Changes In Laboratory Values Research Articles

Safety of an Accelerated Ferric Gluconate Inpatient Infusion Regimen.

Inpatient use of intravenous iron has been increasing. Ferric gluconate is traditionally given once daily. Twice-daily dosing provides faster iron repletion, but there are limited data to support the safety of twice-daily dosing. The aim of this study was to investigate the safety of twice-daily dosing for ferric gluconate compared with daily dosing. This was an institutional review board-approved retrospective observational study of hospitalized adult patients who received intravenous ferric gluconate 250 mg daily or twice daily between January 1 and April 3, 2022. The primary composite safety outcome included hypotension, infusion reaction, rapid response alert, or escalation in level of care. Secondary outcomes included total amount of iron received, hospital length of stay, and changes in laboratory values. A total of 126 patients were included in this study, with 63 patients in each group. The primary outcome occurred in 29 patients (46%) in the twice-daily group compared with 36 patients (57.1%) in the daily group (relative risk = 0.81; 95% CI, 0.57-1.13; P = 0.212). Changes in iron, hemoglobin, and transferrin saturation were similar between the 2 groups. Median length of stay was statistically shorter in the twice-daily group (7.79 days) compared with the daily group (12.9 days; p = 0.006). In this retrospective single-center study of hospitalized adult patients, those who received intravenous ferric gluconate twice daily did not experience an increased rate of a composite safety outcome of hypotension, infusion reactions, or escalation in level of care compared with those with daily dosing.

P110 INITIAL TREATMENT WITH A SINGLE CAPSULE CONTAINING HALF-DOSE QUADRUPLE THERAPY VS STANDARD-DOSE DUAL THERAPY IN HYPERTENSIVE PATIENTS (QUADUAL): A RANDOMIZED, BLINDED, CROSSOVER TRIAL

Background and Objective: Guidelines recognized the dual combination in initial antihypertensive therapy. Studies demonstrated low-dose quadruple combination antihypertensive was superior to monotherapy. However, whether low-dose quadruple therapy is better than dual combination is unknown. Methods: A randomized blinded crossover trial was conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23·75 mg + amlodipine 2·5 mg + indapamide 1·25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg) in the initial treatment of patients with mild to moderate hypertension. Patients were randomly assigned in a 1:1 ratio to two crossover sequences. Each sequence received four-weeks of either half-dose quadruple antihypertensives or standard-dose dual antihypertensives, followed by a two-week washout and crossover for four-weeks. Participants and researchers were blinded, except for randomization and drug coding. The primary outcome was the reduction of mean 24-hour systolic blood pressure in ambulatory blood pressure monitoring. Safety outcomes were adverse events and changes in biochemistry after treatment. Analyses were per intention to treat. This trial was prospectively registered on www.clinicaltrials.gov (NCT05377203), and is now complete. Results: A total of 90 eligible participants were randomized between July 13, 2022, and April 20, 2023. The mean age of the population was 43.88 years, and 25.6% were women. The mean baseline 24-h blood pressure was 145.59/93.84 mm Hg. Half-dose quadruple treatment compared with standard-dose dual treatment further reduced mean 24-hour blood pressure by 4.72/4.17 mm Hg (P < 0.001 for both systolic and diastolic blood pressure). Except for fasting blood glucose (P = 0.029) and blood uric acid increased significantly (P < 0.001) in half-dose quadruple group, other adverse events and changes in laboratory values between the two treatments were not statistical different. Conclusions: Initiating treatment with half-dose quadruple combination therapy was more effective in lowering blood pressure than standard-dose dual therapy. The safety of half-dose quadruple therapy was comparable.

Fluid resuscitation with balanced electrolyte solutions results in faster resolution of diabetic ketoacidosis than with 0.9% saline in adults – A systematic review and meta‐analysis

AbstractFluid resuscitation during diabetic ketoacidosis (DKA) is most frequently performed with 0.9% saline despite its high chloride and sodium concentration. Balanced Electrolyte Solutions (BES) may prove a more physiological alternative, but convincing evidence is missing. We aimed to compare the efficacy of 0.9% saline to BES in DKA management. MEDLINE, Cochrane Library, and Embase databases were searched for relevant studies using predefined keywords (from inception to 27 November 2021). Relevant studies were those in which 0.9% saline (Saline‐group) was compared to BES (BES‐group) in adults admitted with DKA. Two reviewers independently extracted data and assessed the risk of bias. The primary outcome was time to DKA resolution (defined by each study individually), while the main secondary outcomes were changes in laboratory values, duration of insulin infusion, and mortality. We included seven randomized controlled trials and three observational studies with 1006 participants. The primary outcome was reported for 316 patients, and we found that BES resolves DKA faster than 0.9% saline with a mean difference (MD) of −5.36 [95% CI: −10.46, −0.26] hours. Post‐resuscitation chloride (MD: −4.26 [−6.97, −1.54] mmoL/L) and sodium (MD: −1.38 [−2.14, −0.62] mmoL/L) levels were significantly lower. In contrast, levels of post‐resuscitation bicarbonate (MD: 1.82 [0.75, 2.89] mmoL/L) were significantly elevated in the BES‐group compared to the Saline‐group. There was no statistically significant difference between the groups regarding the duration of parenteral insulin administration (MD: 0.16 [−3.03, 3.35] hours) or mortality (OR: −0.67 [0.12, 3.68]). Studies showed some concern or a high risk of bias, and the level of evidence for most outcomes was low. This meta‐analysis indicates that the use of BES resolves DKA faster than 0.9% saline. Therefore, DKA guidelines should consider BES instead of 0.9% saline as the first choice during fluid resuscitation.

Reasonability of Frequent Laboratory Analyses during Therapy with Nivolumab and Nivolumab+Ipilimumab in Patients with Advanced or Metastatic Renal Cell Carcinoma during the Phase 2 Clinical Trial TITAN-RCC.

In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab.

A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

Randomised, phase 1/2a trial of ION-827359, an antisense oligonucleotide inhibitor of ENaC.

Hyperactivity of epithelial sodium channel (ENaC) with increased sodium absorption is a feature of cystic fibrosis (CF). ION-827359 is a 2.5-generation antisense oligonucleotide targeted to reduce ENaC protein. This study evaluated ION-827359 safety, pharmacokinetics and pharmacodynamics. In this three-part phase 1/2a, double-blind, randomised study, healthy volunteers received single doses of placebo or ION-827359 (3, 10, 37.5 or 100 mg; Part 1) or multiple doses of placebo or ION-827359 (5×10 mg, 5×37.5 mg, 5×75 mg or 10×37.5 mg; Part 2). People with CF (pwCF) received multiple doses of placebo or ION-827359 (5×10 mg, 5×37.5 mg, 5×75 mg and 5×100 mg; Part 3). Treatments were administered via Pari eFlow© mesh nebuliser. The primary outcome was safety; pharmacokinetic and pharmacodynamic parameters were also assessed. 64 healthy volunteers and 34 pwCF were enrolled. ION-827359 was well tolerated with an acceptable safety profile. There were no clinically relevant changes in laboratory values, ECG or vital signs. Systemic drug exposure was low (plasma half-life ∼2 weeks). Multiple doses of ION-827359 were associated with dose-dependent reductions in ENaC mRNA in bronchial epithelium. After multiple dosing, forced expiratory volume in 1 s was slightly higher in pwCF receiving ION-827359 (+2.9% with ION-827359 100 mg versus placebo; p=0.27). The tolerability and safety of ION-827359 appear favourable at this stage of investigation. Reduction in ENaC mRNA supports mechanistic efficacy at the doses and regimens tested, and supports further investigation of ION-827359 in pwCF.

Laboratory and Bleeding Frequency Changes in Pediatric Patients after Transitioning from Factor VIII to Emicizumab Prophylaxis -Real World Evidence in Patients with Severe Hemophilia a

Background: Emicizumab, a monoclonal antibody which functions as a bypassing agent by bridging activated factor IX and factor X in the absence of normal factor VIII levels, has recently been approved for routine prophylaxis against bleeding episodes in both adults and pediatric patients with hemophilia A. While complete blood counts are typically normal in patients living with hemophilia, it is generally accepted that some patients with unusually heavy bleeding or persistently long bleeds can have low hemoglobin. This anemia may be more common as a previous study revealed that patients with hemophilia had lower that average values for hemoglobin cross all ages and degrees of severity as evidenced by 31% of patients with values less than the third percentile, 46% less that then tenth percentile, and 83% less than the mean value. Real world impact on hemogram in pediatric patients who have been switched to Emicizumab has not been reported in the past after the medication was approved by FDA for hemophilia management. Methods: We performed a retrospective chart review of a cohort of 12 male pediatric patients with hemophilia A who were transitioned from factor VIII to emicizumab prophylaxis between May 2019 and May 2022 to determine changes in laboratory values and bleeding frequencies. Results: Hematologic metricies in severe hemophilia patients pre and post emicizumab switch :Complete blood counts before emicizumab transition revealed a mean hemoglobin 12.8 g/dL (range 10.4-15.7 g/dL), MCV 80.8 fL (range 67.2-99.1 fL), RDW 13.8% (range 11.8-16.6%), and platelets 297 bil/L (range 166-490 bil/L). Following emicizumab initiation, follow up blood counts demonstrated mean hemoglobin 14.8 g/dL (range 12.0-17.1 g/dL), MCV 83.3 fL (range 77.2-95.4 fL), RDW 12.9% (range 12.0-13.9%), and platelets 303 bil/L (range 199-514 bil/L). Mean hemoglobin was noted to have a significant increase after emicizumab was started (P&amp;lt;0.001). Both minor and breakthrough bleeding frequencies were noted to decrease in all patients. Bleeding Frequency and Overall Satisfaction : The patient /caregiver input to assess changes in bleeding frequency was obtained, after stable treatment with emicizumab was tolerated for at least 6 months. The bleeding frequencies of our cohort of patients on FVIII prophylaxis had a wide range with minor bleed frequencies (defined as any joint, soft tissue or other hemorrhage not requiring additional FVIII administration) occurring as often as daily to once yearly. Breakthrough bleeds that required additional episodic FVIII administration occurred 2-3x/monthly to once yearly. Following transition to emicizumab, patients had a reported an overall decrease in bleeding frequencies with minor bleeds averaging from 2x/month previously to never. 3 of these patients had breakthrough bleeding episodes requiring FVIII with 2 episodes attributed to trauma. Overall, patients' parents were asked to give a subjective verbal rating from 1 to 10 of their experience with emicizumab with 1 being worst and 10 being best. The mean verbal rating of our cohort of patients was 9.3. 11 of 12 patients remain of emicizumab prophylaxis as of May 2023 with one patient returning to FVIII prophylaxis due to pain at injection site. Conclusion: An increase in mean hemoglobin concentration in conjunction with reported decreased bleeding frequencies may suggest emicizumab facilitates an overall reduction in prolonged bleeding episodes. At our center, hemophilia A patients transitioned from factor VIII to emicizumab prophylaxis demonstrated a statistically significant increase in hemoglobin concentrations. This data combined with a notable reported decrease in minor and breakthrough bleeding frequencies in all patients suggests an overall reduction in prolonged bleeding episodes. Patients and their families appear to be very satisfied with emicizumab prophylaxis which may promote changes in the standard of care for hemophilia A patients.

Long-Term Safety and Efficacy of Mitapivat, an Oral Pyruvate Kinase Activator, in Adults with Sickle Cell Disease: Extension of a Phase 1 Dose Escalation Study

BACKGROUND In a Phase I study (NCT04000165, Xu et al, 2022), we showed that mitapivat, an investigational oral allosteric activator of pyruvate kinase (PK), demonstrated an acceptable safety and tolerability profile at multiple ascending dose levels in patients (pts) with sickle cell disease (SCD). We also established proof-of-concept for activating PK as a viable therapeutic approach; mitapivat decreased 2,3- diphosphoglycerate (2,3-DPG) and increased adenosine triphosphate (ATP) levels, improved hematologic parameters, and reduced sickling in pts with SCD (HbSS). In this extension study (NCT04610866), we evaluated the safety, tolerability and efficacy of mitapivat as a long-term maintenance therapy for pts with SCD. METHODS We enrolled 15 adult pts (age &amp;gt;18 years) with confirmed SCD (HbSS) and baseline hemoglobin (Hb) 7.1 - 10.5 g/dL, with no recent blood transfusions, erythropoietin therapy, or changes in SCD-specific therapies including hydroxyurea (HU) and L-glutamine. Thirteen pts had participated in the Phase 1 study and 2 pts were mitapivat naïve. All pts started mitapivat at 50 mg twice daily (BID), escalating after 4 weeks (wks) to 100 mg BID, unless a rapid Hb rise was observed (increase of ≥2 g/dL), the maximum Hb level of 12.5 g/dL had been reached, or per PI discretion. Patients continued on this maintenance dose of mitapivat through the end of the study. Dose reductions were performed at any time during the extension phase for safety and tolerability. After completion of the 24-wk core period, pts had an option to continue on mitapivat treatment in the extension period for up to 6 years. Study visits were conducted every 2 wks (x2), 4 wks (x2), and then every 12 wks for first 2 years (yrs) and will continue every 6 months for the remaining 4 yrs. The extension period of the study is ongoing; here we report data for up to 2 years (data cutoff March 23, 2023). Any and all vaso-occlusive crises (VOCs) that occurred while on study, regardless of attribution, were considered adverse events. RESULTS Of the 15 pts who completed the core period, 14 entered the extension study with 1 pt on 5 mg BID, 1 pt on 50 mg BID, 3 alternating between 50 and 100 mg BID, and the rest on 100 mg BID. Mean age of the 15 pts was 39 yrs (range: 25-57 yrs); 10 were male, and 11 were on HU. As of the cut-off date, median duration of mitapivat treatment for pts who entered the extension period was 84 wks (range: 48-108 wks), 1 pt discontinued after 2 yrs (pt decision) and 10 pts received 72 wks or more of treatment (Table 1) with a total of 1080 pt-wks of drug exposure thus far. Mitapivat was generally well tolerated; no treatment emergent adverse events (TEAEs) resulted in discontinuation of study drug or death during the extension period. The most common TEAEs (reported in 5 or more pts) were VOCs (n=8), estrone decrease (n=7), testosterone increase (n=6) and cough (n = 5); changes in laboratory values were not clinically significant. The most common serious TEAEs (reported in 2 or more pts) were VOCs (n=8) and lung infection (n = 2). Two pts experienced VOCs that were assessed as possibly drug-related (1 during drug escalation, and 1 during drug taper). All VOCs occurred in the setting of known VOC triggers. Three pts required dose reduction, 1 each secondary to pruritis, bloating and insomnia, respectively. In the latter 2 cases, the doses were subsequently increased to 100 mg BID, as TEAEs resolved. Other serious TEAEs were not considered related to study drug. The mean Hb at 24 wks increased significantly from baseline (mean: 1.38 g/dL, SD: 0.88 g/dL; p&amp;lt;0.0001), a result generally upheld at other follow-up periods (Fig. 1). 14/15 (93%) of the pts achieved a Hb response, defined as a ≥ 1 g/dL increase in Hb at any timepoint within the core period, compared to baseline. Improvements in Hb achieved in the core period were accompanied by improvements in markers of hemolysis, oxygen affinity (p50), sickling kinetics (t50), decreases in 2,3-DPG and increases in ATP levels, and were sustained in the extension study (Fig. 1 and 2). Concurrently, there were also improvements in red cell deformability (LORRCA) (Lundt et al, 2022) and trends in improvements in cardiopulmonary status (not shown). CONCLUSION Long-term use of mitapivat is safe and well tolerated in pts with SCD with evidence of sustained long-term improvements in Hb, hemolytic and sickling kinetics. Mitapivat offers a novel disease-modifying approach.

Gambaran Proses Asuhan Gizi Terstandar pada Pasien Penyakit Ginjal Kronik Stadium IV

Background: Chronic kidney disease is a situation where there is a decrease in kidney efficiency which occurs slowly over a long period of time and has remained stable for the last 3 months. Chronic kidney disease patients who are hospitalized are not only given health care, but also given nutritional services in the form of standardized nutritional care. Nutritional care aims to help patients solve nutritional problems by overcoming various factors that cause nutritional status to change or be unbalanced. Research Objective: To describe the process of standardized nutritional care for patients with stage IV chronic kidney disease. Research Method: Observational descriptive method with case studies in patients with stage IV chronic kidney disease. Research Results: The patient on behalf of Mrs. 57 year old R was admitted to hospital with a diagnosis of stage IV chronic kidney disease. From the results of the nutritional assessment, the patient had a low level of consumption of energy, protein, fat and carbohydrates. The results of anthropometric measurements of the patient have good nutritional status. Based on laboratory results, the patient had a high serum creatinine level and the patient's Hb, erythrocyte count, hematocrit, MCH, MCHC examination results were in the low category. The results of the patient's physical and clinical examination were weak and the patient's blood pressure was high. Nutritional diagnoses that can be made include inadequate oral intake, decreased protein and sodium requirements, and changes in laboratory values ​​related to nutrition. The type of diet given is a low protein and low salt diet. The results of monitoring and evaluating the patient's food intake increased to ≥80% on the second day, the patient's nutritional status was good, there were no laboratory developments because the patient did not have another laboratory examination, and the patient's physical and clinical condition was good and the patient's blood pressure was normal. Conclusion: After intervention for 2 days, the results of monitoring and evaluating the patient's food intake increased on the second day, reaching ≥80% for energy, protein and fat. Then, for anthropometric monitoring and evaluation, the patient has good nutritional status. Then, monitoring and evaluating laboratory data could not be carried out because the patient did not undergo another laboratory examination. Furthermore, the results of monitoring and evaluating the patient's physical and clinical condition were good and the patient's blood pressure was normal.

Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans.

itinib is an oral, selective, allosteric inhibitor of tyrosine kinase 2, an intracellular signaling kinase involved in the pathogenesis of immune-mediated inflammatory diseases. The absolute and relative bioavailability (BA) were evaluated in phase 1, open-label studies in healthy adults to assess (1) the absolute BA of the deucravacitinib tablet formulation following single oral administration of a 12-mg tablet and an intravenous microdose infusion of 0.1-mg carbon-13 and nitrogen-15-labeled deucravacitinib ([13 C2 , 15 N3 ] deucravacitinib) solution in 8 subjects, and (2) the relative oral BA of deucravacitinib tablet and capsule formulations at the 3- and 12-mg dose levels in 20 subjects. The absolute oral availability of deucravacitinib in the tablet formulation was near complete at approximately 99%. The total clearance (254mL/min) was low relative to hepatic blood flow, and volume of distribution (∼140L) was greater than total body water, indicating extravascular distribution. Deucravacitinib systemic exposure (maximum plasma concentration, area under the plasma drug concentration curve from time zero to the time of the last quantifiable nonzero concentration, and area under the plasma drug concentration-time curve from time zero extrapolated to infinity) after administration of the tablet formulation were similar to the capsule at the tested 3- and 12-mg doses. In both studies, deucravacitinib was safe with no clinically relevant changes in laboratory values, electrocardiogram parameters, or vital signs.

Pruritus in Hemodialysis Patients: Longitudinal Associations With Clinical and Patient-Reported Outcomes

Cross-sectional studies have reported an association of chronic kidney disease-associated pruritus (CKD-aP) with adverse clinical events and patient-reported outcomes (PROs). We studied the longitudinal associations between changes in CKD-aP and clinical outcomes among patients receiving maintenance hemodialysis. Prospective cohort study. 7,976 hemodialysis recipients across 21 countries in phases 4-6 (2009-2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS) who had 2 CKD-aP assessments approximately 12 months apart. Exposure status was based on the assessment of pruritis initially and again approximately 1 year later. Four groups were identified, including those with moderate or more severe pruritis only at the initial assessment (resolved), only at the second assessment (incident), at neither assessment (absent), or at both assessments (persistent). Laboratory values and PROs ascertained at the initial assessment of pruritis and 1 year later. Linear mixed model to investigate changes in laboratory values and PROs over the 1-year study period across the 4 exposure groups. 51% of patients had moderate to severe CKD-aP symptoms at either assessment (22% at both). The prevalences of depression, restless sleep, and feeling drained increased over the study period (+13%,+10%, and+14%, respectively) among patients with incident pruritus and decreased (-5%,-8%, and-12%, respectively) among patients with resolved pruritus. Minimal changes in PROs over time were observed for the absent and persistent groups. Changes over time in laboratory values (phosphorus, Kt/V) were not detected for either of these groups. Compared with patients with absent CKD-aP, the adjusted HRs for patients with persistent CKD-aP were 1.29 (95% CI, 1.09-1.53) for all-cause mortality, 1.17 (1.07-1.28) for all-cause hospitalization, and 1.48 (1.26-1.74) for cardiovascular events. No interim evaluation of CKD-aP symptoms between the 2 assessments; potential selection bias from patients who died or were otherwise lost to follow-up before the second assessment. CKD-aP symptoms are chronic, and these findings highlight the potential value of repeated assessment of this symptom using standardized approaches. Future research should systematically investigate potential causes of CKD-aP and options for its effective treatment. Previous research has studied itching and its consequences in hemodialysis recipients only at a single time point. We surveyed 7,976 patients receiving maintenance hemodialysis to assess itching over a period of 1 year. We found that, among those experiencing itching at the initial assessment, more than half had persistent symptoms 1 year later. Those in whom itching developed during follow-up were more likely to experience depression, poor sleep, long recovery times after dialysis, and feeling faint or drained. These patients also rated their quality of life as poorer than those who did not experience itching. These findings emphasize the potential value of clinical detection of itching and the pursuit of effective treatments for patients receiving dialysis experiencing these symptoms.

392 Safety of amlitelimab in a Phase 2a clinical trial of patients with moderate-to-severe atopic dermatitis

Abstract Amlitelimab (SAR445229), a fully human, nondepleting, noncytotoxic, monoclonal antibody, binds to OX40Ligand (OX40L) on antigen-presenting cells to block OX40-OX40L interactions. Outcomes from a 36-week, double-blind, Phase 2a trial (NCT03754309) in patients with moderate-to-severe atopic dermatitis are described. This study aims to assess the safety of OX40-OX40L signaling blockade with amlitelimab in patients with moderate-to-severe atopic dermatitis. Eighty-nine patients were randomized to amlitelimab low-dose (LD; 200-mg loading/100-mg maintenance Q4W), high-dose (HD; 500 mg/250 mg Q4W) or placebo. The coprimary safety endpoint was treatment-emergent adverse event (TEAE) incidence to W16. Safety was assessed to W36. Amlitelimab was well tolerated. Related TEAE incidence was similar between amlitelimab [LD 35% (10/29); HD 20% (6/30)] and placebo [31% (9/29)] to W16 and W36 [LD 10% (2/20); HD 0 (0/22); placebo 0 (0/17)]. The TEAEs more common with amlitelimab vs. placebo (≥5% difference) to W16 included headache [LD 0; HD 3 (10%); placebo 1 (3.4%)], upper respiratory tract infection [3 (10.3%); 0; 1 (3.4%)], hyperhidrosis [0; 2 (6.7%); 0], pyrexia [2 (6.9%); 0; 0], aspartate aminotransferase increased [0; 2 (6.7%); 0] and iron-deficiency anemia [2 (6.9%); 0; 0]; and to W36, Herpes simplex [0; 2 (9.1%); 0]. Before W16, one severe adverse event (SAE) of infected dermal cyst was reported as possibly related; it resolved, and the patient completed the study. Post-W16, one unrelated SAE of sudden death occurred 87 days following the final amlitelimab dose. No hypersensitivity or tolerability events, or clinically meaningful changes in laboratory values, vital signs or electrocardiogram recordings were reported. Amlitelimab was well tolerated in a Phase 2a trial of patients with moderate-to-severe atopic dermatitis, confirming the unremarkable safety profile observed in Phase 1.

Effect of a combination of pemafibrate and a mild low-carbohydrate diet on obese and non-obese patients with metabolic-associated fatty liver disease.

Recently, pemafibrate and a low-carbohydrate diet (LCD) have each been reported to improve fatty liver disease. However, it is unclear whether their combination improves fatty liver disease and is equally effective in obese and non-obese patients. In 38 metabolic-associated fatty liver disease (MAFLD) patients, classified by baseline body mass index (BMI), changes in laboratory values, magnetic resonance elastography (MRE), and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) were studied after 1year of combined pemafibrate plus mild LCD. The combination treatment resulted in weight loss (P=0.002), improvement in hepatobiliary enzymes (γ-glutamyl transferase, P=0.027; aspartate aminotransferase, P<0.001; alanine transaminase [ALT], P<0.001), and improvement in liver fibrosis markers (FIB-4 index, P=0.032; 7s domain of type IV collagen, P=0.002; M2BPGi, P<0.001). Vibration-controlled transient elastography improved from 8.8 to 6.9kPa (P<0.001) and MRE improved from 3.1 to 2.8kPa (P=0.017) in the liver stiffness. MRI-PDFF improved from 16.6% to 12.3% in liver steatosis (P=0.007). In patients with a BMI of 25 or higher, improvements of ALT (r=0.659, P<0.001) and MRI-PDFF (r=0.784, P<0.001) were significantly correlated with weight loss. However, in patients with a BMI below 25, the improvements of ALT or PDFF were not accompanied by weight loss. Combined treatment with pemafibrate and a low-carbohydrate diet resulted in weight loss and improvements in ALT, MRE, and MRI-PDFF in MAFLD patients. Although such improvements were associated with weight loss in obese patients, the improvements were observed irrespective of weight loss in non-obese patients, indicating this combination can be effective both in obese and non-obese MAFLD patients.

P375 Izencitinib induction treatment in patients with moderately-to-severely-active Crohn’s Disease: A phase 2 double-blind, randomized, placebo-controlled study

Abstract Background The unmet need in Crohn’s disease (CD) exists for new medications with an optimized risk-benefit ratio with avoidance of systemic side effects. This Phase 2 study evaluated the efficacy and safety of the oral, once-daily, gut-selective pan-Janus kinase inhibitor izencitinib as an induction therapy for CD. Methods This trial was a multicentre, randomized, double-blind, Phase 2 study of adults with moderately-to-severely active CD (≥220 and ≤ 450 CDAI with SES-CD score of ≥6 [or ≥4 if isolated ileal disease]) who were corticosteroid-dependent or had demonstrated failure to aminosalicylates, corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomised 2:3:3 to receive placebo or izencitinib, 80, or 200 mg once daily for 12 weeks. The primary endpoint was change in CDAI score from baseline to week 12 and was analysed using a mixed-model repeated measures analysis. Change from baseline in SES-CD was analysed with an analysis of covariance model and binary endpoints were analyzed using a stratified Cochran-Mantel-Haenszel chi-square test. Results 159 and 145 patients were included in the safety and modified ITT populations, respectively. At week 12, the LS mean change in CDAI was -105.6 (SE: 12.7) and -117.9 (12.4) points for patients randomized to izencitinib 80 and 200 mg, respectively, vs -104.86 (SE: 15.496) for those randomized to placebo. There were no improvements observed in change from baseline in SES-CD. There were non-significant numerical improvements in clinical and endoscopic response between placebo and the highest dose 200mg. No improvements were observed in CDAI-based clinical remission or PRO2 (SF/AP)-based remission at any dose of izencitinib relative to placebo. As expected, plasma izencitinib exposure was low. Serious adverse events (AEs; n = 13) were well balanced among the treatment groups and not considered related to study treatment; no deaths were observed. Exacerbation of Crohn’s Disease, headache, rash, abdominal pain and nausea were the most common treatment-emergent AEs observed with izencitinib treatment. No clinically important changes in laboratory values, electrocardiography parameters, or vital signs were noted in patients treated with izencitinib compared with placebo, and no drug-related AEs of special interest were observed. Conclusion In patients with moderately-to-severely active Crohn’s Disease, izencitinib treatment for 12 weeks did not demonstrate a statistically significant reduction in CDAI or endoscopic severity. Izencitinib at both doses was well tolerated without a new safety signal.

Safety and performance of the Spectra Optia apheresis system for white blood cell depletion in patients with elevated white blood cell counts.

For the past 30 years, white blood cell depletion (WBCD) or leukocytapheresis has been conducted to rapidly reduce excessive circulating white blood cell (WBC) concentrations in patients at risk for or with symptoms of leukostasis due to hyperleukocytosis. The goal of leukocytapheresis is to prevent or treat acute complications from leukostasis, thereby enabling patients to receive potentially curative chemotherapy. This report details the results from a retrospective and a prospective clinical study conducted in the European Union and the People's Republic of China, which assessed the use of the Spectra Optia Apheresis System for leukocytapheresis in patients with hyperleukocytosis. The primary objective of both studies was to the assess the safety and performance of the WBCD procedure in patients with elevated WBC counts. Data were collected from 72 participants completing 87 WBCD procedures. The mean percent change in participant WBC counts post-procedure was 50.3 ± 21.2% and the collection efficiency (CE1) of the WBCD procedures was 53.7 ± 19.8%. Sixty-one participants (95.3%) experienced a total of 279 adverse events (AEs) with the majority of the AEs related to post-procedure changes in laboratory values, which is an anticipated AE in this patient population. The data collected within these studies indicate that the WBCD procedure is safe and well tolerated in patients with hyperleukocytosis as evaluated by percent decrease in WBC count, CE1, and AE incidence.

Activated Partial Thromboplastin Time or Prothrombin Time Prolongation During Rivaroxaban Administration: Clinical Risk Factors and Outcomes Analysis.

Activated partial thromboplastin time (aPTT) or prothrombin time (PT) is often detected after rivaroxaban administration, and it is known that aPTT or PT can be prolonged or normal. However, the clinical risk factors and outcomes of prolongation were unknown. In a single-center, retrospective case-control study, adult inpatients who had aPTT/PT tested before and after administration of rivaroxaban during a designated 12-month period were eligible for inclusion. Depending on whether their aPTT/PT was prolonged, patients were allocated to the prolonged case or normal control group. Demographics, rivaroxaban indications and daily dose, and laboratory values were compared. Multivariate logistic regression was used to identify independent risk factors. The changes in laboratory values and clinical outcomes were analyzed. A total of 155 patients were included in the study among which 54 (34.84%) were reported to have either or both aPTT/PT prolonged. The average prolongation time of PT was between 0.8 and 0.9 s, and 1.8 and 3.5 s for aPTT. Multivariable regression modeling showed that height (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.02-1.22, P = .02) and human albumin replacement (OR 3.19, 95% CI 1.05-9.74, P = .04) were independent risk factors for aPTT/PT prolongation. The incidence of bleeding events and changes in laboratory values were similar between the groups. Patient height and receiving human albumin replacement were independent risk factors for aPTT/PT mild prolongation caused by rivaroxaban. The prolongation was not associated with an increased occurrence of bleeding events.

ASC4START: A Phase IIIb, Open-Label, Randomized Study of Tolerability and Efficacy of Asciminib Versus Nilotinib in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia in Chronic Phase

Objectives: Tyrosine kinase inhibitors (TKIs) have greatly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP), transforming it into a chronic disease requiring long-term treatment. This emphasizes the need for treatments that combine high efficacy with a favorable safety profile, improving over currently available options. Asciminib is a first-in-class BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket (STAMP) which has been approved by the FDA with subsequent approvals worldwide for patients with Philadelphia chromosome-positive (Ph+) CML-CP, previously treated with ≥2 prior TKIs based on the results of the ASCEMBL (NCT03106779) trial. The ABL specificity of asciminib compared with the selectivity of second-generation (2G) TKIs can reduce off-target effects and improve tolerability while maintaining efficacy and reducing the probability of developing resistance. The ongoing ASC4FIRST (NCT04971226) study will evaluate the efficacy and safety of asciminib vs investigator-selected TKI in patients with newly diagnosed Ph+ CML-CP. Additional data on asciminib in newly diagnosed Ph+ CML-CP may help to address patient-centric objectives, in particular the ability of patients to remain on treatment without having to permanently discontinue due to adverse events (AEs). The ASC4START study (NCT05456191) will primarily evaluate the tolerability of asciminib vs the 2G TKI nilotinib in adult patients with newly diagnosed Ph+ CML-CP, as measured by the time to study treatment discontinuation due to adverse event (TTDAE). The study will also report on further safety, efficacy and quality of life (QoL) outcomes. Methods: This is a phase IIIb, multi-center, open-label, randomized study in patients ≥18 years of age with newly diagnosed Ph+ CML-CP. The trial will enroll approximately 541 patients with CML-CP diagnosed within 3 months of study entry and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients cannot be included if they have received previous treatment for CML with any other anticancer agents (except hydroxyurea and/or anagrelide), have confirmed central nervous system infiltration, or present impaired cardiac function or abnormalities in cardiac repolarization. Patients will be randomized 1:1 to receive asciminib 80 mg once daily or nilotinib 300 mg twice daily, both administered orally under fasting conditions; randomization will be stratified based on European Treatment Outcome Study long-term survival (ELTS) score at diagnosis (high vs intermediate vs low) to help achieve balance between the treatment arms (Figure). The primary endpoint is TTDAE, defined as the time from the date of the first dose of study treatment to the date of discontinuation of study treatment due to an AE. Secondary endpoints include type, frequency and severity of AEs; dose modifications due to AE; changes in laboratory values that fall outside pre-determined ranges; clinically notable ECG changes; time to discontinuation due to selected reasons (lack of efficacy/treatment failure/disease progression/suboptimal response/death); major molecular response (MMR), MR4, MR4.5, complete hematological response (CHR), and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, progression-free survival and overall survival. Secondary endpoints related to QoL include change from baseline in overall scores and individual scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CML24. Participants will be treated in the study until approximately 64 discontinuations due to AEs are met; treatment duration for an individual patient is expected to be 2‒4.5 years. Current status: The study is recruiting as of October 2022. This study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PMON69 Effective Suppression of Gonadotropins and Gonadal Steroids Following Oral Administration of Leuprolide

Abstract A platform designed to enable systemic delivery of peptides via the oral-GI route was employed to deliver low doses of leuprolide --- 4 mg qd (Treatment A, n=9), 4 mg bid (Treatment B, n=9), and 10 mg bid (Treatment D, n=12) --- daily for 28 days to regularly-menstruating, healthy female volunteers. Pharmacodynamic (PD) effects on LH, FSH, estradiol, and progesterone, along with leuprolide drug levels, were assessed weekly and compared to those following a single intramuscular injection of leuprolide acetate 3.75 mg (Treatment C, n=5) in a parallel-group design. The primary PD endpoint was the subject incidence of E2 suppression to ≤40 pg/mL on Treatment Day 29; additional endpoints --- E2 suppression rates on Treatment Days 8, 15 and 22, incidence of 'ovulation' defined as progesterone level ≥3 ng/mL, and suppression of LH and FSH levels --- were assessed on Treatment Days 8, 15, 22, and 29. Safety and tolerability of the test drugs was also assessed. Dose-dependent suppression of E2 was seen, with 66.7%, 87.5%, 100% and 100% of subjects in Treatments A, B, C and D, respectively, achieving E2 ≤40 pg/mL. Median E2 levels on days 15, 22, and 29 were &amp;lt;40 pg/mL after 4 mg bid po, and &amp;lt;20 pg/mL after both 10 mg bid po and the 3.75 mg injection. 'Ovulation rates’ on days 22 and 29 were 0% after both 10 mg bid po and 3.75 mg im. Because of the initial burst following injection of the monthly depot, leuprolide Cmax was greater in Treatment C (17.5 ±2.7 ng/mL) on Dosing Day 1 than for oral leuprolide (3.7 ±3.2 ng/mL for 4 mg qd, 4.1 ±5.1 ng/mL for 4 mg bid), though by Day 29, Css in Treatment C (1.7 ±1.2 ng/mL) was lower than that day's Cmax for oral leuprolide (2.7 ±3.6 ng/mL for 4 mg qd, 4.8 ±6.2 ng/mL for 4 mg bid). Cmax and AUC0-24h were dose-dependent but not strictly dose-proportional. Leuprolide "trough" levels prior to oral dosing were frequently below LLQ (25 pg/mL) in subjects treated with 4 mg qd; this occurred in only 6% of samples on 10 mg bid, and 0% on 4 mg bid, thus confirming reliability of oral delivery of leuprolide. There were no Serious or severe Adverse Events, nor changes in laboratory values of concern. One subject discontinued the study due to a transient episode of nausea, vomiting, and headache during her initial dose of 4 mg po. A total of 80 AEs were treatment-emergent, generally mild in intensity, and spread relatively evenly across all 4 treatment groups. This investigation confirms effective suppression of gonadal steroids via oral administration of leuprolide, comparable to that of injectable leuprolide, and to some marketed doses of GnRH antagonists (historical data). Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

EVALUATION OF CLINICAL AND LABORATORY FINDINGS OF THERAPEUTIC PLASMAPHERESIS IN CHILDREN

Therapeutic plasmapheresis is an extracorporeal treatment method. The abnormal component of the patient's plasma is removed from the blood and replaced with the remaining blood components with a selected replacement fluid. We aimed to evaluate the demographic characteristics, procedure indications, procedure methods, differences between pre- and post-procedure laboratory parameters, and procedure-related complications of pediatric patients who underwent therapeutic plasma exchance (TPE). Pediatric patients who underwent therapeutic plasmapheresis in Adana City Training and Research Hospital between 2018-2021 were included in our study. In this period, the number of pediatric patients who underwent therapeutic plasmapheresis was 61, and the total number of procedures was 238. The data of the patients were obtained from the files of the apheresis unit and the hospital registry system by retrospective analysis. Statistical analysis of the study was made with the SPSS v20 program. 25 patients were female, 36 patients were male. Youngest patient was 6 months old and eldest was 17 years old. Patients weight range was between 5 and 104 kilograms. 191 of the procedures were TPE, 47 of them were lipid apheresis. The most common indications were hepatic failure, familial hyperlipidemia, neurological disorders, hematological disorders, sepsis with MODS and intoxications. 119 transactions were in ASFA category-1. Complications were observed on 59 (%24,8) procedures. The most common complications are; vascular access releated (obstruction) (21/59), hypotension (11/59), urticaria (7/59), technical malfunctions (7/59) and hypocalcemia (4/59). No exitus was observed due to the procedures. Therapeutic plasmapheresis procedure doesn't cause serious undesirable changes in laboratory values ​​and serious complications are rare. Therapeutic plasmapheresis can be safely applied to pediatric patients in appropriate indications by making necessary adjustments.

Impact of preoperative Impella support on destination left ventricular assist device outcomes.

Although left ventricular assist device (LVAD) implantation is associated with improved heart failure survival, the impact of pre-implantation Impella support on outcomes is unknown. We undertook this study to evaluate the impact of preoperative Impella support on LVAD outcomes. We conducted a retrospective review of all Heartmate 3 LVAD implants. Primary stratification was by the need for preoperative Impella support with the 5.0/5.5 device. Longitudinal survival was assessed by the Kaplan-Meier method. Multivariable Cox proportional hazards regression models were developed to evaluate mortality. Secondary outcomes included changes in laboratory values during Impella support. From 2017 to 2021, 87 patients underwent LVAD implantation. Sixteen were supported with a single inotrope, 36 with dual inotropes, 27 with Impella, and 3 with extracorporeal membrane oxygenation (ECMO). When stratified by the need for Impella, there was no difference in survival at 30-days (98.3 [88.2-99.8]% vs. 96.3 [76.5-99.5]%, p = .59), 1-year (91.0 [79.8-96.2] vs. 74.9 [51.7-88.2], p = .10), or at 2 years (87.9 [74.3-94.5] vs. 74.9 [51.7-88.2], p = .15). On multivariable modeling, the need for preoperative Impella was not associated with an increased hazard of 1-year (1.24 [0.23-6.73], p = .81) or 2-year mortality (1.05 [0.21-5.19], p = .95). After 7 (5-10) days of Impella support, recipient creatinine (p < .01), creatinine clearance (p = .02), and total bilirubin (p = .053) improved and lactic acidosis resolved (p < .01). Preoperative Impella support is not associated with increased short or long-term mortality but is associated with improved renal and hepatic function as well as total body perfusion before LVAD implantation.