A randomized, double-blind, placebo-controlled 12-week trial of infliximab in patients with juvenile-onset spondyloarthritis.

OBJECTIVE: To assess the efficacy and safety of infliximab versus placebo in the treatment of patients with juvenile-onset spondyloarthritis (JoSpA). METHODS: Phase III, randomized, double-blind, placebo-controlled trial of 12 weeks that included patients ≤ 18 years old with JoSpA not responding to nonsteroidal anti-inflammatory drugs, sulfasalazine, or methotrexate. Patients were randomly assigned 1:1 to the infusion of infliximab 5mg/kg or placebo; completers entered then an open-label extension (OLE) period of 42 weeks. The primary endpoint was the number of active joints. Secondary outcomes included the assessment of disease activity, tender entheses, spinal mobility, serum C-reactive protein (CRP), the Bath Ankylosing Spondylitis Disease Activity and Functional Index, and the Childhood Health Assessment Questionnaire (CHAQ). RESULTS: We randomized 12 patients to infliximab and 14 to placebo. No significant differences were found between groups at baseline. At week 12, the mean number of active joints was 1.4 (SD 2.4) in the infliximab group and 4.1 (SD 3.0) in the placebo group (p = 0.0002). A repeated-measures mixed model analysis that included all endpoints in the study demonstrated sustained favourable outcomes of infliximab for active joints, tender joints, swollen joints, and tender enthesis counts, as well as for CHAQ and CRP (p < 0.01). Adverse events were more frequent in the infliximab group, including infections and infusion reactions, but none of them was serious. CONCLUSION: Infliximab is efficacious for patients with JoSpA with an inadequate response to conventional treatment. No serious adverse events with the use of infliximab were observed.

Long-Term Safety, Tolerability and Survival in Patients with Pulmonary Arterial Hypertension Treated with Macitentan: Results from the SERAPHIN Open-Label Extension.

INTRODUCTION: In SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients. METHODS: Patients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set. RESULTS: Of 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years). CONCLUSIONS: This analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.

The Effects of Transcranial Direct Current Stimulation in Obsessive-Compulsive Disorder Symptoms: A Meta-Analysis and Integrated Electric Fields Modeling Analysis.

Transcranial direct current stimulation (tDCS) has been showing promising effects for the treatment of obsessive-compulsive disorder (OCD), but there is still no conclusion on its efficacy for this disorder. We performed a systematic review and meta-analysis of trials using tDCS for OCD and a computer modeling analysis to evaluate the electric field (EF) strengths of different electrode assemblies in brain regions of interest (ROIs) (PROSPERO-42021262465). PubMed/MEDLINE, Embase, Cochrane Library and Web of Science databases were searched from inception to 25 September 2022. Randomized controlled trials (RCTs) and open-label studies were included. The primary aim was the effect size (Hedges' g) of continuous outcomes and potential moderators of response. For EF modeling, SimNIBS software was used. Four RCTs and four open-label trials were included (n = 241). Results revealed a large effect of tDCS in the endpoint, but no significant effect between active and sham protocols. No predictor of response was found. EF analysis revealed that montages using the main electrode over the (pre)supplementary motor area with an extracephalic reference electrode might lead to stronger EFs in the predefined ROIs. Our results revealed that tDCS might be a promising intervention to treat OCD; however, larger studies are warranted.

Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial.

BACKGROUND: Mucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline. RESULTS: Drug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1±7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion. CONCLUSION: Clinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6-phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI. TRIAL REGISTRATION: Clinical Trials.Gov, NCT03053089 . Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341 . Registered 6 March, 2017.

Effectiveness of agomelatine on anhedonia in depressed patients: an outpatient, open-label, real-world study.

OBJECTIVE: The aim of this real-world study was to evaluate the effect of agomelatine on anhedonia as primary endpoint in outpatients under treatment of major depressive episodes. METHODS: The study was an open-label, multicenter, 8-week phase IV trial. Two hundred fifty-seven (257) patients were recruited, and 143 patients were included in the analysis. Agomelatine was administered orally as a 25-mg tablet. The dose could be increased to 50 mg after 2 weeks of treatment. RESULTS: An improvement in the severity of anhedonia (Snaith-Hamilton Pleasure Scale total score) was observed from 8.5 points at baseline to 4.1 at week 8, statistically significant (p < 0.05) from the first week. Significant decreases in scores on the severity of depression (Quick Inventory of Depressive Symptomatology 16-item Self-Report [QIDS-SR-16]), anxiety (Generalized Anxiety Disorder 7-item scale), and in overall clinical status (CGI) were also found over 8 weeks, independently from the presence of a first or recurrence episode. Response (QIDS-SR-16 score ≥ 50% of baseline) at week 8 was observed in 65.7% of the patients, while 49.6% of the patients achieved remission (QIDS-SR-16 score ≤ 5). CONCLUSION: Agomelatine was shown to be effective on anhedonia, depression, and anxiety in subjects with major depression. The pragmatic design of the study reflects real-world clinical practice providing interesting insights into routine care management.

Good rate of clinical response to cholinesterase inhibitors in mild and moderate Alzheimers disease after three months of treatment: an open-label study / Boa taxa de resposta clínica aos inibidores da colinesterase na doença de Alzheimer leve e moderada, após três meses de tratamento: um estudo Aberto

Life expectancy in Brazil has increased markedly over the last 30 years. Hence, age-related disorders, such as Alzheimer's disease (AD), warrant special attention due to their high prevalence in the elderly. Pharmacologic treatment of AD is based on cholinesterase inhibitors (ChEI) and memantine, leading to modest clinical benefits both in the short and long-term. However, clinical response is heterogeneous and needs further investigation. OBJECTIVE: To investigate the rate of response to ChEI in AD after three months of treatment. METHODS: Patients with mild or moderate dementia due to probable AD or to AD associated with cerebrovascular disease were included in the study. The subjects were assessed at baseline and again after three months of ChEI treatment. Subjects were submitted to the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, Katz Basic Activities of Daily Living, Pfeffer Functional Activities Questionnaire, Neuropsychiatric Inventory and Cornell Scale for Depression in Dementia. Good response was defined by a gain of >ou = 2 points on the MMSE after three months of treatment in relation to baseline. RESULTS: Seventy-one patients, 66 (93%) with probable AD and five (7%) with AD associated with cerebrovascular disease, were evaluated. The good response rate at three months was 31.0%, being 37.2% and 21.4% in mild and moderate dementia, respectively. There were no significant differences on most tests, except for improvement in hallucinations, agitation and dysphoria in moderate dementia patients.CONCLUSION: The rate of good clinical response to ChEI was higher than usually reported. Specific behavioral features significantly improved in the subgroup of moderate dementia.

A expectativa de vida no Brasil aumentou significativamente nos últimos 30 anos. Desse modo, transtornos relacionados à idade, como a doença de Alzheimer (DA), merecem especial atenção, devido à elevada prevalência. O tratamento farmacológico da DA se baseia nos inibidores da colinesterase (IChE) e na memantina, com melhora modesta em curto e longo prazo. Entretanto, a resposta clínica é heterogênea e necessita maior investigação. OBJETIVO: Investigar a taxa de resposta aos IChE em pacientes com DA após três meses de tratamento. MÉTODOS: Pacientes com demência leve ou moderada devida à DA ou DA com doença cerebrovascular foram avaliados antes e após três meses de uso de IChE. Todos foram submetidos ao Mini-Exame do Estado Mental (MEEM), Escala de Demência Mattis, avaliação das atividades básicas de vida diária de Katz, Questionário de Pfeffer, Inventário Neuropsiquiátrico e Escala de Depressão de Cornell. Boa resposta foi definida pelo ganho de > ou = 2 pontos no MEEM em relação à primeira consulta, após três meses.RESULTADOS: Setenta e um pacientes, 66 (93%) com DA provável e cinco (7%) com DA associada à doença cerebrovascular, foram avaliados. A taxa de boa resposta clínica em três meses foi de 31.0%, sendo 37,2% e 21,4% na demência leve e moderada, respectivamente. Não houve diferença significativa na maioria dos testes, exceto para melhora de alucinação, agitação e depressão em pacientes com demência moderada. CONCLUSÃO: A taxa de boa resposta clínica aos IChE foi superior à encontrada na literatura. Observou-se melhora de alguns sintomas comportamentais em pacientes com DA moderada.

Good rate of clinical response to cholinesterase inhibitors in mild and moderate Alzheimer's disease after three months of treatment: An open-label study.

Life expectancy in Brazil has increased markedly over the last 30 years. Hence, age-related disorders, such as Alzheimer's disease (AD), warrant special attention due to their high prevalence in the elderly. Pharmacologic treatment of AD is based on cholinesterase inhibitors (ChEI) and memantine, leading to modest clinical benefits both in the short and long-term. However, clinical response is heterogeneous and needs further investigation. OBJECTIVE: To investigate the rate of response to ChEI in AD after three months of treatment. METHODS: Patients with mild or moderate dementia due to probable AD or to AD associated with cerebrovascular disease were included in the study. The subjects were assessed at baseline and again after three months of ChEI treatment. Subjects were submitted to the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, Katz Basic Activities of Daily Living, Pfeffer Functional Activities Questionnaire, Neuropsychiatric Inventory and Cornell Scale for Depression in Dementia. Good response was defined by a gain of ≥2 points on the MMSE after three months of treatment in relation to baseline. RESULTS: Seventy-one patients, 66 (93%) with probable AD and five (7%) with AD associated with cerebrovascular disease, were evaluated. The good response rate at three months was 31.0%, being 37.2% and 21.4% in mild and moderate dementia, respectively. There were no significant differences on most tests, except for improvement in hallucinations, agitation and dysphoria in moderate dementia patients. CONCLUSION: The rate of good clinical response to ChEI was higher than usually reported. Specific behavioral features significantly improved in the subgroup of moderate dementia.

A expectativa de vida no Brasil aumentou significativamente nos últimos 30 anos. Desse modo, transtornos relacionados à idade, como a doença de Alzheimer (DA), merecem especial atenção, devido à elevada prevalência. O tratamento farmacológico da DA se baseia nos inibidores da colinesterase (IChE) e na memantina, com melhora modesta em curto e longo prazo. Entretanto, a resposta clínica é heterogênea e necessita maior investigação. OBJETIVO: Investigar a taxa de resposta aos IChE em pacientes com DA após três meses de tratamento. MÉTODOS: Pacientes com demência leve ou moderada devida à DA ou DA com doença cerebrovascular foram avaliados antes e após três meses de uso de IChE. Todos foram submetidos ao Mini-Exame do Estado Mental (MEEM), Escala de Demência Mattis, avaliação das atividades básicas de vida diária de Katz, Questionário de Pfeffer, Inventário Neuropsiquiátrico e Escala de Depressão de Cornell. Boa resposta foi definida pelo ganho de ≥2 pontos no MEEM em relação à primeira consulta, após três meses. RESULTADOS: Setenta e um pacientes, 66 (93%) com DA provável e cinco (7%) com DA associada à doença cerebrovascular, foram avaliados. A taxa de boa resposta clínica em três meses foi de 31.0%, sendo 37,2% e 21,4% na demência leve e moderada, respectivamente. Não houve diferença significativa na maioria dos testes, exceto para melhora de alucinação, agitação e depressão em pacientes com demência moderada. CONCLUSÃO: A taxa de boa resposta clínica aos IChE foi superior à encontrada na literatura. Observou-se melhora de alguns sintomas comportamentais em pacientes com DA moderada.