Cendakimab in Patients With Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.

Importance: Cendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases. Objective: To evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD. Design, Setting, and Participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023. Interventions: Patients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo. Main Outcome and Measure: Mean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo. Results: Overall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo. Conclusions and Relevance: The results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04800315.

Pharmacokinetics, safety, and tolerability of BMS-986263, a lipid nanoparticle containing HSP47 siRNA, in participants with hepatic impairment.

BMS-986263 is a retinoid-conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen-specific chaperone protein involved in fibrosis development. This is a phase I, open-label, two-part study evaluating pharmacokinetics and safety of BMS-986263 in participants with hepatic impairment (HI). Part 1 (n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age- and body mass index (BMI)-matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age- and BMI-matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS-986263 infusion. Compared with normal-matched participants, geometric mean area under the plasma concentration-time curve time zero to the time of the last quantifiable concentration (AUC(0-T) ) and AUC from zero to infinity (AUC(INF) ) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal-matched group. Overall, single-dose BMS-986263 was generally safe and well-tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS-986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure-safety/efficacy relationship becomes available.

Relationship between GH response and glycemic fluctuations in the glucagon stimulation test.

OBJECTIVE: Verifying the association between glycemic fluctuation and GH response in the glucagon stimulation test. Basal evaluation of growth hormone (GH) has poor diagnostic accuracy due to its pulsatile secretion. GH-stimulation tests are used for an adequate evaluation of somatotrophic axis. Various stimuli can be employed, among them glucagon, which has an elusive mechanism of action. Since hypoglycemia reportedly occurs during the test, investigation of its role as a stimulus to GH release is granted. DESIGN: Retrospective analysis of glucagon-stimulated GH tests performed in 128 children (36.7% female; age 12.4+3.3 years), at Fleury Functional Tests Facility from July 2000 to 2006. GH and blood glucose (BG) curves, IGF-1, and IGFBP-3 have been assessed. Positive GH response was defined by a peak GH value >or=3.3 microg/L. Normal IGF-1 levels were defined as those between 2.5th and 97.5th percentiles for age and gender. RESULTS: Hypoglycemia under 2.2 mmol/L did not occur during the test. BG decrease occurred with lower magnitude and was not associated to GH response. Comparison between patients with negative and positive GH response showed, respectively, BG nadir 3.74 vs. 3.62 mmol/L, glucose AUC 23.3 vs. 22.4, and glycemic decrease (below 3.3 mmol/L) 19% vs. 35.5% (with P non-significant for all comparisons). CONCLUSION: Hypoglycemia was not seen after glucagon stimulation and decrease in BG occurred above levels physiologically expected to stimulate GH release, being apparently not associated to GH response.

[Tolerance of the oral clonidine test in 180 patients: efficacy of the volemic expantion in controlling arterial hypotension]. / Tolerância ao teste da clonidina em 180 pacientes: estudo da eficácia da expansão volêmica para o controle de hipotensão arterial.

Clonidine stimulation test is widely used to evaluate growth hormone secretion. Side effects are somnolence (35%) and arterial hypotension (AH) (5%). The aims of this paper were to evaluate the tolerance to this test regarding blood pressure (BP) decrease, sedation and the efficacy of saline resuscitation to prevent AH. BP was measured at basal, 60 and 120 min. Sedation was determined by the Ramsay scale. Patients were divided into two groups: Group 1 (n = 80) received saline resuscitation only upon severe AH (drop of mean BP [MBP] > 20% from initial MBP) and/or postural hypotension; Group 2 (n = 100) received saline resuscitation from the beginning of the test. Both groups presented a significant MBP fall and 75% presented somnolence at 60 min. MBP drop did not correlate with either sedation or the clonidine dose. Group 1 presented more hypotension (59% x 28%) and greater MBP drop at 60 min. Only one patient had an asthma attack. We conclude that the hypotension effects caused by oral clonidine diminish with saline resuscitation since the beginning of the test. This test must have specialized medical support with strict BP evaluation and precocious intervention when needed.

Monitorização contínua de glicose: análise crítica baseada em experiência ao longo de um ano / Continuous glucose monitoring: a critical appraisal after one year experience

A avaliação do controle glicêmico no diabetes mellitus (DM) envolve tradicionalmente a observação das taxas de glicemia e hemoglobina glicada. Recentemente o Fleury - Centro de Medicina Diagnóstica implantou o exame de monitorização contínua de glicose (MCG) (Medtronic Minimed - CGMS® System GoldTM) e, neste trabalho, objetivamos descrever a experiência relacionada à realização deste exame durante o ano de 2004. Realizaram-se 141 exames neste período. Do total, 88 por cento (n= 124) pacientes eram diabéticos, sendo 99 usuários de insulina. Encontramos forte correlação entre os valores de glicose obtidos com a MCG e no sangue capilar (r= 0,926; p< 0,005). Nos diabéticos, identificou-se hipoglicemia noturna (< 50mg/dL) em 35 por cento (n= 44), padrões hiperglicêmicos (> 220mg/dL) em períodos determinados do dia em 44 por cento e hiperglicemia sustentada ao longo de toda monitorização em treze casos (10 por cento). Doze exames foram realizados para investigação de hipoglicemias em não diabéticos. Dois exames foram sugestivos de "dumping" e em um caso a MCG reforçou a hipótese de insulinoma. Ocorreram interrupções parciais das monitorizações em 15 por cento dos exames. Concluímos que a MCG é uma metodologia útil para investigação das oscilações glicêmicas, sendo uma importante ferramenta para ajuste terapêutico em pacientes com DM.

Tolerância ao teste da clonidina em 180 pacientes: estudo da eficácia da expansão volêmica para o controle de hipotensão arterial / Tolerance of the oral clonidine test in 180 patients: efficacy of saline resuscitation in controlling arterial hypotension

O teste da clonidina é amplamente usado para avaliar a secreção do hormônio do crescimento. Os efeitos colaterais são sonolência (35 por cento) e hipotensão arterial (HA) (5 por cento). Nossos objetivos foram avaliar a tolerância ao teste quanto à queda da pressão arterial (PA), grau de sedação e eficácia da expansão volêmica para controle da HA. A PA foi medida nos tempos basal, 60 e 120 min. A sedação foi baseada na escala Ramsay. Os pacientes foram divididos em dois grupos: o Grupo 1 (n= 80) recebeu expansão volêmica apenas com HA grave (queda da PA média [PAM] > 20 por cento da PAM inicial) e/ou hipotensão postural; o Grupo 2 (n=100) recebeu expansão volêmica desde o início do teste. Nos dois grupos, a PAM caiu significativamente e 75 por cento apresentaram sonolência aos 60 min. Não houve correlação da queda da PAM com grau de sedação e dose administrada. O Grupo 1 apresentou mais hipotensão (59 por cento x 28 por cento) e maior queda da PAM aos 60 min. Apenas um paciente apresentou broncoespasmo. Concluímos que o efeito hipotensor da clonidina diminui com expansão volêmica desde o início no teste. Este teste deve ser sempre feito com acompanhamento médico especializado para observação estrita da PA e intervenção precoce, se necessária.

[Continuous glucose monitoring: a critical appraisal after one year experience]. / Monitorização contínua de glicose: análise crítica baseada em experiência ao longo de um ano.

Conventional assessment of glycemic control in diabetes mellitus (DM) includes blood glucose attention to glycemia and glycated hemoglobin levels. Recently, we introduced the continuous glucose-monitoring test (CGM) (Medtronic Minimed-CGMS System Gold). Here we describe our experience with this methodology over the year 2004. A total of 141 CGM tests were performed over this period of time. Overall, 88% (n= 124) patients were diabetics (DM), 99 of them were insulin users. We found a strong correlation between glucose values obtained by CGM and capillary glucose measures (r= 0.926; p< 0.005). In diabetic patients, nocturnal hypoglycemia (< 50 mg/dL) was identified in approximately 35% (n= 44), hyperglycemic patterns (> 220 mg/dL) at specific times of day in approximately 44% and sustained hyperglycemia throughout the whole monitoring period in thirteen cases (10%). Twelve tests were performed to investigate the occurrence of hypoglycemia in non-diabetic subjects. Two tests came out very suggestive of "dumping", and in one case the CGMS supported the hypothesis of insulinoma. Partial monitoring interruptions have occurred in 15% of all tests. We concluded that CGMS is a useful methodology to investigate glycemic fluctuations, and it is also an important tool to adjust therapy in diabetic patients.