12-week Regimen Research Articles

Long Term Patient Reported Quality of Life Outcomes and Patient Satisfaction of 1-Week Hypofractionated Whole Breast Radiation Therapy Using IMRT for Early-Stage Breast Cancer

Novel whole breast radiation therapy (WBRT) regimens have been recently reported with the aim of improving patient convenience while preserving local control and breast cosmesis. The UK FAST Forward trial showed that 26 Gy in 5 fx using 3D conformal WBRT was equivalent to the standard 3-week regimen. However, the use of inverse planned intensity modulated radiation therapy (IMRT) for this novel ultra-hypofractionated regimen has not been previously studied. We aim to study the patient reported quality of life (QOL) outcomes and patient satisfaction of WBRT using IMRT delivering 26 Gy in 5 fractions. Patients receiving WBRT with 26 Gy in 5 fractions using IMRT at our institution from 2020 to 2022 were included. Patients were treated with 26 Gy in 5 daily fx with or without a single fx boost of 4-5.2 Gy. IMRT plans were generated using inverse planning with 2 to 3 volumetric modulated arcs (VMAT). To assess patient-reported QOL outcomes, a questionnaire was prospectively administered at 1 month post treatment and yearly thereafter including the EORTC QLQ-BR23 breast cancer module and other patient satisfaction questions. Patient assessment involved a four-point scale (not at all, a little, quite a bit, and very much; very satisfied, moderately satisfied, moderately dissatisfied, and very dissatisfied). Here, we report the 1-year patient reported acute toxicity QOL outcomes and patient satisfaction for those undergoing IMRT based WBRT. Cross-sectional analyses were used to determine the prevalence of "quite a bit" or "very much" effects versus "not at all" or "a little" effects. A total of 96 patients were included. The median age at diagnosis was 65 years. The most common histology was invasive ductal carcinoma (53.1%). ER-positivity was found in 75.5% patients. Oncoplastic reconstruction was used in 51.0% patients. The median tumor size was 1.5 cm. There were 4/98 (4.3%) node positive patients and 22.5% received adjuvant chemotherapy. Endocrine therapy was used in 74.5% patients. A boost fraction was delivered in 95.9% patients. At the 1-year assessment, only 1/35 (2.9%), 2/35 (5.7%), and 4/35 (11.4%) patients reported "quite a bit" or "very much" breast pain, skin problems, and changes in breast appearance respectively. Additionally, 32/35 (91.4%) patients were either "very satisfied" or "moderately satisfied" with their treatment, while 32/35 (91.4%) patients reported "excellent" (n = 12) or "good" (n = 20) physical appearance of the breast. WBRT using inverse planned IMRT with 26 Gy in 5 fx shows excellent patient reported QOL and patient satisfaction at 1-year post RT. Longer follow up is needed to assess the long-term toxicity, normal tissue effects, and cosmetic outcomes of IMRT based delivery of this ultra-hypofractionated regimen.

Developing an Electroencephalography-Based Model for Predicting Response to Antidepressant Medication

Untreated depression is a growing public health concern, with patients often facing a prolonged trial-and-error process in search of effective treatment. Developing a predictive model for treatment response in clinical practice remains challenging. To establish a model based on electroencephalography (EEG) to predict response to 2 distinct selective serotonin reuptake inhibitor (SSRI) medications. This prognostic study developed a predictive model using EEG data collected between 2011 and 2017 from 2 independent cohorts of participants with depression: 1 from the first Canadian Biomarker Integration Network in Depression (CAN-BIND) group and the other from the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) consortium. Eligible participants included those aged 18 to 65 years who had a diagnosis of major depressive disorder. Data were analyzed from January to December 2022. In an open-label trial, CAN-BIND participants received an 8-week treatment regimen of escitalopram treatment (10-20 mg), and EMBARC participants were randomized in a double-blind trial to receive an 8-week sertraline (50-200 mg) treatment or placebo treatment. The model's performance was estimated using balanced accuracy, specificity, and sensitivity metrics. The model used data from the CAN-BIND cohort for internal validation, and data from the treatment group of the EMBARC cohort for external validation. At week 8, response to treatment was defined as a 50% or greater reduction in the primary, clinician-rated scale of depression severity. The CAN-BIND cohort included 125 participants (mean [SD] age, 36.4 [13.0] years; 78 [62.4%] women), and the EMBARC sertraline treatment group included 105 participants (mean [SD] age, 38.4 [13.8] years; 72 [68.6%] women). The model achieved a balanced accuracy of 64.2% (95% CI, 55.8%-72.6%), sensitivity of 66.1% (95% CI, 53.7%-78.5%), and specificity of 62.3% (95% CI, 50.1%-73.8%) during internal validation with CAN-BIND. During external validation with EMBARC, the model achieved a balanced accuracy of 63.7% (95% CI, 54.5%-72.8%), sensitivity of 58.8% (95% CI, 45.3%-72.3%), and specificity of 68.5% (95% CI, 56.1%-80.9%). Additionally, the balanced accuracy for the EMBARC placebo group (118 participants) was 48.7% (95% CI, 39.3%-58.0%), the sensitivity was 50.0% (95% CI, 35.2%-64.8%), and the specificity was 47.3% (95% CI, 35.9%-58.7%), suggesting the model's specificity in predicting SSRIs treatment response. In this prognostic study, an EEG-based model was developed and validated in 2 independent cohorts. The model showed promising accuracy in predicting treatment response to 2 distinct SSRIs, suggesting potential applications for personalized depression treatment.

Impacts of an 8-week regimen of aged garlic extract and aerobic exercise on the levels of Fetuin-A and inflammatory markers in the liver and visceral fat tissue of obese male rats

Obesity-induced chronic low-grade systemic inflammation is linked to the development of numerous diseases. Fetuin-A is known to affect inflammation and insulin resistance in obesity conditions. Free fatty acid (FFA)-induced proinflammatory cytokine expression in adipocytes occurs only in the presence of both Fetuin-A and toll-like receptor 4 (TLR4) and removing either of them prevented FFA-induced insulin resistance. Aged garlic extract (AGE) and exercise training have anti-inflammatory effects; however, the impact of AGE on Fetuin-A is unknown. We examined the effects of AGE with or without aerobic training (AT) on Fetuin-A and inflammatory markers. Forty healthy male Sprague Dawley rats were randomly assigned to normal diet (ND) (n=8) or high-fat diet (HFD) groups (n=32) and fed for 9 weeks. After 9 weeks ND group continued normal diet, and the HFD group was randomly assigned to the HFD, HFD+AGE (600mg/kg, once daily), HFD+AT (5 days/week), and HFD+AGE+AT groups that were continued for 8 weeks (n=8). The significance of differences among groups was assessed using one-way analysis of variance followed by the post-hoc Tukey test. Statistically significant differences were considered for p<0.05. AGE, AT, and AGE+AT significantly decreased body weight, plasma Fetuin-A, HOMA-IR, mRNA and protein levels of Fetuin-A and NFƙB in the liver and mRNA and Protein levels of Fetuin-A, TLR4 and NFƙB in visceral adipose tissue (VAT) compared to HFD. However, only AGE+AT significantly decreased TLR4 protein levels in the liver. Although AT and AGE reduce Fetuin-A and inflammatory markers, a combination of the two may be more effective at lowering inflammation.

Comparison of the efficacy of two different glucocorticoid regimens for treatment of active moderate-to-severe Graves' orbitopathy.

Intravenous glucocorticoids (GCs) are the mainstay of treatment for severe forms of Graves' orbitopathy (GO). Our aim was to assess the effectiveness and safety of a modified monthly regimen (mMR) and to compare them with those of the established weekly regimen (WR). This was a prospective non-randomized single-center study involving 62 patients, divided into two therapeutic groups depending on their referral time. Thirty-one subjects, admitted in the period 2017-2018, were treated with mMR, total dose-5.5g, with intake of oral GCs after completion of intravenous infusions. Thirty subjects, who were referred in the period 2019-2020, were treated with WR, total dose-4.5g One patient refused to be part of the WR group and was treated with mMR. Eye status and therapeutic response were evaluated on the 1st, 3rd and 6th months, quality of life-at 3rd and 6th month. At 1st month and 3rd month, there was no significant difference in the therapeutic response between the two groups. At 3rd month, the proportion of patients with improvement in soft tissue manifestations and subjective complaints was significantly higher in mMR group (65.6% vs. 40% and 81.3% vs. 46.7%, respectively) and the same manifestations were of significantly milder degree. At 3rd month, significant improvement in quality of life was found without significant difference between the two groups. At 6th month, worsening of GO occurred in 3 patients from WR group, while in 5 patients from mMR group further improvement was found. The two GC regimens have comparable efficacy with small differences in the time of onset of the effect and its duration, as well as in the effectiveness on some ocular manifestations. Trial registration number NCT05793359/29.03.2023, retrospectively registered..

Higher training loads affect sleep in endurance runners: Can a high-heat-capacity mattress topper mitigate negative effects?

ABSTRACT This study investigates the impact of a training program on sleep among endurance runners and the benefits of chronically using a high-heat-capacity mattress topper (HMT). Twenty-one trained male athletes performed a 2-week usual training regimen, sleeping on a Low-heat-capacity Mattress Topper (LMT), followed by 2-week overload and taper periods. From overload, participants were assigned into two groups based on the mattress topper used: HMT (n = 11) or LMT (n = 10). Irrespective of the group, overload increased general stress and stress-reaction symptoms evaluated by questionnaires, with no decline in performance on a graded-exercise treadmill test, the majority of participant being “non-overreached” (n = 14). From a daily perspective, each additional 100 A.U. in training load, assessed using the session rating of perceived exertion, was associated with an impairment in subsequent sleep efficiency (β = -0.2%; p < 0.01), wake after sleep onset (β = +0.4 min; p < 0.05) and sleep onset latency (β = +0.5 min; p < 0.05), which was unaffected by HMT use. Practitioners should be aware of sleep needs, especially during excessive training loads, whereas implementing individualised sleep strategies. Further studies should be conducted on potential benefits of HMT among athletes in various sleep conditions.

Efficacy, safety, and tolerability of albendazole and ivermectin based regimens for the treatment of microfilaraemic loiasis in adult patients in Gabon: A randomized controlled assessor blinded clinical trial.

There is a lack of systematic evidence for strategies to control loiasis transmission in highly endemic regions. Here we assessed albendazole and ivermectin based treatment regimens to reduce Loa loa microfilaraemia in Gabon. Eligible adult patients with L. loa microfilaraemia between 5,000 and 50,000 microfilariae/ml were randomized to either a control or one of three intervention groups (1:2:2:2 allocation ratio) consisting of three-week twice daily 400mg oral albendazole followed by 1) no treatment, 2) two further weeks of twice daily 400mg albendazole, or 3) a single dose of ivermectin in this open label randomized assessor blinded controlled clinical trial. The primary outcome was the proportion of participants with L. loa microfilaraemia ≤ 100 mf/ml at Day 168. In the efficacy-population of 42 patients 0 (0%; control group), 1 (9%; 3-week albendazole), 5 (39%; 5-weeks albendazole) and 2 (22%; 3-week albendazole plus single dose ivermectin) participants met the primary outcome of microfilaraemia below 100/ml at day 168. A 80-90% reduction of microfilaraemia was observed in the active treatment groups. The 5-week regimen of albendazole or a 3-week regimen of albendazole followed by ivermectin were most efficacious to reduce microfilaraemia. All therapeutic regimens were well tolerated and safe. Trial registered at the Pan-African Clinical Trials Registry: PACTR201807197019027.

Impact of probiotics on gut microbiota composition and clinical symptoms of coeliac disease patients following gluten-free diet

Coeliac disease (CD) is associated with alterations in gut microbiota composition. This study evaluated the effects of probiotics on gut microbiota composition and clinical symptoms of treated CD patients. In this double-blind, placebo-controlled trial study, 31 CD patients that were randomly classified as probiotics (n = 15) and placebo (n = 16) groups received 109 colony-forming units/capsule for 12 weeks. Fecal samples were collected before and after probiotics, or placebo administration and the changes in intestinal microbiota were assessed by quantitative real-time PCR. Probiotic administration improved the patients' clinical symptoms when compared to the placebo group. Fatigue score was significantly reduced by the intake of probiotic supplements (P = 0.02). Except for Staphylococcus spp., the relative abundances of Bacteroidetes, Lactobacillus spp., Bifidobacterium spp., Clostridium cluster I, Enterobacteriaceae, and Firmicutes were higher in probiotics group. Accordingly, a 12-week multi-strain probiotic treatment regimen may modify the composition of intestinal microbiota and improve GI symptoms in CD patients.

Step-in dosing of bosutinib in pts with chronic phase chronic myeloid leukemia (CML) after second-generation tyrosine kinase inhibitor (TKI) therapy: results of the Bosutinib Dose Optimization (BODO) Study

The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bosutinib Dose Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2nd or 3rd line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II–IV, primary study endpoint) to < 40% (overall rate of 60%; 95% CI: 45–74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926.

Glecaprevir-pibrentasvir for 4 weeks among people with recent HCV infection: The TARGET3D study

Short duration treatment may aid HCV elimination among key populations. This study evaluated the efficacy of glecaprevir-pibrentasvir for 4 weeks among people with recent HCV infection. In this single-arm multicentre international trial, adults with recent HCV (duration of infection <12 months) received glecaprevir-pibrentasvir 300mg-120 mg daily for 4 weeks. Primary infection was defined as a first positive anti-HCV antibody and/or HCV RNA measurement within 6 months of enrolment and either acute clinical hepatitis within 12 months (symptomatic illness or alanine aminotransferase >10x the upper limit of normal) or antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within 6 months and prior clearance (spontaneous or treatment). The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12) in the intention-to-treat (ITT) and per-protocol (PP) populations. Twenty-three participants (96% men, 70% HIV, 57% ever injected drugs) received treatment, of whom 74% had genotype 1a infection and 35% recent reinfection. At baseline, median duration of infection was 17 weeks (IQR 11-29) and HCV RNA was 5.8 log10IU/ml (IQR 5.2-6.9). SVR12 was achieved by 78% (18/23; 95% CI 56-93%) and 82% (18/22; 95% CI 60-95%) of the ITT and PP populations, respectively, and in 100% (12/12; 95% CI 74-100%) of participants with baseline HCV RNA ≤6 log10. There were four cases of virological failure (relapse); three received retreatment with 12 weeks sofosbuvir-velpatasvir or grazoprevir-elbasvir (SVR, n= 2; loss to follow-up, n= 1). No serious adverse events were reported. While most achieved SVR, the efficacy of a 4-week regimen of glecaprevir-pibrentasvir was lower than observed with longer treatment durations (≥6 weeks) among people with recent HCV. Clinicaltrials.gov Identifier: NCT02634008. Short duration treatment may aid HCV elimination among key populations. This investigator-initiated single-arm multicentre international pilot trial demonstrated that efficacy of glecaprevir-pibrentasvir for 4 weeks among people with recent HCV infection was sub-optimal (SVR12 78% ITT, 82% PP). Baseline HCV RNA appeared to impact response, with higher efficacy among participants with lower baseline HCV RNA (≤6 log10; SVR12 100% ITT, 12/12). While most achieved SVR, the efficacy of 4 weeks of glecaprevir-pibrentasvir was below that seen with longer treatment durations (≥6 weeks).

Dietary interventions improve diabetic kidney disease, but not peripheral neuropathy, in a db/db mouse model of type 2 diabetes.

Patients with type 2 diabetes often develop the microvascular complications of diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN), which decrease quality of life and increase mortality. Unfortunately, treatment options for DKD and DPN are limited. Lifestyle interventions, such as changes to diet, have been proposed as non-pharmacological treatment options for preventing or improving DKD and DPN. However, there are no reported studies simultaneously evaluating the therapeutic efficacy of varying dietary interventions in a type 2 diabetes mouse model of both DKD and DPN. Therefore, we compared the efficacy of a 12-week regimen of three dietary interventions, low carbohydrate, caloric restriction, and alternate day fasting, for preventing complications in a db/db type 2 diabetes mouse model by performing metabolic, DKD, and DPN phenotyping. All three dietary interventions promoted weight loss, ameliorated glycemic status, and improved DKD, but did not impact percent fat mass and DPN. Multiple regression analysis identified a negative correlation between fat mass and motor nerve conduction velocity. Collectively, our data indicate that these three dietary interventions improved weight and glycemic status and alleviated DKD but not DPN. Moreover, diets that decrease fat mass may be a promising non-pharmacological approach to improve DPN in type 2 diabetes given the negative correlation between fat mass and motor nerve conduction velocity.

Delivering a Home-Based Exercise Program to Youth With Osteogenesis Imperfecta: Protocol for a Comparative-Approach Study

Background Osteogenesis imperfecta (OI) is a rare bone fragility disorder associated with muscle weakness. Individuals with OI may therefore benefit from exercise interventions aiming to improve muscle and bone strength. Given the rarity of OI, many patients do not have access to exercise specialists who are familiar with the disorder. As such, telemedicine, the provision of health care through technology to provide care at a distance, may be well suited for this population. Objective The main objectives are (1) to investigate the feasibility and cost-effectiveness of 2 telemedicine approaches for the delivery of an exercise intervention for youth with OI and (2) to assess the impact of the exercise intervention on muscle function and cardiopulmonary fitness in youth with OI. Methods Patients with OI type I (the mildest form of OI; n=12, aged 12-16 years) from a pediatric orthopedic tertiary hospital will be randomized to receive a 12-week remote exercise intervention in either (1) a supervised group (n=6), monitored every session, or (2) a follow-up group (n=6), receiving monthly progress update appointments. Participants will undergo the following pre- and postintervention evaluations: sit-to-stand test, push-up test, sit-up test, single-legged balance test, and a heel-rise test. Both groups will be given the same 12-week exercise regimen, which includes cardiovascular, resistance, and flexibility training. For each exercise training session involving the supervised group, a kinesiologist will provide instructions to participants through live video sessions using a teleconferencing application. On the other hand, the follow-up group will discuss their progress with the kinesiologist every 4 weeks over a teleconferencing video call. Feasibility will be assessed by recruitment, adherence, and completion rates. A cost-effectiveness analysis of both approaches will be computed. Changes in muscle function and cardiopulmonary fitness will be examined between the 2 groups, pre- and postintervention. Results It is anticipated that the supervised group will have higher adherence and completion rates compared to the follow-up group, which may be associated with greater physiological benefits; however, it may not be as cost-effective compared to the follow-up approach. Conclusions By determining the most feasible telemedicine approach, this study may serve as a basis for providing increased access to specialized adjunct therapies for individuals with rare disorders. International Registered Report Identifier (IRRID) PRR1-10.2196/40262

Side-by-side Comparative Study of the Immunogenicity of the Intramuscular and Intradermal Rabies Post-exposure Prophylaxis Regimens in a Cohort of Suspected Rabies Virus Exposed Individuals.

All World Health Organization (WHO) pre-qualified rabies vaccines for humans are inactivated tissue culture rabies virus formulations produced for intramuscular (IM) administration. Due to costs and vaccine shortage, dose-saving intradermal (ID) administration of rabies post-exposure prophylaxis (PEP) is encouraged by WHO. This study compared the immunogenicity of the ID 2-site, 3-visit Institut Pasteur Cambodge (IPC) PEP regimen to the IM 1-site, 4-visit 4-dose Essen regimen using Verorab vaccine (Sanofi). The development of neutralizing antibodies (nAbs) and T cell response was assessed in 210 patients with a category II or III animal exposure in a rabies-endemic country. At day 28, all participants developed nAbs (≥0.5 IU/mL), irrespective of PEP scheme, age, or administration of rabies immunoglobulin. T cell response and nAb titers were similar for both PEP schemes. This study demonstrated that the 1-week ID IPC regimen is as effective as the 2-week IM 4-dose Essen regimen in inducing an anti-rabies immune response under real-life PEP.

438 Potentially greater efficacy with CBP-201 for adults with severe vs. moderate atopic dermatitis at baseline: subgroup analyses from the WW001 phase 2 randomized trial

Abstract CBP-201 is a next-generation monoclonal antibody targeting the IL-4Rα subunit. Rapid efficacy with CBP-201 was demonstrated in global phase 2 (WW001) and China-only pivotal trials (CN002) in patients with moderate-to-severe atopic dermatitis (AD). Previous studies of AD therapy demonstrated similar efficacy between moderate and severe disease, with a trend toward greater improvement in moderate patients. It is unknown whether there are differences in clinical response to CBP-201 with moderate vs.severe AD. We report post hoc efficacy analyses at Week 16 with CBP-201 300 mg from WW001 in baseline severity subgroups, based on validated Investigator Global Assessment (vIGA™) scores of 3 (moderate) and 4 (severe). In WW001 (NCT04444752), adults with moderate-to-severe AD were enrolled in a RDBPC 16-week trial of subcutaneous CBP-201 or placebo. For post hoc analysis, data for 300 mg every 2- and 4-week dose regimens were pooled. Investigators assessed AD severity using Eczema Area and Severity Index (EASI), SCORing AD (SCORAD), percent Body Surface Area (BSA) of AD involvement and vIGA. Patient-reported outcomes were assessed with the Dermatology Life Quality Index (DLQI) and Patient Oriented Eczema Measure (POEM). Least squares mean (LSM) score changes were analysed using ANCOVA modeling (including treatment, baseline score and baseline vIGA), with missing data interpolated by last observation carried forward. Responder endpoints were analysed using Clopper–Pearson methodology and, for missing values, nonresponder imputation. P-values are for CBP-201 vs. placebo, per baseline severity subgroup, at Week 16. At baseline, 113 patients had moderate AD (n = 74 CBP-201, n = 39 placebo) and 56 patients had severe AD (n = 39 CBP-201, n = 17 placebo). Baseline EASI scores were lower in the moderate subgroup [mean (SD): CBP-201, 21.5 (7.0); placebo, 22.2 (6.3)] vs. the severe subgroup [CBP-201, 33.6 (11.9); placebo, 31.9 (10.8)]. In both the moderate and severe AD subgroups, significant improvements with CBP-201 vs. placebo were observed. Except for the proportion of patients achieving vIGA 0/1, numerically greater CBP-201 responses were observed in patients with severe vs. moderate AD at Week 16; placebo responses were comparable per subgroup. In the severe and moderate subgroups, LSM SCORAD scores decreased by −42.8% (severe) and −29.8% (moderate), and LSM percent BSA decreased by −29.8% and −17.3%, respectively. Clinically meaningful 2-point improvement in vIGA was reported for 48.7% and 27.0% of patients with severe and moderate AD, respectively. The proportions of patients achieving vIGA 0/1, with 2-point improvement, were 20.5% and 27.0% with severe and moderate AD, respectively. Numerically greater proportions of patients with severe vs. moderate AD experienced EASI responses with CBP-201: EASI-50, 66.7% vs. 54.1%; EASI-75, 53.8% vs. 39.2%; EASI-90, 28.2% vs. 23.0%. Patients with severe vs. moderate AD reported greater improvements in patient reported outcomes with CBP-201: DLQI, −8.7 vs. −7.0; POEM, −12.5 vs. −8.7. Clinically meaningful improvements were observed in patients with AD with either moderate or severe AD after 16 weeks of treatment with CBP-201 300 mg at either 2- or 4-week dosing. There were no differences noted between moderate and severe patients in the placebo treatment group. In most severity readouts, greater proportions of patients with AD with severe disease on study entry experienced clinically meaningful improvements with CBP-201. In future CBP-201 trials, a more severe AD population needs to be examined to determine if this same observation is also noted. Collectively, the WW001 findings support further investigation of CBP-201, at both the 2- and 4-week dosing schedules enrolling larger numbers of moderate and severe patients with AD and with prespecified analyses by baseline AD severity.

Repeated-sprint training in hypoxia boosts up team-sport-specific repeated-sprint ability: 2-week vs 5-week training regimen.

To investigate (1) the boosting effects immediately and 4 weeks following 2-week, 6-session repeated-sprint training in hypoxia (RSH2-wk, n = 10) on the ability of team-sport players in performing repeated sprints (RSA) during a team-sport-specific intermittent exercise protocol (RSAIEP) by comparing with normoxic counterpart (CON2-wk, n = 12), and (2) the dose effects of the RSH by comparing the RSA alterations in RSH2-wk with those resulting from a 5-week, 15-session regimen (RSH5-wk, n = 10). Repeated-sprint training protocol consisted of 3 sets, 5 × 5-s all-out sprints on non-motorized treadmill interspersed with 25-s passive recovery under the hypoxia of 13.5% and normoxia, respectively. The within- (pre-, post-, 4-week post-intervention) and between- (RSH2-wk, RSH5-wk, CON2-wk) group differences in the performance of four sets of RSA tests held during the RSAIEP on the same treadmill were assessed. In comparison with pre-intervention, RSA variables, particularly the mean velocity, horizontal force, and power output during the RSAIEP enhanced significantly immediate post RSH in RSH2-wk (5.1-13.7%), while trivially in CON2-wk (2.1-6.2%). Nevertheless, the enhanced RSA in RSH2-wk diminished 4 weeks after the RSH (-3.17-0.37%). For the RSH5-wk, the enhancement of RSA immediately following the 5-week RSH (4.2-16.3%) did not differ from that of RSH2-wk, yet the enhanced RSA was well-maintained 4-week post-RSH (0.12-1.14%). Two-week and five-week RSH regimens could comparably boost up the effects of repeated-sprint training in normoxia, while dose effect detected on the RSA enhancement was minimal. Nevertheless, superior residual effects of the RSH on RSA appear to be associated with prolonged regimen.

#4623 A NOVEL ELECTRO-HYDRAULIC ACOUSTIC THERAPY REDUCES BLOOD PRESSURE IN HYPERTENSIVE PATIENTS WITH CHRONIC KIDNEY DISEASE: PRELIMINARY RESULTS

Abstract Background and Aims Arterial hypertension (HTN) in association with chronic kidney disease (CKD) is a global healthcare burden, yet clinically proven treatments are limited. electro-Hydraulic Acoustic Therapy (eHAT), using ∼10% of the energy used in shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. eHAT has been demonstrated to enhance healing in tissues such as bone, muscle, and myocardium, via several mechanisms, particularly by promoting neovascularization. Furthermore, previous animal studies demonstrated that eHAT reduces blood pressure (BP) and preserves renal function after ischemic kidney injury. The present pilot study explored the clinical safety and efficacy of eHAT and tested the hypothesis that eHAT would reduce BP and preserve renal function in patients with medically-treated hypertension and CKD. Method So far, a total of 15 patients with HTN and Stage III a/b CKD were enrolled in this prospective, single-arm study. The patients were treated with six sessions of eHAT during a 3-week period. At each session, 2400 shockwaves were applied to each kidney with 0.09 mJ/mm2 at 2.66Hz (NephrospecTM by Curespec LTD, Yehud, Israel). Follow-up (FU) visits were performed at 1, 3, and 6 months. Results The treatment was well tolerated with no major adverse events or need for analgesic treatment. Average Automated Office BP (AOBP) showed a strong tendency for a decrease in diastolic BP from baseline to the Primary Efficacy Objective at FU II (3 months post last treatment), which progressively decreased further at FU III (6 months) (Table 1). Similarly, average Office BP (OBP) detected a strong trend for a progressive decrease in systolic BP from baseline to the Primary Efficacy Objective (Table 1). Levels of eGFR appeared to slightly rise throughout the study, but this change has not reached statistical significance levels (Table 1). Conclusion The current study demonstrates that the eHAT procedure is tolerable and safe in this cohort. Moreover, a 3-week regimen tended to reduce BP and preserve eGFR in patients with controlled HTN and CKD. Therefore, electro-Hydraulic Acoustic Therapy may emerge as a novel, safe, and non-invasive alternative therapeutic approach in the management of HTN in the context of CKD.

Eblasakimab, a novel IL-13 receptor alpha 1 monoclonal antibody, blocks STAT6 phosphorylation with low dose in human volunteers

Eblasakimab is a first-in-class monoclonal antibody under investigation for the treatment of atopic dermatitis (AD), which targets IL-13Rα1, a subunit of the Type 2 receptor complex. IL-13Rα1 stimulates phosphorylation of signal transducer and activator of transcription 6 (STAT6) to drive inflammation. This brief report investigates the mechanistic basis of eblasakimab and its effects on IL-13Rα1 signaling as part of a phase 1a, open-label, single ascending dose study. Single ascending doses of eblasakimab were administered by intravenous or subcutaneous injection to healthy male volunteers. The impact of eblasakimab on IL-13Rα1 receptor occupancy and STAT6 phosphorylation was assessed in participant blood monocytes. No serious treatment emergent adverse events were reported. Eblasakimab effectively blocked the IL-13Rα1 receptor and inhibited STAT6 phosphorylation with single doses of 3 mg/kg intravenously and 300 mg subcutaneously. Results support further clinical development of eblasakimab as a novel biologic for AD, with potential for 2- to 4-week dosing regimens.

Phase 2 study of ISA101b (peltopepimut-S) and cemiplimab in patients with advanced HPV16+ oropharyngeal cancer who failed anti-PD1 therapy.

6028 Background: ISA101b (peltopepimut-S), a therapeutic vaccine against the HPV-specific E6/E7 oncoproteins, induces specific expansion of HPV16 targeted T-cells when given together with cemiplimab, an anti-PD-1 agent. Previously we showed that ISA101 with nivolumab achieved a higher response rate compared to immune checkpoint inhibitor (ICI) alone in trials for patients with recurrent/metastatic (R/M) HPV16+ oropharyngeal cancer (OPC)1,2. Methods: In this single arm phase 2 study, patients with R/M HPV16+ OPC with progressive disease (PD) within 6 months after prior 1st or 2nd line anti-PD-1 ICI were treated with ISA101b (subcutaneously 100µg/peptide on days 1, 29, and 50) with cemiplimab (intravenously 350mg as a 3-weekly regimen) until PD. Patients without PD at 6 months were offered a booster ISA101b injection. HPV16 positive tumor status was confirmed by a central reference laboratory with an established PCR assay. The primary efficacy endpoint was defined as overall response rate (ORR) as per RECIST1.1. An analysis was planned at the end of Stage 1, when 26 patients who had received at least one dose of ISA101b had been followed for 6 months. The cut-off date for this analysis, approved by the DSMB, was 31 January 2023. Results: Twenty-six patients (mean age 60.7 ±12.9 years; 22 (84.6%) male and 4 (15.4%) female) enrolled in Stage 1. Median follow-up was 16.2 weeks (range 1.6-78.8). Three patients were confirmed with partial response (PR) (11.5%); two of the 3 patients with PR never responded to previous ICI treatment. In 13 patients (50.0%) best overall response (BOR) was stable disease (SD); in 8 patients (30.8%) BOR was PD. Two (7.7%) patients did not have a tumor assessment after baseline: one patient died on day 8 due to OPC and one patient withdrew consent shortly after enrolment. The clinical benefit ratio (CBR) was 61.5%. Nine (34.6%) patients received a booster injection. At the time of the booster, 2 patients had PR and 5 patients had meaningful (≥6 months) SD. Time to response ranged between 127 and 307 days. Median duration of study treatment was 13.1 weeks (range 1.1-75.9), with 4 patients still on treatment. There were two grade 3 adverse events (AEs) related to ISA101b: erythema at the injection site and diarrhea. Two patients (7.7%) had grade 3 ICI-related auto-immune events. Grade 4-5 AEs related to study treatment did not occur. Median overall survival was 8.1 months (range 0.3-17.5). Conclusions: This treatment appears promising for HPV16+ OPC patients who failed prior anti-PD-1 ICI therapy, with an ORR of 11.5% and a CBR of 61.5%. In this small, ongoing study the combination of cemiplimab and ISA101b was well tolerated with a safety profile resembling anti-PD-1 monotherapy. This is the first study of the combination of ISA101b and cemiplimab in 2nd/3rd line R/M anti-PD-1 refractory OPC patients. 1Massarelli E. JAMA Oncol 2019 2de Sousa LG. J Immunother Cancer 2022. Clinical trial information: NCT04398524 .

First-in-human phase 1/2 study of ubamatamab, a MUC16xCD3 bispecific antibody, administered alone or in combination with cemiplimab in patients with recurrent ovarian cancer.

TPS5624 Background: Mucin-16 is a cell surface glycoprotein that is overexpressed in epithelial ovarian cancer (OC). Ubamatamab (REGN4018) is a mucin-16 x cluster of differentiation 3 (MUC16xCD3) bispecific antibody that promotes T cell–mediated cytotoxicity by facilitating contact between cancer cells and T cells. In mouse model studies, ubamatamab demonstrated dose-dependent antitumor activity against MUC16-expressing OC tumor cells.1 Cemiplimab is an anti–programmed cell death-1 monoclonal antibody. In a Phase 1 study (NCT03564340) in patients with recurrent OC, ubamatamab monotherapy demonstrated an acceptable safety profile, durable clinical activity across a range of doses between 20 mg and 800 mg intravenous (IV) weekly (as measured by RECIST and cancer antigen 125 [CA-125] response rates), and linear pharmacokinetics up to 800 mg IV weekly.2 These clinical data support further evaluation of a once every 3-week (Q3W) regimen of ubamatamab alone and in combination with cemiplimab. The study is currently recruiting patients to combination dose escalation, monotherapy dose expansion, and the randomized Phase 2 cohort. Methods: In Phase 2, up to 150 patients with advanced platinum-resistant OC and elevated serum cancer antigen-125 will be randomized to three arms (1:1:1) to receive ubamatamab 250 mg IV Q3W or 800 mg IV Q3W as monotherapy, or ubamatamab 250 mg IV Q3W in combination with cemiplimab 350 mg Q3W. All arms will include weekly step-up dosing of ubamatamab (1 mg week 1, 20 mg week 2, and full dose weeks 3 and 4) to limit risk of cytokine release syndrome prior to proceeding to Q3W dosing. Expansion cohorts will use a Simon 2-stage study design, with an interim analysis after the first 20 patients. Any arm with ≥3 objective responses will be expanded to 50 patients. The primary objective of the dose expansion phase is to assess the preliminary efficacy of ubamatamab as monotherapy or in combination with cemiplimab, separately by cohort. Secondary objectives include characterization of the safety profile by cohort, and the pharmacokinetics of ubamatamab alone or in combination with cemiplimab, as well as patient-reported outcomes for all cohorts. In this dose expansion phase the primary endpoint will be the objective response rate for each arm as defined by RECIST 1.1 criteria. Secondary endpoints include evaluation of duration of response and progression-free survival as well as further evaluation of safety and pharmacokinetics. Exploratory endpoints include evaluation of baseline tumor MUC16 immunohistochemistry expression and other biomarkers as predictors of response. The impact of ubamatamab on quality of life and physical functioning will also be assessed.

A NOVEL ELECTRO-HYDRAULIC ACOUSTIC THERAPY REDUCES BLOOD PRESSURE IN HYPERTENSIVE PATIENTS WITH CHRONIC KIDNEY DISEASE: PRELIMINARY RESULTS

Objective: Electro-Hydraulic Acoustic Therapy (eHAT), using ∼10% of the energy used in shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. eHAT has been demonstrated to enhance healing in tissues such as bone, muscle, and myocardium, via several mechanisms, particularly by promoting neovascularization. Furthermore, previous animal studies demonstrated that eHAT reduces blood pressure (BP) and preserves renal function after ischemic kidney injury. The present pilot study explored the clinical safety and efficacy of eHAT and tested the hypothesis that eHAT would reduce BP and preserve renal function in patients with medically-treated hypertension and CKD. Design and method: So far, a total of 15 patients with HTN and Stage III a/b CKD were enrolled in this prospective, single-arm study. The patients were treated with six sessions of eHAT during a 3-week period. At each session, 2400 shockwaves were applied to each kidney with 0.09 mJ/mm2 at 2.66Hz (NephrospecTM by Curespec LTD, Yehud, Israel). Follow-up (FU) visits were performed at 1, 3, and 6 months. Results: The treatment was well tolerated with no major adverse events or need for analgesic treatment. Average Automated Office BP (AOBP) showed a strong tendency for a decrease in diastolic BP from baseline to the Primary Efficacy Objective at FU II (3 months post-last treatment), which progressively decreased further at FU III (6 months) (Table 1). Similarly, average Office BP (OBP) detected a strong trend for a progressive decrease in systolic BP from baseline to the Primary Efficacy Objective (Table 1). Levels of eGFR appeared to slightly rise throughout the study, but this change has not reached statistical significance levels (Table 1). Conclusions: The current study demonstrates that the eHAT procedure is tolerable and safe in this cohort. Moreover, a 3-week regimen tended to reduce BP and preserve eGFR in patients with controlled HTN and CKD. Therefore, electro-Hydraulic Acoustic Therapy may emerge as a novel, safe, and non-invasive alternative therapeutic approach in the management of HTN in the context of CKD.

Repeated Inhalation of Peppermint Essential Oil Improves Exercise Performance in Endurance-Trained Rats.

Peppermint essential oil, being natural and safe, with antioxidant and anti-inflammatory properties, has long been a research interest in relieving fatigue and improving exercise performance. However, the related studies report controversial results, and the mechanisms remain unclear. Here we found that inhalation of peppermint essential oil significantly extended the exhaustion time in rats subjected to 2-week weight-bearing swimming training. Sprague-Dawley rats were subjected to a 2-week weight-loaded forced swimming regimen. Prior to each swimming session, the rats were administered peppermint essential oil via inhalation. An exhaustive swimming test was performed at the end of the protocol. Rats treated with essential oil had significantly extended time to exhaustion compared with exercised rats without essential oil treatment. In addition, treated rats also showed reduced oxidative damage induced by endurance exercise. Notably, the rats receiving two-week essential oil inhalation while not subjected to swimming training did not show improved exercise performance. The findings demonstrate that repeated inhalation of peppermint essential oil enhances the effects of endurance training and improves exercise performance partially by preventing oxidative damage.