Stable Regimen Research Articles

Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.

Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

Successful glucocorticoid withdrawal in Chinese lupus nephritis patients: A single centre experience

ObjectiveTo evaluate the proportion of patients successfully withdrawn from glucocorticoids (GC) in a longitudinal cohort of patients with lupus nephritis over a period of 20 years, clinical and pathological predictors of patients with GC withdrawal and renal outcomes after GC withdrawal were further explored. MethodsPatients with successful GC withdrawal were identified for the cohort, and the following data were collected: demographic characteristics, clinical manifestations, pathological findings at disease onset, flares, and renal outcomes subsequent to GC withdrawal. ResultsThere were 365 patients with lupus nephritis included with a median follow-up of 109.5 (83.5,165.3) months in our cohort. A total of 21 patients (5.8 %) achieved successful GC discontinuation, with a median duration of 7.5 (3,10) years necessary for GC withdrawal. The average duration of GC reduction from 7.5 mg/d to complete withdrawal lasted for approximately 25 months (18,30). Patients in the GC-withdrawal group had a lower prevalence of nephrotic syndrome (NS) at onset (28.5 % vs. 47.3 %, P = 0.035), a higher prevalence of positive anti–double-stranded DNA (anti-dsDNA) antibody (85.7 % vs. 61.6 %, P = 0.028) and more severe endocapillary hypercellularity in the renal histopathology evaluations (3(2.5,3) vs. 3(2,3), P = 0.022). NS at disease onset was an independent risk factor to predict unachievable GC withdrawal (OR 0.296, 95 % CI (0.104,0.842), P = 0.022) by multivariate analysis. With a median follow-up of 34 (20,42) months, none of these patients had flares after GC withdrawal. ConclusionsThe discontinuation of GC therapy in LN patients with complete remission and a stable treatment regimen for at least 5 years was feasible without an increased risk of flares, ESKD or death. Low-dose GC withdrawal necessitates a prolonged duration of time and meticulous monitoring.

Phase 1/2 Study of the Activin Receptor-like Kinase-2 Inhibitor Zilurgisertib (INCB000928, LIMBER-104) As Monotherapy or with Ruxolitinib in Patients with Anemia Due to Myelofibrosis

Introduction:Elevated levels of the iron regulator hepcidin can cause functional iron deficiency anemia. Hepcidin dysregulation is central to anemia of chronic inflammation observed in several malignancies including myelofibrosis (MF). Activin receptor-like kinase-2 (ALK2 [ie, ACVR1]) contributes to MF-associated anemia via hepcidin upregulation. We evaluated the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of zilurgisertib-a potent and selective oral ALK2 inhibitor-in patients (pts) with anemia due to MF. Methods:This ongoing open-label, multicenter, phase 1/2 dose-escalation/expansion INCB 00928-104 study (NCT04455841) is evaluating zilurgisertib alone (treatment group A [TGA]) or with ruxolitinib (RUX; treatment group B [TGB]). Eligible pts are ≥18 years old with primary/secondary MF of intermediate (Int)-1 (TGB only) or Int-2/high-risk (TGA and TGB) per the Dynamic International Prognostic Scoring System (DIPSS) and with anemia, including pts who are transfusion dependent (≥4 units of red blood cell transfusions during the 28 days or 8 weeks before Cycle [C] 1 Day [D] 1 for hemoglobin [Hb] &amp;lt;8.5 g/dL in the absence of bleeding or treatment-induced anemia) or are nontransfusion dependent with symptomatic anemia (Hb &amp;lt;10 g/dL during screening on 3 separate occasions ≥7 days apart and not meeting criteria for transfusion dependence). The zilurgisertib starting dose in TGA was 50 mg once daily (qd), with dose increases of ≤2-fold performed until a grade ≥2 toxicity with reasonable probability of being related to the treatment group was observed; subsequent dose increases were limited to ≤50% until the maximum tolerated dose (MTD) was reached or the recommended doses(s) for expansion were identified. In TGB, pts were on a stable regimen of RUX for ≥12 weeks before initiating zilurgisertib at 100 mg qd. The primary endpoints are safety and tolerability, including determination of dose-limiting toxicities (DLTs) and MTD. Secondary endpoints include efficacy (per anemia response parameters), PK, and PD (hepcidin measurement). Results:A total of36 pts were enrolled at the time of analysis (data cutoff, February 15, 2023), with 20 in TGA and 16 in TGB. Median (range) age was 73 (53-84) years for TGA and 75.5 (54-85) years for TGB; 65% of TGA pts had received prior RUX therapy. Overall, 89% had Int-2 risk DIPSS, and the remainder had high-risk DIPSS (1 in TGA, 3 in TGB). In total, 55% of pts in TGA and 25% in TGB were transfusion dependent at time of enrollment. Median (range) baseline Hb was 7.7 (7-10) g/dL in TGA and 8.0 (5-9) g/dL in TGB. Baseline median (range) hepcidin was high in both cohorts (TGA, 171 [18-535] ng/mL; TGB, 126 [7-421] ng/mL; normal range, 0-50 ng/mL). At the time of analysis, dose escalation was ongoing in both treatment groups. No DLTs occurred in either treatment group, and the MTD had not been reached. Treatment-emergent adverse events (TEAEs) were mainly low grade without apparent dose dependence. Grade ≥3 TEAEs occurred in 11 pts, with thrombocytopenia the most common (n=4). The PK profile for zilurgisertib at steady state was consistent with that observed with previous healthy volunteer studies, with observed time of maximum concentration at 2-4 hours after administration and predicted half-life of approximately 24 hours. Maximum reduction in hepcidin following zilurgisertib dosing in C1D1 was observed at 6-8 hours postdose; the highest doses tested in both TGA and TGB demonstrated more effective maintenance of hepcidin suppression over time compared with lower doses. Among non-transfusion-dependent pts, anemia improvement (Hb increase of ≥1.5 g/dL vs baseline) was observed in both treatment groups (Figure). Among transfusion-dependent pts, anemia response of transfusion independence had not been observed at data cutoff. All pts with anemia improvement have maintained Hb increase in the absence of transfusion and remain on study. Conclusions:Treatment with zilurgisertib monotherapy or in combination with RUX in this pt population was generally well tolerated, with predominantly grade 1/2 TEAEs. Reduced hepcidin levels were observed at all dose levels with both monotherapy and in combination with RUX, with greater control of hepcidin over time observed at higher zilurgisertib doses. Preliminary improvements in anemia were observed in non-transfusion-dependent pts during dose escalation, suggesting potential for therapeutic activity.

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial

Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis. This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965. Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 μmol/L (95% CI 18·6 to 30·6), 20·1 μmol/L (14·8 to 25·3), 11·9 μmol/L (9·2 to 14·7), 22·5 μmol/L (15·9 to 29·1), and 19·0 μmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 μg/L (52·2 to 114.4), 65·5 μg/L (32·1 to 98·9), 62·8 μg/L (33·8 to 91·9), 150·0 μg/L (86·6 to 213.3), and 94·3 μg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment. Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis. Protagonist Therapeutics.

Integration of clinical pharmacists to assist with medication surveillance for patients receiving gender-affirming hormone therapy in a community ambulatory setting within the United States

BackgroundGender-affirming care (GAC) for gender diverse individuals (includes transgender and nonbinary persons) requires a comprehensive approach to medication surveillance, including monitoring and follow-up. Limited access to these health services can present a barrier to follow-up for routine care. Integration of a pharmacist into therapeutic management has shown positive clinical outcomes; however, their involvement with gender-affirming hormone therapy (GAHT), including routine laboratory monitoring, is not well established. ObjectiveThis study aimed to describe the development and implementation of a protocol involving the integration of clinical pharmacists into GAC for gender diverse patients in a community ambulatory setting. Practice descriptionCleveland Clinic’s Center for LGBTQ+ Care is embedded in a primary care practice and has an established protocol for GAHT management. The health system also has an established model that uses pharmacists for the management of patients, within the primary care and specialty clinic settings, under a collaborative practice agreement (CPA). Practice innovationThe medical director of the Cleveland Clinic’s Center for LGBTQ+ Care and the institution’s primary care pharmacists collaborated to propose an update to the CPA to include GAHT monitoring to improve access to routine GAHT follow-up. Evaluation methodsGAHT management was approved to be added to the pharmacist CPA in May of 2022 and the pharmacists started seeing patients in February of 2023. The team opted to start with those patients already established on GAHT for at least 6 months, at least 1 year after transition, and with a primary care provider managing their GAHT. ConclusionAccess to follow-up for individuals receiving GAHT may be improved through the utilization of pharmacist services. The incorporation of a CPA with pharmacists for GAHT management can allow for a multidisciplinary approach once a patient is on a stable regimen, thereby increasing provider access to new patients.

SAT297 Major Immunophenotypic Abnormalities In Patients With Primary Adrenal Insufficiency Of Different Etiology

Abstract Disclosure: H.F. Nowotny: None. T. Marchant Seiter: None. J. Ju: None. A. Gottschlich: None. H. Schneider: None. S. Zopp: None. F. Vogel: None. L. Tschaidse: None. M.K. Auer: None. C. Lottspeich: None. S. Kobold: None. S. Rothenfusser: None. F. Beuschlein: None. M. Reincke: None. L. Braun: None. N. Reisch: None. Background: Increased risk of infection, adrenal crises and a higher mortality rate have been reported for patients with primary adrenal insufficiency (PAI). Such dismal outcomes have been inferred to immune cell dysregulation as a consequence of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid deficiency. Methods: The present cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 patients after bilateral adrenalectomy due to Cushing’s syndrome (BADx), 21 patients with Addison’s disease (AD) and 52 healthy controls. All patients with PAI were on a stable glucocorticoid replacement regimen using a median dose of 25 mg hydrocortisone (IQR 5 mg for BADx and AD and IQR 10 mg for CAH) per day. Heparinized blood samples were processed to isolate peripheral blood mononuclear cells. All samples were processed for analysis of immune cell subsets using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate (PMA)/Ionomycin, as well as analysis of natural killer (NK-) cell cytotoxicity and clock gene expression. Results: Analysis of immune cell profiles revealed reduced percentages of IFNγ-secreting T helper (Th1) in AD (p = 0.0024) and cytotoxic (Tc1) cells in CAH (p = 0.0055) and AD patients (p = 0.0075) compared to controls. Moreover, we observed a downregulation of the percentage of IL-4+ Th2 cells in AD patients (p = 0.0157) and Tc2 cells in AD (p = 0.0154) and CAH patients (p = 0.0012) compared to controls. Th17 and Tc17 cells were also downregulated in patients with AD compared to the other patient groups and controls (p &amp;lt; 0.0001). NK-cell cytotoxicity (NKCC) using bioluminescence measurements was reduced in all subsets of PAI patients compared to controls with the lowest change in patients with CAH (mean specific lysis 57.5% in controls, 21.7% in CAH, -0.5% in AD and -28.7% in BADx). The percentage of activated NK-cells was upregulated in BADx (p = 0.0008) and AD patients (p = 0.0348) compared to controls, also expressed as an increase in CD107a expression as a marker of NK-cell degranulation (BADx p &amp;lt; 0.0001; AD p = 0.0002). While the percentage of NK-cell activating receptor expressing NK-cells did not differ from controls, expression percentage of NK-cell inhibiting receptor CD94 was upregulated in both BADx and AD patients (p &amp;lt; 0.0001). Conclusion: In patients with three different etiologies of PAI, distinct differences in T- and NK-cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight so far unsuspected differences in immune cell composition and NK-cell function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment. Presentation: Saturday, June 17, 2023

THU392 Type B Insulin Resistance: A Rare Cause Of Hypoglycemia

Abstract Disclosure: S.Z. Bhat: None. A. Sidhaye: None. A.H. Hamrahian: None. Introduction: Non-diabetic hypoglycemia in patients with diabetes mellitus is rare. Type B insulin resistance syndrome (TBIRS), caused by insulin receptor antibodies, presents with severe insulin resistance, but can uncommonly result in a hypoglycemic picture. Clinical Case: A 59-year-old woman with a history of SLE, T2DM, and primary hyperparathyroidism was admitted for acute confusion and found to have a POC glucose of 30 mg/dl. Her symptoms improved after IV glucose administration. She was on a stable basal-bolus insulin regimen of 0.8 U/kg/day and had unintentional 100-pound weight loss over 1 year. Significant exam findings included BMI of 29 kg/m2, gingival hyperplasia, and acanthosis nigricans. Aside from insulin, she took no medications strongly associated with hypoglycemia. Labs including CBC, CMP, TFTs, and morning cortisol were normal. HbA1C and adiponectin levels were 7.7%, and 28 µg/ml (5-28), respectively. Given the suspicion of exogenous insulin-mediated hypoglycemia, only correctional insulin was used during hospitalization. She had a repeat hypoglycemic episode on the 2nd day with minimal insulin use. A 72-hour fasting test showed a whole blood glucose of 44 mg/dL with concurrent serum C-peptide of 1.72 ng/mL, serum insulin 55 mIU/L and pro-insulin 21.9 pmol/L 12 hours into fasting. MRCP showed an 11 mm cystic lesion in the pancreas and widespread lymphadenopathy. The CGM noted significant fasting and post-prandial hypoglycemia. Diagnosis of insulinoma was considered unlikely due to persistent post-prandial hyperglycemia. Oral hypoglycemic panel and insulin autoantibodies were negative. The patient’s history of SLE, high-normal adiponectin, history of hyperglycemia and the presence of acanthosis nigricans favored work-up for insulin resistance syndromes. Due to the non-availability of insulin receptor antibody testing in the US, blood work was sent to Dr. Lutz Schomburg’s lab at Institute for Experimental Endocrinology, Berlin, Germany. The patient’serum was positive for insulin receptor antibodies, tested via an immunoassay technique, with elevated binding index (BI) of 248, 251 and 247 on 3 different samples of the patient, and normal binding index in the control sample, leading to the diagnosis of type B insulin resistance syndrome (BI &amp;gt;3 is positive, &amp;gt;10 indicates high positivity). The patient was treated with diet modification and CGM use, with improvement in the frequency of hypoglycemic episodes. She declined immunomodulation therapy. Conclusion: Hypoglycemia is an uncommon presentation of TBIRS and should be considered in the differential of non-diabetic hypoglycemia, particularly in patients with a history of auto-immune disease. The mechanism for hypoglycemia is purported to be an insulin-mimetic effect of insulin receptor antibodies at low titers. Presentation: Thursday, June 15, 2023

SAT665 Effects Of Weight Cycling On Hepatic Protein Carbonylation And Lipid Peroxidation

Abstract Disclosure: M.A. Djalali-Gomez: None. J.A. Bogart: None. S. Duran Ortiz: None. D.E. Berryman: None. J.J. Kopchick: None. E.O. List: None. Over two-thirds of the U.S. population is overweight or obese which has been shown to increase oxidative stress. Oxidative stress damages biological molecules such as lipids, proteins, and DNA, ultimately contributing to the development of numerous diseases including cancer and diabetes. Increasing awareness of the health issues caused by obesity leads many to attempt weight loss. Unfortunately, successful weight loss is usually temporary as an estimated 80% of individuals who lose weight will gain it back within a year. Repeated cycles of weight gain and weight loss are known as weight cycling. While the prevalence of obesity and weight cycling has increased in recent years, research on the long-term health consequences of weight cycling is limited. In the current study, we evaluated how diet stability (i.e., weight-cycled diets vs stable diets) and immediate diet (i.e., diet at the time of tissue collection; high fat vs low fat) affect oxidative stress by measuring hepatic lipid peroxidation and protein carbonylation from mice exposed to long term weight cycling or a stable diet regimen with high or low-fat diets. Our results indicate that the immediate diet significantly impacted hepatic oxidative stress, as mice on a high-fat diet prior to sacrifice had significantly greater levels of hepatic protein carbonylation (p=.020) as well as hepatic lipid peroxidation (p=.010) compared to mice on a low-fat diet. Importantly, our results also indicate that diet stability significantly impacted hepatic oxidative stress as weight cycled mice had significantly greater levels of hepatic protein carbonylation (p=.030) and hepatic lipid peroxidation (p=.008) compared to mice fed stable diets. Overall, our results indicate that weight cycling, independent of immediate diet, increases oxidative damage in the livers of mice compared with mice fed stable (non-cycled) diet regimens. Presentation: Saturday, June 17, 2023

Switching to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat in heavily antiretroviral-experienced, virologically suppressed HIV-infected adults receiving complex regimens.

To evaluate the efficacy and safety of the two-pill regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat as a switching strategy in heavily treatment-experienced people living with HIV (PLWH). Multicentre, prospective, single-arm pilot clinical trial. Participants were virologically suppressed adults receiving a stable antiretroviral regimen of at least three pills from at least three drug families due to previous virological failures and/or toxicities with no documented resistance to integrase strand transfer inhibitors or darunavir (≥15 points, Stanford). Clinical and laboratory assessments were performed at 0, 4, 12, 24, 36 and 48 weeks. HIV-1 proviral DNA was amplified and sequenced by Illumina at baseline. Plasma bictegravir concentrations were determined in 22 patients using UHPLC-MS/MS. The primary study endpoint was viral load (VL)< 50 copies/mL at Week 48 (ITT). We enrolled 63 participants (92% men) with median baseline CD4 count of 515 cells/mm3 (IQR: 334.5-734.5), 24 years on ART (IQR: 15.9-27.8). The median number of pills was 4 (range: 3-10). At baseline, proviral DNA was amplified in 39 participants: 33/39 had resistance mutations. Three participants discontinued owing to toxicity. At 48 weeks, 95% had VL < 50 copies/mL by ITT and 100% by PP analysis. A modest increase was observed in the bictegravir plasma concentration, and a significant decrease in estimated glomerular filtration rate was observed only at Week 4, probably related to interaction with renal transporters. Our data suggest that BIC/FTC/TAF + darunavir/cobicistat is an effective, well-tolerated regimen that may improve convenience and, potentially, long-term success in stable heavily pre-treated PLWH.

Efficacy and safety of Transcranial Direct Current Stimulation (tDCS) on cognitive function in chronic schizophrenia with Tardive Dyskinesia (TD): a randomized, double-blind, sham-controlled, clinical trial

ObjectivePrevious studies have shown that transcranial direct current stimulation(tDCS) led to an improvement of cognitive function in patients with schizophrenia, but rare study has explored the effect of tDCS on long-term hospitalized chronic schizophrenia with tardive dyskinesia (TD). The present research explored if cognitive function in patients with long-term hospitalized chronic schizophrenia with TD could be improved through tDCS.MethodsThis study is a randomized, double-blind, sham-controlled clinical trial. Of the 52 patients, 14 dropped out, and 38 completed the experiment. Thirty-eight patients on stable treatment regimens were randomly assigned to receive active tDCS(n = 21) or sham stimulation(n = 17) on weekdays of the first, third, and fifth weeks of treatment. Patients performed the Pattern Recognition Memory (PRM) and the Intra/Extradimensional Set Shift (IED) from the Cambridge Neuropsychological Test Automated Battery (CANTAB) at baseline and the end of week 3, week 5. Clinical symptoms were also measured at the baseline and the fifth week using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS). Side effects of tDCS were assessed with an experimenter-administered open-ended questionnaire during the whole experiment.ResultsThere were no significant differences in PRM and IED performance metrics, SANS total score and PANSS total score between active and sham tDCS groups at the end of week 5 (p > 0.05). Furthermore, there was a significant difference in the adverse effects of the tingling sensation between the two groups (p < 0.05), but there was no significant difference in other side effects (p > 0.05).ConclusionAccording to these findings, no evidence supports using anodal stimulation over the left dorsolateral prefrontal cortex to improve cognitive function in patients with long-term hospitalized chronic schizophrenia with TD.

Perceptions of Long-Acting Injectable Antiretroviral Therapy Among People Living with HIV Who Use Drugs and Service Providers: a Qualitative Analysis in Rhode Island.

Long-acting injectable antiretroviral therapy (LAI-ART) is a novel method to deliver HIV treatment, and the first regimen was approved in the USA in 2021. LAI-ART may mitigate barriers to oral treatment adherence, but little is known about LAI-ART perceptions among people living with HIV (PLWH) who use drugs, despite these populations facing greater barriers to treatment retention and ART adherence. We assessed LAI-ART perceptions and implementation considerations among PLWH who use drugs and health and ancillary service providers in Rhode Island. Data was collected from November 2021 to September 2022, and include in-depth interviews with 15 PLWH who use drugs and two focus groups with HIV clinical providers (n = 8) and ancillary service providers (n = 5) working with PLWH who use drugs. Data were analyzed thematically, with attention paid to how levels of structural vulnerability and social-structural environments shaped participants' LAI-ART perceptions and the HIV care continuum. Willingness to consider LAI-ART was impacted by HIV outcomes (e.g., viral suppression) and previous experiences with oral regimens, with those on stable regimens reluctant to consider alternative therapies. However, LAI-ART was seen as potentially improving HIV outcomes for PLWH who use drugs and enhancing people's quality of life by reducing stress related to daily pill-taking. Recommendations for optimal implementation of LAI-ART varied across participants and included decentralized approaches to delivery. HIV care delivery must consider the needs of PLWH who use drugs. Developing patient-centered and community-based delivery approaches to LAI-ART may address adherence challenges specific to PLWH who use drugs.

Comparative safety of adding serotonin and norepinephrine reuptake inhibitors (SNRIs) versus nonsteroidal anti-inflammatory drugs (NSAIDs) to short-acting opioids for non-malignant pain in nursing homes.

The comparative safety of serotonin and norepinephrine reuptake inhibitors (SNRIs) as adjuvants to short-acting opioids in older adults is unknown even though SNRIs are commonly used. We compared the effects of SNRIs versus nonsteroidal anti-Inflammatory drugs (NSAIDs) on delirium among nursing home residents when SNRIs or NSAIDs were added to stable regimens of short-acting opioids. Using 2011-2016 national Minimum Data Set (MDS) 3.0 and Medicare claims data to implement a new-user design, we identified a cohort of nursing home residents receiving short-acting opioids who initiated either an SNRI or an NSAID. Delirium was defined from the Confusion Assessment Method in MDS 3.0 assessments and ICD9/10 codes using Medicare hospitalization claims. Propensity score matching balanced underlying differences for initiating treatments on 39 demographic and clinical characteristics (nSNRIs = 5350; nNSAIDs = 5350). Fine and Gray models provided hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for the competing risk of death. Hydrocodone was the most commonly used short-acting opioid (48%). Residents received ~23 mg daily oral morphine equivalent at the time of SNRIs/NSAIDs initiation. The majority were women, non-Hispanic White, and aged ≥75 years. There were no differences in any of the confounders after propensity matching. Over 1 year, 10.8% of SNRIs initiators and 8.9% of NSAIDs initiators developed delirium. The rate of delirium onset was similar in SNRIs and NSAID initiators (HR(delirium in nursing home or hospitalization for delirium):1.10; 95% CI: 0.97-1.24; HR(hospitalization for delirium): 1.06; 95% CI: 0.89-1.25), and were similar regardless of baseline opioid daily dosage. Among nursing home residents, adding SNRIs to short-acting opioids does not appear to increase risk of delirium relative to initiating NSAIDs. Understanding the comparative safety of pain regimens is needed to inform clinical decisions in a medically complex population often excluded from clinical research.

Effects of Amantadine Sulfate on Motor Impairment and Execution of Motor Sequences in Patients With Parkinson Disease.

Intravenous application of amantadine sulfate induces a rapid improvement of motor behavior in patients with Parkinson disease. To determine efficacy of daily infusion of 200 mg amantadine sulfate on scored motor symptoms and performance of standardized movement sequences with components of low and high cognitive efforts. Thirty-one participants received infusions of amantadine sulfate in addition to their previous stable drug regimens on 3 consecutive days. Motor symptoms of upper limbs were determined with selected items of the part motor examination of the Unified Parkinson's Disease Rating Scale. Instrumental tasks were executed under cued conditions before and after the infusions. Scored motor symptoms and components with a need for a higher cognitive load became better. Performance of motion series, characterized by an automated set with low cognitive efforts, did not improve. Our trial outcomes suggest that the amantadine has a positive impact on cognitive abilities, drive, and vigilance, all of which are necessary for carrying out of higher brain functions.

NOVEL BIOMARKERS OF KIDNEY CELL PATHOLOGY, INFLAMMATION AND FIBROSIS IN CONTROLLED AND UNCONTROLLED HYPERTENSION

Objective: A significant reduction in kidney function is needed to detect a decrease in estimated glomerular filtration rate (eGFR), and only a minority of patients with hypertension (HT) have elevated urinary albumin excretion (UAE), leaving these biomarkers insensitive for early hypertensive organ damage. Low-grade inflammatory processes and fibrosis may have a key role in the pathogenesis of HT and HT-mediated kidney damage. Finding a panel of biomarkers related to HT and kidney damage at an early stage, that varies with modifiable risk factors, may aid targeted treatment. Several biomarkers of kidney cell pathology, markers of inflammation and fibrosis are of interest. In this nationwide cross-sectional multicentre study, we aimed to assess the associations between biomarkers and hypertension in four groups of patients; (1) healthy controls, (2) controlled HT, (3) uncontrolled HT, (4) uncontrolled HT with presence of kidney damage based on UAE and eGFR. We hypothesized that: (1) plasma levels of biomarkers are different between the 4 groups, (2) plasma levels of biomarkers are associated with the different HT groups. Design and method: Hypertensive patients (n = 183) were &gt; = 18 years old with eGFR &gt;30 mL/min/1.73m2, prescribed &gt; = 2 antihypertensive agents and on a stable treatment regimen for at least 4 weeks. Age and sex matched healthy controls had undergone kidney donation assessment (n = 39). Biomarkers were analyzed in duplicate by a custom made Luminex bead-based immunoassay. The ethics committee approved the studies. All patients signed written informed consent. Results: Plasma levels of IL-1RA, NGAL and uromodulin were significantly different between healthy controls (n = 39) and hypertensive patients (n = 183). Levels of IL-1RA and NGAL were significantly different between the three groups of hypertensive patients. In multivariable models on hypertensive subjects none of the biomarkers were associated with uncontrolled HT (n = 126). IL-18, vWF-A2, NGAL and uromodulin were associated with uncontrolled HT with presence of kidney damage (n = 65). None of the biomarkers were associated with any of the HT groups after adjustment for eGFR. Conclusions: Selected biomarkers may add information to identify hypertensive patients at risk for kidney damage, but further and longitudinal analysis are needed.

Efficacy and safety of luseogliflozin in Caucasian patients with type 2 diabetes: results from a phase III, randomized, placebo-controlled, clinical trial

IntroductionMost data demonstrating the efficacy and safety of luseogliflozin (luseo) in people with type 2 diabetes mellitus (T2DM) originate from the Japanese population. This study evaluated luseo versus placebo (PCB)...

CAN SERUM CONSENTRATION MEASUREMENTS OF ANTIHYPERTENSIVE DRUGS IMPROVE BLOOD PRESSURE CONTROL? A MULTICENTER DOUBLE BLINDED RANDOMIZED CONTROLLED TRIAL

Objective: Drug concentration in urine or serum using liquid chromatography coupled to mass-spectrometry (UHPLC-MS/MS) may disclose non-adherence. Whether this direct method will improve adherence is still unknown. In this multicenter randomized controlled trial with a double-blinded approach, we aimed to investigate if measurements and standardized information about serum concentrations of antihypertensive drugs (therapeutic drug monitoring (TDM)), could improve blood pressure (BP) control in documented non-adherent hypertensive patients. Design and method: Patients were &gt; = 18 years old with eGFR &gt;30 mL/min/1.73m2, prescribed &gt; = 2 antihypertensive agents and on a stable treatment regimen for at least 4 weeks. Experienced pharmacologists assessed adherence status based on serum drug concentrations, dose and patient-reported time since last intake of the drugs. Patients received no information regarding use of blood samples to screen for non-adherence. The ethics committee approved the study. All patients signed written informed consent. Non-adherent patients with a systolic daytime ambulatory BP (ABPM) &gt; = 135 mmHg were randomized 1:1 to TDM-intervention or not. The number of visits during 6 months follow-up were equal in both groups and antihypertensive medication regimens remained unchanged. Standardized TDM-information was given to the intervention-group at baseline and after 1 and 3 months. The control group remained uninformed about serum drug measurements until after completion of the study. Life style advice and information on necessity of BP treatment, how to remember to take medications and potential hypertension mediated end-organ damage were given to both groups. Investigators and patients were masked for BPs, and separate personnel measuring BPs were blinded to randomization group. Results: From 2017 to 2022, 606 patients (52.3%) of 1159 patients investigated had uncontrolled HT. The non-adherent patients were younger (57.8 vs 64.0 years, p &lt; 0.001), duration of hypertension was shorter (12 vs 16 years, p = 0.024) and daytime diastolic ABPM (90 vs 84 mmHg, p &lt; 0.001) and heart rate (76 vs 70 bpm, p &lt; 0.001) were higher. Uncontrolled and non-adherent patients were enrolled into the subsequent randomized study performed with a double-blinded approach. Conclusions: There was no difference in the primary end-point, daytime systolic ABPM at 3 months, between TDM and control group (-6.7 vs -7.3 mmHg, p = 0.897).

0591 Effectiveness and Optimization of Lower-Sodium Oxybate in Participants With Narcolepsy Switching From Sodium Oxybate (SEGUE)

Abstract Introduction Lower-sodium oxybate (LXB, Xywav®) contains 92% less sodium than higher-sodium oxybate (SXB, Xyrem®) and is approved for treating cataplexy or excessive daytime sleepiness in patients with narcolepsy (≥7 years of age) and idiopathic hypersomnia in adults. The SEGUE study examines the safety, tolerability, effectiveness, and treatment optimization in participants with narcolepsy transitioning from SXB to LXB. Methods Eligible participants in this multicenter, open-label study were adults with narcolepsy type 1 or 2 who were on a stable dose (maximum 9 g/night; no single dose &amp;gt;6 g) and regimen (once, twice, or thrice nightly) of SXB. After 2 weeks on a stable SXB dose/regimen (baseline period), participants switched to the same dose/regimen of LXB (intervention period; 6 weeks). If needed, LXB dose/regimen was titrated to optimize efficacy/tolerability. Assessments included the Patient Global Impression of Change (PGIc), a forced preference questionnaire (FPQ), an ease of switching medication scale (EOSMS), and the Epworth Sleepiness Scale (ESS); all collected at end of treatment or early discontinuation. Results Of 60 participants who entered the intervention period, a majority were female (62%) and White (88%); mean (SD) age was 43.9 (15.33) years. Starting and ending (end of treatment or early discontinuation) median total nightly doses of LXB were 8.5 g and 9.0 g, respectively. In terms of regimen, most took LXB twice nightly (93% at both time points). Fifty-six participants completed the transition period; mean (SD) time to stable dose was 2.5 (4.82) days, and median (range) number of changes in dose/regimen was 0.0 (0, 1). At end of treatment or early discontinuation, most participants reported improvement (very much/much/minimal; 45%) or no change (48%) in narcolepsy symptoms on the PGIc, preferred LXB over SXB on the FPQ (79%), and reported the transition to LXB was easy, extremely easy, or not difficult at all on the EOSMS (93%). Mean (SD) change from baseline on the ESS (n=55) was −0.7 (2.31). Conclusion Most participants with narcolepsy switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition process was easy. Effectiveness of oxybate treatment (ESS) was maintained after transition, and most preferred LXB over SXB. Support (if any) Jazz Pharmaceuticals.

Effectiveness and Optimization of Low-Sodium Oxybate in Participants With Narcolepsy Switching From High-Sodium Oxybate: Interim Data from the Substitution of Equal Grams of Uninterrupted Xyrem to Xywav (SEGUE) Study (P5-13.003)

<h3>Objective:</h3> The SEGUE study examines safety, tolerability, effectiveness, and treatment optimization in participants with narcolepsy transitioning from sodium oxybate (SXB) to lower-sodium oxybate (LXB; Xywav^®). <h3>Background:</h3> LXB contains 92% less sodium than SXB and is approved for treating cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy (≥7 years of age). <h3>Design/Methods:</h3> Eligible participants in this ongoing, multicenter, open-label study (NCT04794491) are adults with narcolepsy (type 1 or 2) on an SXB stable dose (maximum 9 g/night; no single dose &gt;6 g) and regimen (once, twice, or thrice nightly). After 2 weeks on SXB (baseline period), participants switch to the same LXB dose/regimen (intervention period; 6 weeks). If needed, LXB dose/regimen is titrated to optimize efficacy/tolerability. Assessments include the Patient Global Impression of Change (PGIc), forced preference questionnaire (FPQ), and ease of switching medication scale (EOSMS; all collected at end of treatment/early discontinuation). An interim analysis (first 24 completers) is reported. <h3>Results:</h3> Most participants were White (92%); 54% were female; mean (SD) age was 45.5 (16.20) years. Starting and ending (end of treatment/early discontinuation) median total nightly doses of LXB were both 9.0 g. Most participants took LXB twice nightly (88%). Twenty-two participants completed the transition period; mean (SD) time to optimized dose was 1.4 (1.56) days, and median (range) number of dose/regimen changes was 0.0 (0, 1). At end of treatment/early discontinuation, most reported improvement (very much/much/minimal; 57%) or no change (43%) in narcolepsy symptoms on the PGIc, preferred LXB over SXB on the FPQ (86%), and reported the transition was easy (easy/extremely easy/not difficult at all) on the EOSMS (91%). Most treatment-emergent adverse events reported were mild to moderate. <h3>Conclusions:</h3> Participants switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition was easy. Efficacy of oxybate treatment was maintained or improved, and most participants preferred LXB over SXB. <b>Disclosure:</b> Dr. Leary has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Leary has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Proper. Dr. Leary has stock in Jazz Pharmaceuticals. Dr. Kirby has received personal compensation for serving as an employee of Jazz Pharmaceuticals, Inc. Dr. Kirby has stock in Jazz Pharmaceuticals, Inc.. Dr. Skowronski has nothing to disclose. Mr. Xu has received personal compensation for serving as an employee of Jazz Pharmaceuticals Inc. Mr. Pfister has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Mr. Pfister has stock in Jazz Pharmaceuticals. Dr. Macfadden has received personal compensation for serving as an employee of Jazz pharma. Dr. Macfadden has stock in Jazz pharma.

Long-term Safety and Efficacy of IPX203 in Parkinson’s Disease Patients with Motor Fluctuations: A 9-Month Open-label Extension Trial (S32.006)

Long-term Safety and Efficacy of IPX203 in Parkinson’s Disease Patients with Motor Fluctuations: A 9-Month Open-label Extension Trial (S32.006)

Moving Beyond Amyloid in Alzheimer's Therapeutics

Moving Beyond Amyloid in Alzheimer's Therapeutics