Impact of geographical and cultural factors on clinical trials in acute mania: lessons from a ziprasidone and haloperidol placebo-controlled study

Clinical trials today are conducted in multiple countries to enhance patient recruitment and improve efficiency of trials. However, the demographic and cultural diversity may contribute to variations in study outcomes. Here we conducted post-hoc analyses for a placebo-controlled study with ziprasidone and haloperidol for the treatment of acute mania to address the demographic, dosing, and outcome disparities in India, Russia and the USA. We compared the baseline characteristics, outcomes and discontinuations in patients and explored the relationship between the outcome measures across these countries. We found substantial differences in baseline characteristics of subjects, administered dosage and disease severity in India compared to the USA and Russia. Conversely, US subjects had a higher placebo response compared to subjects in Russia and India. These results are probably due to demographic differences in patient populations and psychiatric clinical practice across countries. While we offer initial ideas to address the disparities identified in this analysis, it is clear that further research to improve our understanding of geographical differences is essential to ensure globally applicable results for clinical trials in psychiatry.

A Randomized, Placebo-controlled Trial of Preemptive Antifungal Therapy for the Prevention of Invasive Candidiasis Following Gastrointestinal Surgery for Intra-abdominal Infections.

BACKGROUND: Patients undergoing emergency gastrointestinal surgery for intra-abdominal infection are at risk of invasive candidiasis (IC) and candidates for preemptive antifungal therapy. METHODS: This exploratory, randomized, double-blind, placebo-controlled trial assessed a preemptive antifungal approach with micafungin (100 mg/d) in intensive care unit patients requiring surgery for intra-abdominal infection. Coprimary efficacy variables were the incidence of IC and the time from baseline to first IC in the full analysis set; an independent data review board confirmed IC. An exploratory biomarker analysis was performed using logistic regression. RESULTS: The full analysis set comprised 124 placebo- and 117 micafungin-treated patients. The incidence of IC was 8.9% for placebo and 11.1% for micafungin (difference, 2.24%; [95% confidence interval, -5.52 to 10.20]). There was no difference between the arms in median time to IC. The estimated odds ratio showed that patients with a positive (1,3)-β-d-glucan (ßDG) result were 3.66 (95% confidence interval, 1.01-13.29) times more likely to have confirmed IC than those with a negative result. CONCLUSIONS: This study was unable to provide evidence that preemptive administration of an echinocandin was effective in preventing IC in high-risk surgical intensive care unit patients with intra-abdominal infections. This may have been because the drug was administered too late to prevent IC coupled with an overall low number of IC events. It does provide some support for using ßDG to identify patients at high risk of IC. CLINICAL TRIALS REGISTRATION: NCT01122368.

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)-a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group-a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.

Le raisonnement clinique de l'infirmier(ère) expert(e) lors de l'évaluation de la douleur chez l'enfant ventilé et non communicant, sous analgésie et sédation, aux soins intensifs de pédiatrie

Dans le contexte des soins intensifs pédiatriques, la douleur est une préoccupation majeure et quotidienne pour l'équipe soignante. Les patients sont vulnérables de par leur condition et les multiples stimulations douloureuses auxquelles ils sont exposés. En dépit des données probantes démontrant l'importance d'une évaluation de la douleur, le traitement de celle-ci reste non optimal dans cette population vulnérable. Une douleur inadéquatement traitée peut causer de nombreuses complications à moyen et à long terme. L'évaluation de la douleur chez le patient ventilé et non communicant représente un défi important, rendu complexe par l'utilisation concomitante de médicaments sédatifs et analgésiques qui peuvent masquer ou altérer les comportements de la douleur. Il existe des outils d'évaluation adaptés à cette population vulnérable, mais l'interprétation des scores reste difficile. L'évaluation de la douleur demande aux infirmières des connaissances et compétences élevées à même d'être mobilisées lors d'un processus complexe lié au raisonnement clinique. Le but de cette étude descriptive et observationnelle est de déterminer les indicateurs utilisés par les infirmières expertes des soins intensifs de pédiatrie lors de l'évaluation de la douleur chez le patient ventilé et non communicant, sous analgésie et sédation. Un échantillon de convenance de dix infirmières expertes travaillant dans une unité de soins intensifs pédiatriques d'un hôpital universitaire de Suisse romande a participé à cette étude. Les données ont été récoltées par l'enregistrement de la verbalisation du raisonnement clinique au lit du patient, complété par une observation non participante et un entretien semi-structuré. Le développement d'un cadre théorique constitué d'un modèle de raisonnement clinique expert et d'une modélisation du décodage de la douleur a permis de réaliser une analyse de contenu des enregistrements. Les résultats montrent une utilisation importante des indicateurs physiologiques, en lien avec la stabilité clinique du patient qui est un critère essentiel pour la prise de décision lors de la gestion de la douleur. La difficulté à discriminer l'agitation résultant de la douleur ou d'autres causes est également omniprésente. Les expertes anticipent et préviennent la survenue de la douleur en s'appuyant sur leurs connaissances et les situations de patient déjà rencontrées. Le contexte clinique influence de manière prépondérante le raisonnement clinique et les indicateurs utilisés lors de l'évaluation et la gestion de la douleur. Celle-ci doit être évaluée de manière combinée avec la stabilité clinique du patient et son niveau de sédation. De futures recherches sont nécessaires pour confirmer ces résultats réalisés avec un échantillon de petite taille et un devis observationnel.

Randomized, crossover, double-blind, placebo-controlled trial to assess the lipid lowering effect of co-formulated TDF/FTC

Abstract INTRODUCTION: Previous studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1-3] It is unknown, however, if TDF has an intrinsic lipid-lowering effect or such findings are due to the addition or removal of other offending agents or other reasons. MATERIALS AND METHODS: RESULTS: 46 subjects with a median age of 43 (40-48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL-cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL-cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL-cholesterol (p<0.001) and HDL-cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total-cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL-cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure. CONCLUSION: Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF.

Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study.

BACKGROUND: The ongoing Ebola outbreak led to accelerated efforts to test vaccine candidates. On the basis of a request by WHO, we aimed to assess the safety and immunogenicity of the monovalent, recombinant, chimpanzee adenovirus type-3 vector-based Ebola Zaire vaccine (ChAd3-EBO-Z). METHODS: We did this randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a trial at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Participants (aged 18-65 years) were randomly assigned (2:2:1), via two computer-generated randomisation lists for individuals potentially deployed in endemic areas and those not deployed, to receive a single intramuscular dose of high-dose vaccine (5 × 10(10) viral particles), low-dose vaccine (2·5 × 10(10) viral particles), or placebo. Deployed participants were allocated to only the vaccine groups. Group allocation was concealed from non-deployed participants, investigators, and outcome assessors. The safety evaluation was not masked for potentially deployed participants, who were therefore not included in the safety analysis for comparison between the vaccine doses and placebo, but were pooled with the non-deployed group to compare immunogenicity. The main objectives were safety and immunogenicity of ChAd3-EBO-Z. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02289027. FINDINGS: Between Oct 24, 2014, and June 22, 2015, we randomly assigned 120 participants, of whom 18 (15%) were potentially deployed and 102 (85%) were non-deployed, to receive high-dose vaccine (n=49), low-dose vaccine (n=51), or placebo (n=20). Participants were followed up for 6 months. No vaccine-related serious adverse events were reported. We recorded local adverse events in 30 (75%) of 40 participants in the high-dose group, 33 (79%) of 42 participants in the low-dose group, and five (25%) of 20 participants in the placebo group. Fatigue or malaise was the most common systemic adverse event, reported in 25 (62%) participants in the high-dose group, 25 (60%) participants in the low-dose group, and five (25%) participants in the placebo group, followed by headache, reported in 23 (57%), 25 (60%), and three (15%) participants, respectively. Fever occurred 24 h after injection in 12 (30%) participants in the high-dose group and 11 (26%) participants in the low-dose group versus one (5%) participant in the placebo group. Geometric mean concentrations of IgG antibodies against Ebola glycoprotein peaked on day 28 at 51 μg/mL (95% CI 41·1-63·3) in the high-dose group, 44·9 μg/mL (25·8-56·3) in the low-dose group, and 5·2 μg/mL (3·5-7·6) in the placebo group, with respective response rates of 96% (95% CI 85·7-99·5), 96% (86·5-99·5), and 5% (0·1-24·9). Geometric mean concentrations decreased by day 180 to 25·5 μg/mL (95% CI 20·6-31·5) in the high-dose group, 22·1 μg/mL (19·3-28·6) in the low-dose group, and 3·2 μg/mL (2·4-4·9) in the placebo group. 28 (57%) participants given high-dose vaccine and 31 (61%) participants given low-dose vaccine developed glycoprotein-specific CD4 cell responses, and 33 (67%) and 35 (69%), respectively, developed CD8 responses. INTERPRETATION: ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase 2 and phase 3 efficacy trials in Africa. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme.

Avaliação do efeito analgésico preemptivo do lumiracoxibe comparado com placebo nas primeiras 24 horas de pós-operatório

OBJETIVO: Testar o lumiracoxibe, utilizado preemptivamente contra um placebo, e analisar o consumo de analgésicos (dipirona e tramadol) nas primeiras 24h do pós-operatório. MÉTODOS: Sessenta pacientes submetidas à mamoplastia de aumento, sob anestesia peridural, foram selecionadas e divididas de forma randomizada em dois grupos - GI e GII. Sessenta minutos antes da operação, por via oral, as 30 pacientes do GI receberam um comprimido de lumiracoxibe 400mg, e as 30 do GII um comprimido de placebo. A dor pós-operatória foi avaliada através da escala analógica visual, graduada de 0 (sem dor) a 10 (dor de maior intensidade), sendo aplicada sempre que houvesse referência de dor. Para escores obtidos iguais ou menores que 4, a paciente recebia 15mg/kg de dipirona, até máximo de um grama, via venosa. Para escores de 5, 6 ou 7, recebia 50mg de tramadol por via venosa. Escores de 8 ou mais eram tratados com 0,5mg/kg de meperidina endovenosa. RESULTADOS: Os escores obtidos no GI foram significativamente menores que os do GII dentro das primeiras 24 horas, resultando em consumo 20% menor de dipirona e 56% menor de tramadol. Da mesma forma, observou-se que o tempo para solicitação de analgésicos pela primeira vez no pós-operatório foi de 191 minutos maior no GI. CONCLUSÃO: O emprego do lumiracoxibe preemptivamente mostrou-se efetivo no combate à dor pós-operatória, reduzindo consideravelmente o consumo global de analgésicos nesse período e aumentando o tempo de solicitação de analgésico pela primeira vez.

Vitamina D e cicatrização de pele: estudo prospectivo, duplo-cego, placebo controlado na cicatrização de úlceras de perna

OBJETIVO: Estudar a relação entre deficiência de vitamina D e cicatrização de pele em pacientes com úlceras de perna, relacionar esta deficiência com características da úlcera e avaliar se a reposição de vitamina D nos indivíduos deficientes acelera a cicatrização da úlcera. MÉTODOS: Foram escolhidos aleatoriamente 26 pacientes com úlceras venosas de perna e 26 sem úlcera pareados para sexo, idade, HAS e tabagismo. Os grupos foram comparados com relação à dosagem sérica de vitamina D. O grupo úlcera foi dividido em dois subgrupos: um que tomou placebo e outro que recebeu vitamina D 50.000UI por semana durante dois meses. Foi realizada a dosagem da 25-OH-vitamina D e avaliados o tamanho da úlcera e a gravidade da dor, antes e após o tratamento. RESULTADOS: A maioria dos pacientes apresentava níveis insuficientes de vitamina D. Não foi encontrada correlação entre o tamanho da úlcera sem tratamento e os níveis de vitamina D. Nos pacientes que receberam vitamina D, após o tratamento, o tamanho mediano da área da úlcera, diminui de 25cm², para 18cm² e no grupo placebo, de 27cm² para 24,5cm² (p=0,7051 e p=0,7877, respectivamente). Considerando-se a variabilidade da área da úlcera do grupo vitamina D versus placebo, a mediana foi igual a -0,75cm² no primeiro grupo e 4cm² no segundo grupo (p=0,0676). CONCLUSÃO: Pacientes com úlcera de perna têm mais deficiência de vitamina D que os sem. A deficiência de vitamina D não influiu nas características das lesões. A cicatrização nos pacientes com hipovitaminose D mostrou tendência para ser maior naqueles que receberam reposição vitamínica.

Estudo comparativo entre misoprostol e placebo para o amadurecimento cervical e indução do parto

Objetivo: avaliar a eficácia e segurança da aplicação intravaginal de misoprostol para amadurecimento cervical e indução do parto em gravidez a termo quando comparado com placebo.Pacientes e Métodos: cinqüenta e uma mulheres com gestação de alto risco, a termo, e cérvix imatura foram alocadas em estudo duplo cego para aplicação de misoprostol intravaginal (40 mg de 4/4 h) ou placebo intravaginal (4/4 h). Resultados: entre as 51 pacientes estudadas, 32 receberam misoprostol e 19 receberam placebo. Os grupos foram homogêneos quanto à idade materna, idade gestacional, paridade e indicação para indução (p > 0,05). No grupo Misoprostol observamos 87,5% de eficácia e no grupo placebo 21,1% de eficácia (p=0,0000087). Em relação à via de parto, no grupo Misoprostol 75% dos partos foram vaginais e 25% cesáreos, Já no grupo placebo, apenas 32% foram partos vaginais e 68% cesáreos (p = 0,0059). O Apgar neonatal foi semelhante em ambos grupos. Conclusão: misoprostol se apresentou extremamente eficaz e seguro no amadurecimento cervical e indução do parto, surgindo como nova opção em obstetrícia em gestações de alto risco, a termo, com cérvix imatura e com necessidade de resolução do parto a curto prazo.

Ensaio clínico placebo-controlado com isoflavonas da soja para sintomas depressivos em mulheres no climatério

OBJETIVOS: avaliar a eficácia do uso de isoflavonas da soja no tratamento de sintomas depressivos em mulheres com síndrome climatérica. MÉTODOS: estudo experimental placebo-controlado, randomizado e duplo-cego, com 84 pacientes climatéricas atendidas ambulatorialmente no Hospital Universitário Lauro Wanderley, em João Pessoa (PB). Na avaliação de sintomas depressivos empregou-se o Questionário de Auto-avaliação da Escala de Hamilton para Depressão (QAEH-D) nas visitas pré-tratamento (VT1) e na 8ª (VT2) e na 16ª (VT3) semana pós-tratamento. O grupo experimental (GExp) recebeu extrato de isoflavonas da soja, 120 mg por dia, e o controle (GCont), placebo. A comparação dos escores do QAEH-D entre os grupos em VT1, VT2 e VT3 constituiu a medida primária de eficácia (teste t, p<0,05). Análise secundária incluiu estimativa do "efeito dominó" e avaliação clínica e laboratorial de eventos adversos. RESULTADOS: houve redução significativa dos escores do QAEH-D no GExp (VT20,05). De VT1 para VT3, evidenciou-se diferença estatisticamente significativa de 8,9% na redução dos escores entre os grupos (p=0,03). Não houve correlação da redução dos sintomas depressivos com resposta dos sintomas vasomotores (p>0,05). Houve redução das concentrações de FSH apenas no GExp (p=0,02), sem alterações do estradiol. Não ocorreram eventos adversos clinicamente relevantes. CONCLUSÕES: o efeito do extrato de isoflavonas foi superior ao do placebo, porém de pequena magnitude e apenas após 8 semanas de tratamento. Este pequeno efeito atribuído ao tratamento experimental, de boa tolerabilidade, poderá beneficiar pacientes que têm efeitos colaterais aos estrógenos ou que preferem não usar estes hormônios.