Effects of Dose Titration on Dipyridamole-Induced Headache: A Randomized, Double-Blind Clinical Trial

<b><i>Purpose:</i></b> The aim of this study is to investigate the effect of gradual dipyridamole titration and the incidence of dipyridamole-induced headache in patients with ischemic stroke or transient ischemic attack (TIA). <b><i>Methods:</i></b> A randomized, double-blind, double-placebo, parallel group, phase 4 clinical trial (KCT0005457) was conducted between July 1, 2019, and February 25, 2020, at 15 medical centers in South Korea. The study included patients aged &#x3e;19 years diagnosed with a noncardioembolic ischemic stroke or TIA within the previous 3 weeks. The participants were randomized 1:1:1 to receive Adinox® (aspirin 25 mg/dipyridamole 200 mg) and aspirin (100 mg) once daily for the first 2 weeks followed by Adinox® twice daily for 2 weeks (titration group), Adinox® twice daily for 4 weeks (standard group), and aspirin 100 mg once daily for 4 weeks (control group). The primary endpoint was incidence of headache over 4 weeks. The key secondary endpoint was mean cumulative headache. <b><i>Results:</i></b> Ninety-six patients were randomized into the titration (<i>n</i> = 31), standard (<i>n</i> = 32), and control (<i>n</i> = 33) groups. The titration and standard groups (74.1% vs. 74.2%, respectively) showed no difference in the primary endpoint. However, the mean cumulated headache was significantly lower in the titration group than in the standard group (0.31 ± 0.46 vs. 0.58 ± 0.51, <i>p</i> = 0.023). Further, adverse drug reactions were more common in the standard group than in the titration group (28.1% vs. 9.7%, respectively, <i>p</i> = 0.054), although not significantly different. <b><i>Conclusion:</i></b> The titration strategy was effective in lowering the incidence of cumulative dipyridamole-induced headache.

Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma

Background Exposure–response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. Methods Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. Results Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46–0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67–0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02–1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. Conclusions The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib’s therapeutic benefit/risk ratio. Clinical trial registration number NCT02365597.

Initial response of young people with thyrotoxicosis to block and replace or dose titration thionamide

Objective Patients with thyrotoxicosis are treated with anti-thyroid drug (ATD) using block and replace (BR) or a smaller, titrated dose of ATD (dose titration, DT). Design A multi-centre, phase III, open-label trial of newly diagnosed paediatric thyrotoxicosis patients randomised to BR/DT. We compared the biochemical response to BR/DT in the first 6 months of therapy. Methods Patients commenced 0.75 mg/kg carbimazole (CBZ) daily with randomisation to BR/DT. We examined baseline patient characteristics, CBZ dose, time to serum thyroid-stimulating hormone (TSH)/free thyroxine (FT4) normalisation and BMI Z-score change. Results There were 80 patients (baseline) and 78 patients (61 female) at 6 months. Mean CBZ dose was 0.9 mg/kg/day (BR) and 0.5 mg/kg/day (DT). There was no difference in time to non-suppressed TSH concentration; 16 of 39 patients (BR) and 11 of 39 (DT) had suppressed TSH at 6 months. Patients with suppressed TSH had higher mean baseline FT4 levels (72.7 vs 51.7 pmol/L; 95% CI for difference 1.73, 31.7; P = 0.029). Time to normalise FT4 levels was reduced in DT (log-rank test, P = 0.049) with 50% attaining normal FT4 at 28 days (95% CI 25, 32) vs 35 days in BR (95% CI 28, 58). Mean BMI Z-score increased from 0.10 to 0.81 at 6 months (95% CI for difference 0.57, 0.86; P < 0.001) and was greatest in patients with higher baseline FT4 concentrations. Conclusions DT-treated patients normalised FT4 concentrations more quickly than BR. Overall, 94% of patients have normal FT4 levels after 6 months, but 33% still have TSH suppression. Excessive weight gain occurs with both BR and DT therapy.

2022 European Thyroid Association Guideline for the management of pediatric Graves’ disease

Hyperthyroidism caused by Graves’ disease (GD) is a relatively rare disease in children. Treatment options are the same as in adults – antithyroid drugs (ATD), radioactive iodine (RAI) or thyroid surgery, but the risks and benefits of each modality are different. The European Thyroid Association guideline provides new recommendations for the management of pediatric GD with and without orbitopathy. Clinicians should be alert that GD may present with behavioral changes or declining academic performance in children. Measurement of serum TSH receptor antibodies is recommended for all pediatric patients with hyperthyroidism. Management recommendations include the first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years or more), a preference for dose titration instead of block and replace ATD, and to avoid propylthiouracil use. Where definitive treatment is required either total thyroidectomy or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI activity. We recommend avoiding RAI in children under 10 years of age but favor surgery in patients with large goiter. Pediatric endocrinologists should be involved in all cases.

Contribution of Gut Microbiota to Immune Tolerance in Infants

The prevalence of food allergy has increased in recent years, especially among the pediatric population. Differences in the gut microbiota composition between children with FA and healthy children have brought this topic into the spotlight as a possible explanation for the increase in FA. The gut microbiota characteristics are acquired through environmental interactions starting early in life, such as type of delivery during birth and breastfeeding. The microbiota features may be shaped by a plethora of immunomodulatory mechanisms, including a predominant role of Tregs and the transcription factor FOXP3. Additionally, a pivotal role has been given to vitamin A and butyrate, the main anti-inflammatory metabolite. These observations have led to the study and development of therapies oriented to modifying the microbiota and metabolite profiles, such as the use of pre- and probiotics and the determination of their capacity to induce tolerance to allergens that are relevant to FA. To date, evidence supporting these approaches in humans is scarce and inconclusive. Larger cohorts and dose-titration studies are mandatory to evaluate whether the observed changes in gut microbiota composition reflect medical recovery and increased tolerance in pediatric patients with FA. In this article, we discuss the establishment of the microbiota, the immunological mechanisms that regulate the microbiota of children with food allergies, and the evidence in research focused on its regulation as a means to achieve tolerance to food allergens.

Evaluation of Anticoagulation Control among Patients Taking Warfarin in University of Gondar Hospital, Northwest Ethiopia

Introduction. Warfarin is a widely used oral anticoagulant in clinical practice. It has variable intraindividual and interindividual dose response and a narrow therapeutic index. Therefore, it requires frequent and regular international normalized ratio (INR) determination to maintain the INR within the therapeutic range. The study evaluated parameters of anticoagulation control among patients on warfarin. Methods. A cross-sectional study was conducted at University of Gondar hospital. A consecutive sampling method was used to recruit study subjects. The anticoagulation control was evaluated by determining the proportion of desired INRs and the proportion of time spent in the therapeutic range (TTR). Logistic regression analysis was used to identify associated factors with adequate TTR. A P value <0.05 was used to declare significant association. Result. A total of 338 study subjects were included in the study. The mean age of patients was 48.8 (SD = 16.4) years. Atrial fibrillation was the commonest indication for warfarin therapy. One-third (33%) of study subjects achieved the desired INRs of 2.0–3.0, while about one-tenth (13%) of patients attained good INR control (TTR ≥ 65%). Multivariate logistic regression analysis revealed no significant association of sociodemographic and clinical characteristics with good TTR outcome. Conclusion. The level of anticoagulation control with warfarin among study subjects was very low. The authors recommend to implement a validated warfarin-dose titration protocol and to establish anticoagulation clinics to mitigate the low anticoagulation level.

Current Advances of Artificial Pancreas Systems: A Comprehensive Review of the Clinical Evidence

Since Banting and Best isolated insulin in the 1920s, dramatic progress has been made in the treatment of type 1 diabetes mellitus (T1DM). However, dose titration and timely injection to maintain optimal glycemic control are often challenging for T1DM patients and their families because they require frequent blood glucose checks. In recent years, technological advances in insulin pumps and continuous glucose monitoring systems have created paradigm shifts in T1DM care that are being extended to develop artificial pancreas systems (APSs). Numerous studies that demonstrate the superiority of glycemic control offered by APSs over those offered by conventional treatment are still being published, and rapid commercialization and use in actual practice have already begun. Given this rapid development, keeping up with the latest knowledge in an organized way is confusing for both patients and medical staff. Herein, we explore the history, clinical evidence, and current state of APSs, focusing on various development groups and the commercialization status. We also discuss APS development in groups outside the usual T1DM patients and the administration of adjunct agents, such as amylin analogues, in APSs.

A Phase 1 Dose Escalation Study of Dual PI3K and DNA PK Inhibitor, BR101801 in Adult Patients with Advanced Hematologic Malignancies

Background: BR101801 not only blocks the signaling responsible for cell growth caused by PI3K, but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation and stimulates decreasing stability of the oncogenic protein, c-Myc(AACR2020 abstract #655). This phase I study evaluated safety, tolerability, pharmacokinetics and preliminary activity of the BR101801 (PI3Kγ/δ and DNA PK inhibitor) in patients with advanced hematologic malignancies. Method: This is a Phase I, multi-center, open-label, first-in-human study. The Phase Ia (dose escalation) part of the study was designed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of BR101801. BR101801 was administered orally once daily in 28-day cycles. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results: 11 patients were enrolled and have been treated at 4 dose levels: 50mg, 100mg, 200mg, 325mg and expanded 200mg through fifth cohort escalation. Pathological subtypes include 7 PTCL, 2 DLBCL, 1 MZBL and 1 composite CTCL/MF. 3 females and 8 males have been treated to date. Median age is 58 (range 30-71) and ECOG PS is in the range of 0-1. All patients had taken at least one prior chemotherapy. 10 of total patients have completed at least one cycle except 1 premature drop-out case due to disease progression. First interim analysis after completion of cycle 3 of the last patient of 200mg QD cohort had been conducted, which was to include 5 patients (1 DLBCL and 4 PTCLs). No DLT had been identified in Cohorts 1-3, and 2 patients discontinued the study treatment due to adverse event (G4 thrombocytopenia, not related to IP) and disease progression, respectively. The PK values from multiple dosing range of 50mg to 200mg cohort resulted in an approximate 2.92-fold and 4.97 fold increase in exposure based on Cmax and AUCtau, respectively. BR101801 PK profile showed that the exposure of concentration increased in a dose dependent manner and there was no accumulation observed in the dose range of 50mg to 200mg. 2 DLTs was observed at 325mg QD cohort. The dose was de-escalated to the previous lower dose level (200mg QD) and was expanded to 3 additional patients. The expansion cohort is ongoing at present. 2 of 11 patients had G3 skin reaction and 3 had G3 hepatotoxicites. All adverse effects were manageable and recovered to grade 0-1 upon BR1010801 discontinuation. Total 5 patients have been currently ongoing. For overall tumor response assessment, 4 SDs and 2 PRs have been obsereved. Summary/Conclusion: 200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL. This study is registered at clinicaltrials.gov identifier NCT04018248. Disclosures Kim: AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Curran: Servier pharmaceuticals and Amgen: Consultancy. Kim: Boryung pharmaceuticals: Current Employment.