabolites, AP32960 and AP32914, were minor components in plasma, accounting for only 0.275% of total plasma radioactivity as the majority of mobocertinib-related material was covalently bound to plasma proteins. The geometric mean percentage of the administered radioactive dose recovered in the urine and feces was 3.57% and 76.0%, respectively. Only 0.39% of the oral dose of [14C]-mobocertinib was recovered in the urine as mobocertinib; thus, indicating that renal excretion of unchanged drug was a very minor pathway of elimination. In both treatment periods, mobocertinib was generally safe and well-tolerated as all adverse events were Grade 1 in severity. (Trial registration number ClinicalTrials.gov NCT03811834. Registration date January 22, 2019).

Longitudinal Retrospective Study of a Wearable NMES System to Determine the Effects on Arm Usage in Hemiparetic and Hemiplegic Patients

ABSTRACT Introduction Brain disorders such as traumatic brain injury (TBI), stroke, cerebral palsy (CP), and surgical interventions can result in aberrant motor function in the contralateral limbs, resulting in paralysis, weakness, and/or spasticity. It is known that, in the short term, neuromuscular electrical stimulation (NMES), the application of low-level electrical currents to motor nerves to induce muscle contractions in paralyzed muscles, can stimulate affected muscle groups and increase arm mobility. However, there remains a paucity of longitudinal evidence examining NMES-mediated improvements of arm usage. Objective The aim of this study was to determine the effectiveness of a long-term BioSleeve intervention on the recovery of arm mobility in hemiparetic patients. Study Design The design of this study is a retrospective cohort study. Methods We examined self-reported arm usage in patients with 1) TBI, 2) stroke, 3) hemispherectomy, or 4) CP who wore Axiobionics’ BioSleeve NMES device and compared this to arm usage achieved from years of conventional therapy. Results The device was well-tolerated. Patients reported an average increase in arm usage from 9.9% to 43.5%, with the TBI subcohort reporting a consistent increase in arm usage of 5.7% per year over the treatment period. Conclusions This study supports the literature suggesting that longitudinal NMES can be used to increase arm usage in hemiplegic patients. Clinical Relevance Statement This study supports the use of wearable NMES intervention in the treatment of arm hemiparesis.

Assessment of depression symptoms among cancer patients: a cross-sectional study from a developing country

Cancer patients experience psychological symptoms such as depression during the cancer treatment period, which increases the burden of symptoms. Depression severity can be assessed using the beck depression inventory (BDI II). The purpose of the study was to use BDI-II scores to measure depression symptoms in cancer patients at a large tertiary hospital in Palestine. A convenience sample of 271 cancer patients was used for a cross-sectional survey. There are descriptions of demographic, clinical, and lifestyle aspects. In addition, the BDI-II is a tool for determining the severity of depression. Two hundred seventy-one patients participated in the survey, for a 95% response rate. Patients ranged in age from 18 to 84 years, with an average age of 47 years. The male-to-female ratio was approximately 1:1, and 59.4% of the patients were outpatients, 153 (56.5%) of whom had hematologic malignancies. Most cancer patients (n = 104, 38.4%) had minimal depression, while 22.5%, 22.1%, and 17.0% had mild, moderate, and severe depression, respectively. Education level, economic status, smoking status, and age were significantly associated with depression. The BDI-II is a useful instrument for monitoring depressive symptoms. The findings support the practice of routinely testing cancer patients for depressive symptoms as part of standard care and referring patients who are at a higher risk of developing psychological morbidity to specialists for treatment as needed.

Re-evaluating the placebo response in recent canine dietary epilepsy trials

The placebo response is a common phenomenon. Limited evidence is available about its magnitude in canine epilepsy trials, even though it can significantly influence the efficacy evaluation of new treatments. It was hypothesised that the placebo response is diminished when epilepsy trials are conducted in a prospective crossover design. Seizure data spanning six months from three previous multicenter epilepsy studies were analysed. The monthly seizure frequency of 60 dogs diagnosed with idiopathic epilepsy was calculated, comparing baseline data with placebo treatment. Furthermore, differentiation was made between dogs randomised to the placebo group early (Phase 1: first 3 months) or later during the study (Phase 2: second 3 months).The analysis did not reveal any placebo response in terms of monthly seizure frequency. Instead, an increase was noted during the placebo treatment period, with a mean of 2.95 seizures per month compared to 2.30 seizures per month before study entry (p = 0.0378). Additionally, a notable phase effect was observed. Dogs receiving the placebo in the second study phase exhibited a significant increase in monthly seizure frequency compared to baseline (p = 0.0036). Conversely, no significant difference from baseline was observed for dogs receiving the placebo in the first study phase. These findings underscore the considerable variability in placebo responses observed in trials for canine epilepsy, contrasting with previous limited data. The identified phase effect should be carefully considered in the design and evaluation of canine epilepsy trials to ensure a more accurate assessment of efficacy for new treatments.

P.011 Efficacy and safety of ravulizumab in adults with AQP4+ NMOSD: interim analysis from the ongoing phase 3 CHAMPION-NMOSD trial

Background: CHAMPION-NMOSD (NCT04201262) is an ongoing global, open-label, phase 3 study evaluating ravulizumab in AQP4+ NMOSD. Methods: Adult patients received an intravenous, weight-based loading dose of ravulizumab on day 1 and a maintenance dose on day 15 and every 8 weeks thereafter. Following a primary treatment period (PTP; up to 2.5 years), patients could enter a long-term extension (LTE). Results: 58 patients completed the PTP; 56/2 entered/completed the LTE. As of June 16, 2023, median (range) follow-up was 138.4 (11.0-183.1) weeks for ravulizumab (n=58), with 153.9 patient-years. Across the PTP and LTE, no patients had an adjudicated on-trial relapse during ravulizumab treatment. 91.4% (53/58 patients) had stable or improved Hauser Ambulation Index score. 91.4% (53/58 patients) had no clinically important worsening in Expanded Disability Status Scale score. The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events was 94.8% and 25.9%, respectively. Most TEAEs were mild to moderate in severity and unrelated to ravulizumab. TEAEs leading to withdrawal from ravulizumab occurred in 1 patient. Conclusions: Ravulizumab demonstrated long-term clinical benefit in the prevention of relapses in AQP4+ NMOSD with a safety profile consistent with prior analyses.

#430 Risk factors for major bleeding in patients with non-valvular atrial fibrillation and CKD G3-G5D on oral anticoagulants

Abstract Background and Aims We previously published a register-based cohort study comparing direct oral anticoagulants (DOAC) and warfarin in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) GFR category 3-5 (G3-G5) including patients on dialysis (G5D) (1). This study showed that DOAC was associated with lower risk of major bleeding but similar risk of ischemic stroke compared to warfarin. Bleedings were however more common than strokes, especially in advanced CKD (G5-G5D) where the risk of major bleeding was up to 10 times higher than the risk of stroke. Subsequently, the stroke- and bleeding risk in patients with AF and advanced CKD must be carefully evaluated when deciding on whether to prescribe oral anticoagulants (OAC) or not. Available stroke- and bleeding scoring systems do not perform well in CKD (2, 3). This study aims to present risk factors associated with major bleeding in a Swedish cohort of OAC-treated patients with CKD G3-G5D. Method Data was collected from high quality Swedish healthcare registers including Swedish Renal Registry and Auricula, a register for atrial fibrillation and oral anticoagulants and the National Patient Register. Patients with eGFR&amp;lt;60 ml/min/1.73m2 and non-valvular atrial fibrillation and either DOAC (apixaban, rivaroxaban, edoxaban and dabigatran) or warfarin treatment between 2009-2018 where included. DOAC treatment periods were collected from the Swedish Prescribed Drug Register (PDR), starting from dispense date covering assumed standard pill use and an additional 30 days grace period. Warfarin treatment periods were collected directly from Auricula. An undefined treatment was a period of no OAC or a period of warfarin from PDR not matching a treatment period in Auricula. All periods of OAC treatment with either DOAC or warfarin were evaluated in a multivariate Cox regression model regarding the risk of major bleeding requiring inpatient care. Time-dependent covariates adjusted for in the model were age, sex, years from study start, GFR category, congestive heart failure, diabetes mellitus, hypertension, excessive alcohol use, liver disease, vascular disease, previous gastrointestinal bleeding, intracranial bleeding, other bleeding, ischemic stroke/ transient ischemic attack (TIA), myocardial infarction, PCI and exposures (DOAC, warfarin and periods of undefined treatment). Results Of 2453 included patients, 59% had warfarin (time in therapeutic range, TTR, 67%) and 41% DOAC at inclusion, predominantly apixaban (81% of DOAC users). The mean age was 77 years, 28.3% had G3, 45.4% G4, 9.1% G5 and 17.3% G5D (Table 1). Mean follow up was 2.2 years. During follow up 424 major bleedings occurred yielding 8.9 (95% confidence interval 8.1-9.8) bleedings per 100 patient-years. Table 2 shows effect estimates of each covariate on the outcome major bleeding. Covariates, besides warfarin, associated with increased risk of major bleeding were GFR category, G5/5D versus G3, hazard ratio 1.92 (95% CI 1.43-2.56), previous GI bleeding, 1.77 (1.39-2.25) and previous other bleeding 1.33 (1.09-1.62). Other factors associated with major bleeding were congestive heart failure 1.36 (1.11-1.68), male sex 1.28 (1.03-1.60) and vascular disease, 1.35 (1.01-1.79). Conclusion Patients with non-valvular atrial fibrillation and CKD G3-G5D on OAC are at high risk of major bleeding. Previous major bleeding and kidney failure are strongly associated with major bleeding, this reiterates the results of many previous studies. The present study also shows an association between OAC-associated major bleeding in CKD and male sex, congestive heart failure and vascular disease. Similar associations have been showed in non-CKD cohorts previously but is inadequately studied in CKD. Knowledge about risk factors for major bleeding on OAC in advanced CKD is essential when deciding on when to anticoagulate or not.

#2267 IL-33 Inhibition with tozorakimab for diabetic kidney disease: a randomized, placebo-controlled phase 2b study

Abstract Background and Aims In patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), persistent, low-grade inflammation is a significant risk factor for adverse kidney outcomes. Previously, we identified interleukin-33 (IL-33) as an over-expressed inflammatory cytokine in kidney biopsies from patients with CKD and showed a significant benefit of inhibiting IL-33 signaling in a rodent model of diabetic kidney disease (DKD). Here, we investigate the therapeutic potential of tozorakimab, a high-affinity IL-33-neutralizing immunoglobulin G1 monoclonal antibody, in patients with DKD. Method FRONTIER-1 (NCT04170543) was a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of tozorakimab in patients with DKD; defined as T2D with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2, a urinary albumin-to-creatinine ratio (UACR) of 100-3,000 mg/g, and on angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) for &amp;gt; 6 weeks before the treatment period. Participants were randomly assigned to four different doses of tozorakimab or volume-matched placebo, administered subcutaneously every 28 days for 24 weeks. The randomization process was stratified based on region and the use of SGLT2 inhibitors (SGLT2i). All participants received 10 mg of dapagliflozin Days 85–168, discontinuing existing SGLT2i if applicable. The primary objective of the study was to evaluate the effect of tozorakimab on UACR. A sample size of 565 patients provided at least 80% power to detect a 30% reduction in the change from baseline to week 24 in UACR between each tozorakimab treatment group and placebo. Efficacy endpoints were evaluated in the Per Protocol Population (PPP; initiated dapagliflozin treatment), whereas safety and tolerability were assessed for all dosed participants. Results Between 11 December 2019 and 16 May 2023, we assessed 1,575 patients for eligibility in Argentina, Canada, Chile, Peru, South Korea, Japan, and the United States. 599 (38%) participants were assigned to tozorakimab or placebo. Owing to the COVID-19 pandemic, the study was temporarily halted between March and June 2020. This precautionary measure resulted in the discontinuation of 26 participants. Upon resuming, the study incorporated significant modifications to adapt to the pandemic environment. 573 participants (Full Analysis Population) were randomized after the study was restarted: 29.7% were female; their mean age (±SD) was 67 years (±10); mean eGFR was 48 mL/min/1.73 m2 (±15); and the geometric mean UACR was 460 mg/g (coefficient of variation = 151%). Most participants were taking an ACEi (30%) or ARB (65%), and 28% an SGLT2i. 139 participants received placebo, while 96, 91, 95, and 152 participants received 30, 60, 120, and 300 mg tozorakimab, respectively. The baseline characteristics were balanced across treatment groups, and significant target engagement was observed in all dose arms. Tozorakimab was generally well tolerated and the incidences of adverse events (Aes), serious Aes, discontinuations, and death were similar to placebo. Initial evaluation identified 476 participants in the PPP with 109, 81, 80, 72, and 134 on placebo, 30, 60, 120, and 300 mg tozorakimab, respectively. The primary efficacy analysis demonstrated an inhibition of IL-33 signaling but failed to establish a statistically significant difference in UACR reduction between placebo and treatment groups. The median %-change from baseline was –22% (–46%, 24%) in the placebo group and ranged from –23% to –25% in the tozorakimab groups at week 24. Similarly, no significant effect on eGFR was observed. Following study completion, Good Clinical Practice concerns arose at one clinical trial site with 15 participants. The investigation of these issues is ongoing, but significant alterations to the study results are not anticipated. Conclusion This study did not demonstrate a clinically meaningful reduction in UACR with tozorakimab treatment in patients with T2D and CKD. Further investigation is warranted to clarify the role of IL-33 in DKD.

#3142 Evaluation of antipruritic effect of tacrolimus on hemodialysis patients with uremic pruritus, a double-blind, randomized, clinical trial

Abstract Background and Aims Pruritus in patients undergoing hemodialysis is a highly prevalent complication that affects quality of life. Several medications are currently used for the treatment of uremic pruritus, but these are not satisfactory. There are few studies about the beneficial effect of oral Tacrolimus on dermatologic problems such as pruritus. Considering the condition of hemodialysis in ESKD patients and the probable presence of oral Tacrolimus in their future treatment plan, this trial is designed to assess the antipruritic effect of Tacrolimus compared with placebo. Method This multicenter, randomized, double-blind, placebo-controlled clinical trial included 75 patients undergoing hemodialysis. The patients were randomized to a treatment group (Tacrolimus 1 mg/day) or a control group (placebo). The treatment lasted eight weeks, followed by a 2-week observational period. Visual Analogue Scale (VAS), % affected Body Surface Area (%BSA), and 12-Pruritus Severity Scale questionnaire (12-PSS) were measured before and after treatment periods. Moreover, sleep quality and the effect of sex were also evaluated. Results Seventy-five patients under hemodialysis (mean age of 58.18 ± 09.39 years) completed the study. Mean changes in VAS, %BSA, and 12-PSS after the interventions (Tacrolimus vs. placebo, mean ± SD) were as follows, respectively: −3.77 ± 2.13 vs. −1.07 ± 1.17, −18.97 ± 12.20 vs. 2.44 ± 3.23, and −4.67 ± 3.21 vs. −1.32 ± 2.45 (P &amp;lt; 0.0001). An improvement in sleep quality was found in 52.6% (20/38) of patients after Tacrolimus intake (P &amp;lt; 0.01). Overall, Tacrolimus was more effective in women than men (P &amp;lt; 0.016). Conclusion Based on the preliminary results of this study, Tacrolimus can be introduced as an effective drug for the management of pruritus and can be an add-on therapy in uremic patients.

#3018 Aciclovir or valaciclovir neurotoxicity in renal patients: increasing number of neurotoxicity cases are diagnosed in Sweden by a blood test

Abstract Background and Aims Kidney transplant patients are at high risk for developing zoster infections, as well as patients with impaired renal function. Aciclovir (ACV) and its prodrug valaciclovir are effective medications to treat these herpes infections. The medications typically have mild side effects such as nausea and vomiting, headache, and skin rash. More uncommon but serious side effects include elevated creatinine, acute kidney failure, and aciclovir-induced neuropsychiatric symptoms (AINS). The latter is difficult to distinguish from the viral infection treated, thus prolonged treatment with ACV may cause further deterioration and increase the chance for coma and need for intensive care treatment. ACV is excreted by glomerular filtration and tubular secretion and should be doses according to renal function. A small part is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase to its main metabolite 9-carboxymethoxymethylguanine (CMMG), but as renal function decreases more CMMG is found in the urine, serum, and CSF. We have earlier shown that a serum CMMG cut-off level of 10.8 µmol/L is predictive of AINS. Hemodialysis alleviates the symptoms dramatically, but AINS need to be diagnosed first. The knowledge about our method has increased in Sweden, but has more AINS cases been diagnosed in Sweden now than for 10 years ago? Method Data from our therapeutic drug monitoring (TDM) database of ACV and CMMG levels were studied during the period 2013 to 2023. Serum samples with a CMMG concentration above 10.8 µmol/L were collated and compared to the total number of samples per year. Some patients were monitored with more than one blood sample during the treatment period and the number of single patients was also included. Results The database consisted of 4521 serum ACV and CMMG samples during the study period with 727 samples with a CMMG concentration above 10.8 µmol/L. The number of CMMG serum samples increased from 278 in 2013 to 601 in 2023. A total of 363 patients had at least one sample above 10.8 µmol/L. A median of 33 (range 17 to 59) single patients were diagnosed with AINS per year. Conclusion Measurement of both ACV and CMMG has increased the number of AINS cases in Sweden and are requested to a higher extent now than 10 years ago. Two more laboratories in Sweden measure or will start to measure ACV and CMMG, one laboratory in Bristol have had the method since 2007, but there are too few laboratories performing the analysis in other countries, causing severe suffering for patients and high costs for healthcare.

Near vision in patients with DME and RVO treated with aflibercept and correlation with NEI VFQ-25 questionnaire

BackgroundThe aim of this study is to evaluate near and distance visual acuity (VA) and their correlation with the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) outcomes in patients with diabetic macular edema (DME) and macular edema due to retinal vein occlusion (RVO) treated with aflibercept.MethodsIn this prospective study, we included 87 eyes of patients diagnosed with DME (n = 61) and RVO (n = 26), who received aflibercept treatment and were followed until the 8th injection. Near VA was examined on the 1st, 2nd, 3rd, 4th, 6th, and 8th injection, and patients completed the NEI VFQ-25 on the 1st, 4th, and 8th aflibercept injection.ResultsThe mean near VA at baseline in all eyes was 0.89 ± 0.12 logMAR. With every administration, there was a statistically significant improvement; on the 4th (0.70 ± 0.19; p = 0.000) and the 8th application (0.60 ± 0.19; p = 0.000). At baseline, the mean NEI VFQ-25 total score was 71 ± 14%, and improved to 81 ± 13% (p = 0.000) on the 8th injection. The most significant score gain was recorded in the near VA subscale (+ 20 ± 14%, p = 0.000). There was no statistically significant difference between DME and RVO group in the questionnaire or near VA outcomes.ConclusionAflibercept treatment resulted in a remarkable improvement of near vision by 4 lines of logMAR optotype after the 8th application. The near vision questionnaire subscale, initially scoring the lowest, exhibited the greatest gain during the treatment period. This underscores the importance of near vision and reading ability for patients with DME and RVO.

Effects of ultrasound-assisted dry-curing on water holding capacity and tenderness of reduced‑sodium pork by modifying salt-soluble proteins

This study investigated the effects of ultrasound-assisted dry-curing (UADC) on water holding capacity (WHC) and tenderness of pork at different powers and times, and the mechanism was discussed by considering the functional and structural properties of salt-soluble proteins (SSP). The results showed the application of appropriate UADC treatments (300 W, 60 min) have disruptively affected the muscle structure and decreased the size of the SSP particles (P < 0.05), resulting in the increased concentration of active sulfhydryl and surface hydrophobicity (P < 0.05). These modifications facilitated the dissociation of the myofibrillar structure and the dissolution of more connected proteins, which in turn improved the WHC and tenderness of the pork (P < 0.05). Nevertheless, extended periods of high-power UADC treatments negatively affected the WHC and tenderness of dry-cured pork (P < 0.05). In general, using SSP modified by UADC provides a novel strategy for enhancing the WHC and tenderness of dry-cured products.

Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis, Bowen's Disease, and Squamous Cell Carcinoma: A Systematic Review.

Actinic keratoses (AK) are premalignant skin lesions caused by chronic sun exposure, topically managed by 5-fluorouracil (5-FU), diclofenac 3% gel, and imiquimod. Despite their effectiveness, long treatment duration and severe adverse local skin reactions have limited patient concordance. Calcipotriol has recently been used as a combination agent for existing topical AK treatments. A systematic review was performed to determine the clinical efficacy of 5-FU and calcipotriol for the treatment of AK, Bowen's disease, and squamous cell carcinoma (SCC). A systematic literature search was conducted on Medline, Embase, and Cochrane Library. Among the 84 records screened, 12 were retrieved for full-text review and 8 were included in the final analysis. Among the 8 studies, there were 214 control patients and 288 patients who received the intervention. The combination 5% 5-FU with calcipotriol resulted in a significant reduction in the number of AKs on the face, scalp, right upper extremity, and left upper extremity for all sites at 8 weeks (P < .0001). No significant difference in SCC incidence was observed at 1 or 2 years, but there was a significant reduction observed at 3 years for SCC on face and scalp. No study assessed the combination for Bowen's disease. Combination 5% 5-FU with calcipotriol is an effective treatment for Aks; however, future trials may consider longer treatment and follow-up periods for the treatment and prevention of AK, SCC in situ, and SCC.