Nonadherence to immunosuppressives and treatment in kidney transplant: ADHERE BRAZIL Study

OBJECTIVE To estimate the prevalence and variability of nonadherence to immunosuppressives and nonpharmacological treatment across kidney transplantation centers and two health access-disparate regions in Brazil. METHODS In a cross-sectional design, a random multistage sample of 1,105 patients was included, based on center transplantation activity (low/moderate/high) and region (R1: North/Northeast/Mid-West; and R2: South/Southeast). Nonadherence to immunosuppressives (implementation phase) was assessed using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS)©. Self-report questionnaires assessed nonadherence to physical activity, smoking cessation, alcohol intake, and appointment keeping. We compared regions using the adjusted-χ2 or t-test. RESULTS Most patients were men (58.5%), white (51.4%), and had a mean age of 47.5 (SD = 12.6) years. Regarding kidney transplantation centers, 75.9% were from R2 and 38.2% had low activity. The patients in R2 were older, white-majority, had more frequently steady partners, and received peritoneal dialysis. Nonadherence to immunosuppressives ranged from 11–65.2%; 44.5–90% to physical activity; 0–23.7% to appointment keeping; and 0–14% to smoking cessation. The total prevalence of nonadherence and by region (R1 versus R2) were: for immunosuppressives, 39.7% (44.9% versus 38.1%, p = 0.18); for smoking, 3.9% (1% versus 5%, p < 0.001); for physical activity, 69.1% (71% versus 69%, p = 0.48); for appointment keeping, 13% (12.7% versus 12%, p = 0.77); and for alcohol consumption, 0%. CONCLUSION Despite differences among centers and high variability, only the nonadherence to smoking cessation was higher in the region with greater access to kidney transplantation. We suppose that differences in healthcare access may have been overcome by other positive aspects of the post kidney transplantation treatment

Não aderência no pós-transplante renal : validação do instrumento the basel assessment of adherence with imunossupressive medication scale e condições associadas

Chronic Kidney Disease (CKD) is now an important medical and public health problem. Kidney transplantation is currently the best therapeutic option for patients with CKD, both from the medical, the social or economic´s points of view. To promote safety and therapeutic control of clinical and surgical complications, some strategies are fundamental. An issue that is considered very important is nonadherence (NA) to the use of medications and the proposed treatment. Adherence is defined as the degree of agreement between the behavior of a patient in relation to the advice of the physician and/or other healthcare professional. It is a multidimensional phenomenon that involves factors determined by socio-economic issues, the health system, health professionals, factors related to therapy and to the patient. For the diagnosis of NA we can apply direct and indirect methods. This study aimed to validate to the Brazilian transplant population the instrument “The Basel Assessment of Medication Adherence with Imunossupressive Scale” (BAASIS), using a sample of renal transplant patients, form the outpatient clinic of the NúcleoInterdisciplinar de Estudos e PesquisasemNefrologia da Universidade Federal de Juiz de Fora (Niepen),to assess the frequencyof NAin the studied population, evaluatedby employingthree diagnostic methodsand to evaluate theassociation betweenrisk factorsand the presence ofNA. This is a cross-sectional study of 100 renal transplant recipients with more than one year of transplant, followed as an outpatient at Niepen. The BAASIS (English version) was transculturally adapted and psychometric properties were assessed. Transcultural adaptation was performed using the Guillemin protocol (i.e. translation, back translation, analysis by an expert committee, and pre-testing). Psychometric testing included intra and inter observer reproducibility,Cronbach’salpha,correlation between BAASIS and Measure of Adherence to Treatment and factorial analysis. In alsounivariate and multivariate analyzes for factors associated with NA. Patients were classified into two groups: adherent and non-adherent using three diagnostic methods (The BAASIS, the professionals' opinion and imunossupressivesblood levels) and the conditions associated with NA were collected from a questionnaire and medical files. The mean age of patients was 45 ± 13.5 years, 65% were men and 89% received a graft from a living donor. On testing the psychometric properties of reliability, intra-observer reproducibility showed a variance of 0.007, with inter-observer reproducibility having a variance of 0.003, suggesting preciseness was achieved. For Validity, in construct validity, exploratory factorial analysis demonstrated unidimensionality of the first three questions (r=0.76; r=0.80, and r=0.68). For criterion validity, the adapted BAASIS was correlated with another self-reporting instrument – Measure of Adherence to Treatment (MAT) and showed good congruence/correlation (r=0.65). Cronbach's alpha was0.7. 51% of patients were considered nonadherente using three methods to assess adherence to immunosuppressive treatment. Variables related to NA were: living more than 100 km from the transplant center (54.9 vs. 38.8%, p<0.07), family income higher than five minimum wages (21.6 vs. 4%, p<0.009), and access to lab tests from health insurance (35.3% vs. 18.4%, p<0.01). In the logistic regression model only low family income higher than five minimum wages was a risk factor for NA (OR 5.0 CI: 1.01 to 25.14, p<0.04). The results showed the BAASIS has good psychrometric properties and this study enables its use in clinical practice and in researches on adherence in kidney transplant. In this sample, the variables associated with NA were related to socioeconomic conditions: living far from the transplant center, better income and having access to private health insurance. We emphasize that this is the first Brazilian study, with appropriate methodology, on risk factors and frequency of NA post kidney transplantation.A Doença Renal Crônica (DRC) constitui hoje um importante problema médico e de saúde pública. O transplante renal é, atualmente, a melhor opção terapêutica para o paciente com DRC, tanto do ponto de vista médico, quanto social ou econômico. Para proporcionar maior segurança terapêutica e controle de complicações clínicas e cirúrgicas existem estratégias que são fundamentais. Uma questão considerada relevante é a não aderência (NA) ao uso das medicações e ao tratamento proposto. A aderência é definida como o grau de concordância entre o comportamento de um paciente em relação às orientações do médico e/ou de outro profissional da saúde. É um fenômeno multidimensional que envolve fatores determinados por questões socioeconômicas, pelo sistema de saúde, pelos profissionais de saúde, por fatores relacionados à terapia e ao paciente. Para o diagnóstico da NA podemos utilizar métodos diretos e indiretos. Este estudo teve como objetivos adaptar e validar para a população de transplantados brasileiros o instrumento The Basel AssessmentofAdherencewithImunossupressiveMedicationScale (BAASIS), utilizando uma amostra de transplantados renais atendidos no ambulatório do Núcleo Interdisciplinar de Estudos e Pesquisas em Nefrologia da Universidade Federal de Juiz de Fora (Niepen), determinar a frequência de NA na população estudada, avaliada através do emprego três métodos diagnósticos e avaliar a associação entre os fatores de risco e a presença de NA. Trata-se de um estudo transversal onde foram analisados 100 pacientes transplantados renais com mais de um ano de transplante em acompanhamento ambulatorial no Niepen. A adaptação cultural foi realizada utilizando o protocolo de Guillemin (i.e. tradução, retrotradução, análise por comitê de especialistas e pré-teste). Para verificação das propriedades psicométricas foram aplicados os testes de reprodutibilidadeintra e interobservador, alfa de Cronbach, correlação do BAASIS com a Medida de Aderência ao Tratamento – MAT e análise fatorial. Além de análise univariada e multivariada para os fatores associados a NA. Os pacientes foram classificados em dois grupos: aderentes e não aderentes através da utilização de três métodos diagnósticos (BAASIS, opinião dos profissionais e nível sangúineo dos imunossupressores) e as condições associadas aNA foram coletadas através de um questionário e do prontuário. A média de idade dos pacientes foi de 45±13,5 anos, 65% eram homens e 89% receberam o enxerto de um doador vivo. O instrumento BAASIS foi adaptado transculturalmente para língua portuguesa sem dificuldades. Em relação às propriedades psicométricas, encontramos baixa variância, de 0,007 e 0,003 nos testes de reprodutibilidade intra e interobservador; a correlação com o MAT foi de 0,65; cargas fatoriais aceitáveisdas três primeiras questões do BAASIS (r=0,76; r=0,80, and r=0,68), e alfa de Cronbach de 0,7. 51% dos pacientes foram considerados não aderentes utilizando-se três métodos para avaliar a aderência ao tratamento imunossupressor. As variáveis relacionadas com a NA foram: residir a mais de 100 km do centro transplantador (54,9 vs. 38,8%, p<0,07), renda familiar maior que 5 salários mínimos (21,6 vs. 4%, p<0,009), e ter acesso a exames por seguro de saúde (35,3% vs. 18,4%,p<0,01). No modelo de regressão logística apenas renda familiar maior que cinco salários foi fator de risco para NA (OR 5,0 IC:1,01 - 25,14; p<0,04). Os resultados demonstraram que a BAASIS apresenta boas propriedades psicométricas, e este estudo viabliza o seu uso na prática clínica e em pesquisas sobre aderência em TxR. Nesta amostra, as variáveis associadas com a NA foram relacionadas às condições socioeconômicas: morar distante do centro transplantador, melhor renda familiar e ter acesso a exames por seguro de saúde. Ressaltamos que este é o primeiro estudo brasileiro com metodologia adequada sobre fatores de risco e frequência de NA no pós TxR.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superio

Não aderência farmacológica e não farmacológica em transplantados renais no Brasil: resultados do estudo multicêntrico ADERE Brasil

Introduction: Pharmacologic and nonpharmacologic adherence after kidney transplantation contributed to the worsening of long-term graft survival. Understanding nonadherence to immunosuppressives and health behaviors such as physical activity, smoking, alcohol use and frequent visits (nonpharmacologic adherence) is fundamental to propose interventions. Brazil, with the largest public transplant program in the world and with regional differences in transplantation activity, is in a unique position to study this approach. Objectives: To identify the prevalence and variability of nonadherence to immunosuppressives and nonpharmacologic treatment in Brazilian services and regions and to describe the strategies used to manage the ADERE Brasil study. Methods: An observational and multicenter study that included 20 Brazilian kidney transplant centers. The centers were chosen for convenience, following multistage sampling strategy, based on strata, considering the following characteristics: center (low / moderate / high) transplantation activity and regions (South / Southeast and Northeast / North / Mid-West) . Patient selection was randomized and proportional to the size of the center within each stratum. The prevalence of nonadherence to immunosuppressive treatment was assessed using the self-report instrument, the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS). To evaluate the nonpharmacologic adherence, the patient was considered no adherent to the physical activity the patient who did less than 150 minutes per week, to smoking the one who smoked in the period of data collection, to alcohol due to excessive consumption and frequency of appointment keeping that lacked more than one of the last five scheduled, using instruments established for this purpose. Data were collected over a period of 24 months, with information obtained during the regular visits to the transplant outpatient clinic in the Electronic Research Data System. Data entry was performed by a trained professional of the transplant service team. Data collection began in December 2015 and ended in June 2017. For statistical analysis, the adjusted chi-square test and t test was used. Results: A total of 1,105 patients were included in the study. 58.5% of the patients were male, 51.4% were white, age 47.5 ± 12.6 years. Of the services, 75.9% were from the south / southeast region, 38.2% performed <50 transplants / year and 95.8% had a multiprofessional team. The prevalence of non-adherence in Brazil and in the regions (South / Southeast vs. North / Northeast / Mid-West) were respectively: for immunosuppressives 39.7%; 38.1% vs. 44.9%, p = 0.18; for smoking 3.9%; 5% vs. 1%, p <0.001; for physical activity 69.1%; 69% vs. 71%, p = 0.48; appointment keeping 12.7%; 13% vs. 12%, p = 0.77 and 0% for alcohol consumption. Nonadherence in services ranged from 11 to 65.2% for immunosuppressives; 44.5 to 90% to FA; 0 to 23.7% to FC; 0 to 14% to smoking. Conclusion: This is the first study about the prevalence and variability of nonadherence to kidney transplant treatment in the Brazilian regions. Despite the differences between the centers and great variability, only the nonadherence to smoking was greater in the region of greater access to renal transplantation.Introdução: A não aderência (NAd) aos imunossupressores nos pós transplante renal é fator de risco para pior sobrevida do enxerto. A NAd não farmacológica, como prática de atividade física, abstenção ao tabagismo e ao uso de álcool e comparecimento às consultas, é também parte do tratamento, porém menos estudada. Estudos multicêntricos observacionais num país de grandes dimensões como o Brasil são um desafio operacional. Objetivos: Identificar a prevalência e variabilidade da NAd aos imunossupressores e ao tratamento não farmacológico nos serviços de transplante renal e regiões brasileiras e descrever as estratégias utilizadas para o gerenciamento do estudo ADERE Brasil. Métodos: Estudo observacional, transversal e multicêntrico que incluiu 20 centros de transplante renal. Os centros foram escolhidos por conveniência, seguindo estratégia de amostragem por múltiplos estágios, considerando a atividade transplantadora das regiões (Sul/Sudeste e Nordeste/Norte/Centro-Oeste) e dos centros (baixa - até 50 transplantes/ano; moderada – de 50 a 150 e alta – mais do que 150). A seleção dos pacientes foi randomizada. A prevalência da NAd aos imunossupressores foi avaliada pela Escala Basel para Avaliação da Aderência aos Imunossupressores (BAASIS). Foi considerado não aderente à atividade física menos de 150 minutos por semana; à abstenção ao tabagismo, aquele que fumava no período da coleta; ao álcool pelo consumo excessivo e ao comparecimento às consultas, a falta de pelo menos uma das últimas cinco agendadas. Resultados: O gerenciamento do estudo foi feito através de quatro coordenações: geral, de regulação e de comunicação com centros e estatística, com reuniões semanais até o final da coleta dos dados. Foram criadas identidade visual e estratégias de aproximação e envolvimento dos centros. Da amostra calculada de 1.139 pacientes, 1.105 (97%) foram incluídos no estudo. A maioria dos pacientes eram do sexo masculino (58,5%), 51,4% brancos, com idade de 47,5 ± 12,6 anos. Dos serviços, 75,9% eram da região sul/sudeste, 38,2% eram de baixa atividade e 95,8% tinham equipe multiprofissional. As prevalências de NAd na amostra total e nas regiões (Sul/Sudeste vs. Norte/Nordeste/Centro-Oeste) foram respectivamente: para os imunossupressores 39,7%; 38,1% vs. 44,9% (p = 0,18); para tabagismo 3,9%; 5% vs. 1% (p < 0,001); para atividade física 69,1%; 69% vs. 71% (p = 0,48); falta às consultas 12,7%; 13% vs.12% (p = 0,77) e 0% para o consumo de álcool. A NAd em cada serviço variou de 11 a 65,2% aos imunossupressores; 44,5 a 90% à atividade física; 0 a 23,7% à frequência às consultas; 0 a 14% ao tabagismo. A impressão dos pacientes sobre as práticas clínicas dos centros foi diferente entre as regiões (Sul/Sudeste vs. Norte/Nordeste/Centro-Oeste): insatisfação com a estrutura da sala de espera do serviço 33,4 % vs. 71,9% (p=0,001); insatisfação com o número de profissionais de saúde 39,6% vs. 61,7% (p=0,01); adequação do número de consultas 86,1% vs. 87,9% (p=0,05) e local de retirada dos imunossupressores ser distante 49,9% vs. 66, 9% (p=0.002). Conclusão: Neste primeiro estudo sobre prevalência e variabilidade da NAd ao tratamento em transplante renal nas regiões do Brasil, observamos que a despeito das diferenças entre os centros, apenas a não aderência ao fumo foi maior na região de maior acesso ao transplante renal

Nonadherence to immunosuppressives and treatment in kidney transplant: ADHERE BRAZIL Study

To estimate the prevalence and variability of nonadherence to immunosuppressives and nonpharmacological treatment across kidney transplantation centers and two health access-disparate regions in Brazil.; In a cross-sectional design, a random multistage sample of 1,105 patients was included, based on center transplantation activity (low/moderate/high) and region (R1: North/Northeast/Mid-West; and R2: South/Southeast). Nonadherence to immunosuppressives (implementation phase) was assessed using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS)©. Self-report questionnaires assessed nonadherence to physical activity, smoking cessation, alcohol intake, and appointment keeping. We compared regions using the adjusted-χ2 or t-test.; Most patients were men (58.5%), white (51.4%), and had a mean age of 47.5 (SD = 12.6) years. Regarding kidney transplantation centers, 75.9% were from R2 and 38.2% had low activity. The patients in R2 were older, white-majority, had more frequently steady partners, and received peritoneal dialysis. Nonadherence to immunosuppressives ranged from 11-65.2%; 44.5-90% to physical activity; 0-23.7% to appointment keeping; and 0-14% to smoking cessation. The total prevalence of nonadherence and by region (R1 versus R2) were: for immunosuppressives, 39.7% (44.9% versus 38.1%, p = 0.18); for smoking, 3.9% (1% versus 5%, p < 0.001); for physical activity, 69.1% (71% versus 69%, p = 0.48); for appointment keeping, 13% (12.7% versus 12%, p = 0.77); and for alcohol consumption, 0%.; Despite differences among centers and high variability, only the nonadherence to smoking cessation was higher in the region with greater access to kidney transplantation. We suppose that differences in healthcare access may have been overcome by other positive aspects of the post kidney transplantation treatment

ANÁLISE DE DESEMPENHO DOS TÉCNICOS E AUXILIARES DE ENFERMAGEM DA ATENÇÃO PRIMÁRIA À SAÚDE

A avaliação de serviço e desempenho é uma estratégia essencial em todo o sistema de saúde, uma vez que, permite identificar fragilidades e pontos positivos da assistência. Além disso, é necessária para o planejamento das ações e estratégias de intervenções. O presente estudo teve como objetivo avaliar se os técnicos e auxiliares de enfermagem desempenham suas atribuições de acordo com o que é estabelecido pela Atenção Primária à Saúde. Trata-se de uma pesquisa quantitativa de caráter avaliativo. Os dados foram coletados por meio da aplicação do instrumento de avaliação da atenção primária Primary Care Assessment Tool – Brasil, versão profissionais. Participaram do estudo 87 técnicos e 3 auxiliares de enfermagem que atuam na Atenção Primária à Saúde (APS) do município de Juiz de Fora.  Foram atribuídos escores geral, essencial e derivado, para cada atributo da APS (acessibilidade, longitudinalidade, coordenação, integralidade, orientação familiar e orientação comunitária). Os escores médios iguais ou maiores que 6,6 correspondem à alta orientação dos Técnicos e Auxiliares de enfermagem para a APS. Em relação aos escores geral e essencial, os resultados indicaram baixa orientação no desempenho dos técnicos e auxiliares de enfermagem para a APS. Diferente do escore derivado que obteve um resultado altamente orientado do serviço para a APS. O estudo mostrou que as fragilidades estão relacionadas, principalmente, aos aspectos estruturais e processuais dos serviços. Conclui-se que os técnicos e auxiliares de enfermagem desenvolvem suas atividades de acordo com os atributos derivados da APS, mas não com os considerados essenciais.

Prevalence and correlates of non-adherence to immunosuppressants and to health behaviours in patients after kidney transplantation in Brazil - the ADHERE BRAZIL multicentre study: a cross-sectional study protocol

BACKGROUND: Non-adherence to immunosuppressive therapy is a prevalent risk factor for poor clinical and after kidney transplantation (KT), and has contributed to the lack of improvement in long-term graft survival over the past decade. Understanding the multilevel correlates and risk factors of non-adherence is crucial to determine the optimal level for planning interventions, namely at the patient, health care provider, KT centre, and health care system level. Brazil, having the largest public transplantation program in the world and with regional differences regarding access to health services and service implementation, is in a unique position to study this multilevel approach. Therefore, the Adhere Brazil Study (ADHERE BRAZIL) was designed to assess the prevalence and variability of non-adherence to immunosuppressants and to health behaviours among adult KT recipients in Brazil, and to assess the multilevel correlates of non-adherence to immunosuppressive medication. We describe the rationale, design, and methodology of the ADHERE BRAZIL study. METHODS/DESIGN: This is an observational, cross-sectional, multicentre study that includes 20 Brazilian KT centres. A stratified sampling approach is used, based on strata, with the following characteristics considered: geographical region and transplant activity (number of KTs per year). A random sample of patients (proportional to the size of the centre within each stratum) is selected from each centre. The prevalence of different health behaviours is assessed through self-report. The assessment of multilevel correlates of non-adherence is guided by the ecological model that considers factors at the level of the patient, health-care professional, and transplant centre, using established instruments or instruments developed for this study. Data will be collected over an 18-month period, with information obtained during the regular follow-up visits to the transplant outpatient clinic and directly entered into the Research Electronic Data Capture (RedCap) system. Data entry is performed by a trained professional who is part of the transplant team. The data collection began in December 2015. DISCUSSION: This multicentre study is the first to evaluate multilevel correlates of non-adherence in KT patients and will provide a reliable estimate of non-adherence in Brazilian KT patients. TRIAL REGISTRATION: ClinicalTrials.gov on 10/10/2013, NCT02066935 .status: publishe

Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study

Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system.status: publishe

Prevalence and correlates of non-adherence to immunosuppressants and to health behaviours in patients after kidney transplantation in Brazil - the ADHERE BRAZIL multicentre study: a cross-sectional study protocol

Non-adherence to immunosuppressive therapy is a prevalent risk factor for poor clinical and after kidney transplantation (KT), and has contributed to the lack of improvement in long-term graft survival over the past decade. Understanding the multilevel correlates and risk factors of non-adherence is crucial to determine the optimal level for planning interventions, namely at the patient, health care provider, KT centre, and health care system level. Brazil, having the largest public transplantation program in the world and with regional differences regarding access to health services and service implementation, is in a unique position to study this multilevel approach. Therefore, the Adhere Brazil Study (ADHERE BRAZIL) was designed to assess the prevalence and variability of non-adherence to immunosuppressants and to health behaviours among adult KT recipients in Brazil, and to assess the multilevel correlates of non-adherence to immunosuppressive medication. We describe the rationale, design, and methodology of the ADHERE BRAZIL study.; This is an observational, cross-sectional, multicentre study that includes 20 Brazilian KT centres. A stratified sampling approach is used, based on strata, with the following characteristics considered: geographical region and transplant activity (number of KTs per year). A random sample of patients (proportional to the size of the centre within each stratum) is selected from each centre. The prevalence of different health behaviours is assessed through self-report. The assessment of multilevel correlates of non-adherence is guided by the ecological model that considers factors at the level of the patient, health-care professional, and transplant centre, using established instruments or instruments developed for this study. Data will be collected over an 18-month period, with information obtained during the regular follow-up visits to the transplant outpatient clinic and directly entered into the Research Electronic Data Capture (RedCap) system. Data entry is performed by a trained professional who is part of the transplant team. The data collection began in December 2015.; This multicentre study is the first to evaluate multilevel correlates of non-adherence in KT patients and will provide a reliable estimate of non-adherence in Brazilian KT patients.; ClinicalTrials.gov on 10/10/2013, NCT02066935

Management strategies for implementing a multicenter cross-sectional study: lessons from the ADHERE Brazil study

BACKGROUND: Epidemiological studies involving large samples usually face financial and operational challenges. OBJECTIVES: To describe the planning and execution of ADHERE Brazil, an epidemiological study on 1,105 kidney transplant patients, and report on how the study was structured, difficulties faced and solutions found. DESIGN AND SETTING: Cross-sectional multicenter study in 20 Brazilian kidney transplantation centers. METHODS: Actions developed in each phase of implementation were described, with emphasis on innovations used within the logistics of this study, aimed at estimating the prevalence of nonadherence to treatment. RESULTS: Coordination of activities was divided into four areas: general, regulatory, data collection and statistics. Weekly meetings were held for action planning. The general coordination team was in charge of project elaboration, choice of participating centers, definition of publication policy and monitoring other coordination teams. The regulatory team provided support to centers for submitting the project to ethics committees. The data collection team prepared a manual on the electronic collection system, scheduled web meetings and was available to respond to queries. It also monitored the data quality and reported any inadequacies found. Communication with the centers was through monthly reports via e-mail and distribution of exclusive material. The statistical team acted in all phases of the study, especially in creating the data analysis plan and data bank, generation of randomization lists and data extraction. CONCLUSIONS: Through these logistics, we collected high-quality data and built a local research infrastructure for further studies. We present supporting alternatives for conducting similar studies. CLINICAL TRIAL ANNOTATION: http://clinicaltrials.gov/ on October 10, 2013; NCT02066935