The WAVE-bd study (NCT01062607) is a multinational, multicentre, observational, longitudinal or cohort study of patients diagnosed with BD type I or II with at least one mood event in the 12 months prior to the study start (Time 0, Figure ).
The study comprises two different follow-up phases; one retrospective and one prospective (ambispective design). The retrospective phase for each patient started from the index event, which occurred a maximum of 12 months and minimum of 3 months before Time 0, and ended when the patient signed the informed consent form. Information from medical records related to the patient and their disease during that period (i.e. retrospective information - from index event to inclusion) was recorded in the electronic case report form (eCRF) at the inclusion visit. The prospective phase started when the first patient signed the informed consent form and will end when the last patient included in the study attends their final visit. Data for prospective analysis are collected as described at all visits (including the inclusion visit). All throughout the prospective phase, the required information will be recorded in the eCRF and the questionnaires completed every time the patient attends the psychiatrist's office (unless otherwise stated). The psychiatrist will schedule visits according to real-life clinical practice. No interventions, extra procedures, or extra visits will be required for the purpose of the study.
The study design means that patients will spend variable amounts of time in the study depending on the date of signing the informed consent form, the length of the enrolment period, and the date of their index episode. The minimum time in the study is 12 months and the maximum 27 months, considering the retrospective and prospective phases, and the 6 month enrolment period together (Figure ).
One aim of the study is to determine how patients with BD are managed in different settings and countries (Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela). It is therefore important to obtain a patient population that is representative of real-world practice. The inclusion of sites and patients was determined on that basis.
Sites and investigators
Since the type of site is a variable that might influence the management of patients with BD and the profile of patients attending each type of site may be different, it was necessary to select different types of sites to obtain a representative sample. Generally, patients with BD are seen in mental health centres, clinics, private settings, hospitals or specialised units. Since this distribution varies from one country to another, the study centre selection process had to be adapted locally.
Selection of participating sites was based on the percentage of patients that attend different types of sites in each country, thus ensuring that patients attending one specific site type are not over-represented in the study sample (Table ). These percentages were obtained either from the literature or from expert panels from each participating country.
Patient recruitment by country and type of study centre
The number of participating investigators is sufficient to ensure: 1) that there is a representative sample of the whole psychiatrist population in each country; and 2) inclusion of a sufficient number of patients to provide the required sample size calculated for the study. No other criteria were applied to selection and inclusion of investigators, in order to avoid any selection bias.
Approximately 250 study centres in 10 countries are participating in the study. Based on the criteria described above, target percentages of patients recruited by each type of study centre were devised to reflect management practices in each of the participating countries (Table ). The study data will be able to provide a global perspective on comparisons between public vs private care, academic hospital vs standard hospital care, and hospital vs non-hospital care.
Each investigator identified all patients with at least one mood event in the 12 months prior to the beginning of the study (Time 0), except for those whose index mood event occurred in the 3 months before the study start.
The aim of the study is to achieve systematic inclusion of patients, therefore, where possible, every eligible patient identified at each of the study centres was invited to participate. The main exceptions were at those sites that saw a high number of eligible patients during the recruitment period. At these sites, investigators were allowed to recruit a representative sample using an electronic application, which makes selections by simple randomisation, in order to avoid any type of selection bias.
Patients aged ≥ 18 years, with a diagnosis of BD type I or II (DSM-IV-TR [1
]) in any phase of the disorder and who had at least one mood event (depression, mania, hypomania or mixed) according to the DSM-IV-TR definitions during the 12 months prior to the beginning of the study were eligible for recruitment, except for those starting the index mood event less than 3 months before Time 0, subject to their providing informed consent. However, those patients starting the index mood event more than 3-months before Time 0 were eligible even if the index event was not resolved, or if the index event had resolved and they subsequently initiated another event.
Patients not eligible to participate in the study were those participating in an interventional clinical study and any patients unable to complete Patient Reported Outcomes questionnaires.
The WAVE-bd study aims to provide a wide-ranging picture of BD management practices, and impact on patients, caregivers and healthcare resource use across a range of countries. For this reason, several measuring instruments are being employed to maximise the types of data collected. All instruments have been validated before the study start, including linguistic validation where needed. In all cases, the scales were also psychometrically validated, at least in the original language. Information regarding demographics (sex, race, age, educational level, professional status, degree of disability, degree of independence or co-residence), alcohol and other substance abuse, medical history, disease characteristics (date of first diagnosis, type of BD, family history of psychiatric diseases, episodes during the last 12 months, presence of psychotic symptoms, hospital admissions, and suicide attempts), treatments received (drug, schedule and dose, and whether the patient received psychologist or group therapy), healthcare resources use, and clinical outcomes will be collected throughout the study (Table ).
An electronic adaptation of the National Institute of Mental Health prospective Life Chart Methodology (NIMH-LCM™) will be used specifically for assessing clinical outcomes during both the retrospective and the prospective phases of the study. It allows the daily assessment of mood and episode severity, based on the degree of mood-associated functional impairment. The NIMH-LCM provides a visual method of tracking the patient's mood at each visit. Each form covers a 1-month period, and clinicians rate both mania and depression on the chart, list the medications taken by the patient during the month, and record any other non-mood symptoms (prospective phase only), if applicable [12
During the prospective phase of the study the following assessments will be performed to evaluate clinical outcomes, adherence to treatment, quality of life, patient functioning and caregiver burden:
this is an adaptation of the Clinical Global Impressions (CGI) scale designed to assess global illness severity and change in patients with BD. It contains nine items [13
the Drug Attitude Inventory (DAI) is a self-applied scale to measure subjective responses to medication. This instrument reveals whether the patient is satisfied with their treatment and evaluates their understanding of how the treatment is affecting them. The reduced version 'DAI-10' has ten highly specific items of subjective experience. These are based on the true recorded and transcribed accounts of patients, and response options are true/false only. These items were selected for their capacity to discriminate between medication adherence grades in a way that can be analysed statistically. Although the DAI is specific for schizophrenia, it has also been used to investigate treatment adherence in patients with BD [14
the Medication Possession Ratio (MPR), first described by Sclar et al
], is a formula used to determine adherence measured from the first to the last prescription, with the denominator being the duration from index to the exhaustion of the last prescription and the numerator being the days supplied over that period from first to last prescription. The MPR will also be used for the retrospective phase of the study.
this is a standardised instrument used to measure health outcomes [16
]. It is applicable to a wide range of health conditions and treatments, and it provides a simple descriptive profile and a single index value for health status. The respondent is asked to indicate their health state by marking the box against the most appropriate statement in each of the five dimensions. This decision results in a one-digit number expressing the level selected for each dimension. The digits for five dimensions can be combined in a five-digit number describing the respondent's health state. It should be noted that the numerals 1-3 have no arithmetic properties and should not be used as a cardinal score.
the Functioning Assessment Short Test (FAST) is a brief instrument designed to assess the main functional problems experienced by psychiatric patients, particularly bipolar patients. It comprises 24 items that assess impairment or disability in six specific function domains: autonomy, occupational functioning, cognitive functioning, financial issues, interpersonal relationships and leisure time. The total score across all domains will be measured [17
The Burden Assessment Scale (
BAS) was developed by Reinhard and Horwitz [18
] and will be assessed once during the study. The questionnaire contains 19 items that capture both objective and subjective consequences of providing ongoing care to the seriously mentally ill. The scale distinguishes burden from the measurement of the ill relative's disruptive behaviours and the family's care-giving activities. These are viewed as predictors rather than aspects of burden [18
Descriptive statistics will include frequency tables (n, mean, median, standard deviation, minimum and maximum for continuous variables and n, frequency and percentage for categorical values). For the population estimation of the variables, the two-sided 95% confidence interval will be obtained.
In order to assess the association of patient characteristics (including functioning and quality of life status) and clinical management (an independent variable) with clinical outcome variables (clinical evolution, mood events, treatment-related events, suicide attempts, variation in scales), logistic and general linear models have been planned. Interest will focus separately on the management differences between the models or groups of models. Model-based point estimates of odds ratios and corresponding 95% confidence intervals will be reported. P-values will be reported for the comparison between different treatments. Since visit-by-visit information from the study index event is being collected, there will be data on patient status during the whole study period. Therefore, it will be possible to analyse data, relative to the time of mood event initiation.
Cox models for survival outcomes, and mixed models for longitudinal data using country as indicator variables, adjusted for age and gender, have been planned in order to investigate differences in clinical outcomes and related factors between countries. A descriptive analysis has been planned to assess factors related to consumption of healthcare resources and caregiver burden, according to caregiver-reported outcomes.
The sample size was calculated in order to ensure that the study obtains meaningful data for descriptive purposes of general clinical management and clinical outcomes at a country level. The main outcome used in the sample size calculation was the proportion of episodes in 1.5 years and the goal was to estimate this proportion in the study population. The minimum number of patients required was estimated, based on an expected proportion of patients with episodes in one year of 35%, assuming an alpha = 0.05, power = 0.80 and a precision of 0.05 (with a 95% confidence interval). The estimated sample size was 370 patients per country (or 400 if it is assumed that approximately 10% will be lost to follow up). Fewer patients per country would provide information on the proportion of episodes with a precision less 5%. It was estimated that approximately 3,200 patients across different countries would be included in the study, but that this number might vary depending on the number of participating countries and sample size in each.
The non-interventional nature of this study means that safety data will not be collected proactively. However, spontaneously reported safety events will be communicated to the appropriate health authority, as required by post-marketing pharmacovigilance regulations.
Study ethics and patient confidentiality
The study will be performed in accordance with ethical principles that are consistent with the Declaration of Helsinki 2008 revision of the International Conference on Harmonisation - Good Clinical Practice (ICH GCP) guidelines and the applicable legislation on non-interventional studies.
The study protocol and informed consent form were approved in writing by the relevant ethics committees in each participating country, as follows: Austria; EC of Salzburg: Belgium; Comité d'Ethique, CUB Hôpital Erasme; Ethische Commissie, vzw Gezondheidszorg Oostkust; Comité d'Ethique, Hôpital Saint Joseph; Comité d'Ethique Hospitalier/HPBV, Hôpital Psychiatrique du Beau Vallon; Comité d'Ethique OM045, Clinique St.-Pierre; Comité d'Ethique Hospitalier-Facultaire Universitaire de Liège, Centre Hospitalier Universitaire du Sart Tilman; Ethische Commissie/Coördinator klinische studies, AZ Sint-Lucas Brugge; Commissie voor Medische Ethiek, Psychiatrisch Zkh. Onze Lieve Vrouw; Comité d'Ethique, Cliniques Universitaires UCL de Mont-Godinne; Commissie Medische Ethiek - Toetsingscommissie, Campus Gasthuisberg; Comité d'Ethique, U.C.L. - Faculté de Médecine; Commissie voor Ethiek, AZ St.-Jan Brugge; Comité d'Ethique, C.H.P. Petit Bourgogne; Toetsingscommissie Ethiek GGZ Broeders van Liefde, U.P.C. Sint-Kamillus; Comité d'Ethique, C.H.P. Les Marronniers; Secrétariat du Comité d'Ethique ISPPC, CHU A. Vésale; Comité d'Ethique, CUB Hôpital Erasme; Comité d'Ethique, Vivalia Centre Universitaire Provincial La Clairière: Brazil; Comissão Nacional de Ética em Pesquisa; Comitê de Ética em Pesquisa da Maternidade Climério de Oliveira; Comitê de Ética em Pesquisa do Hospital Irmãos Penteado - Irmandade de Misericórdia de Campinas; Comissão de Ética para Análise de Projetos de Pesquisa - CAPPesq da Diretoria Clínica do Hospital das Clínicas e da Faculdade de Medicina da USP; Comitê de Ética em Pesquisa da Faculdade de Medicina de Botucatu; Comitê de Ética em Pesquisa da Universidade Federal de Goiás (CEPHMA/HC/UFG); Comitê de Ética em Pesquisa do Hospital Pró-Cardíaco; Comitê de Ética em Pesquisa da Secretaria de Estado da Saúde de Santa Catarina - CEP-SES/SC; Comite de Ética em Pesquisa da Faculdade de Medicina do ABC: France: IEC of of Ile de France VI; Doctors Governing Body: Germany; Ethikkommission.Ernst-Moritz Arndt Universität Greifswald: Portugal; Data Privacy Authority (Comissão Nacional de Protecção de Dados); Comissão de Ética para a Saúde; Comissão de Ética do Hospital dos Lusíadas; Comissão de Ética da Clínica Psiquiátrica de S. José; Comissão de Ética do Hospital de Magalhães Lemos, EPE; Comissão de Ética da Saúde do Hospital de São João; Comissão de Ética do Hospital Infante D. Pedro EPE; Comissão de Ética do Centro Hospitalar Médio Tejo, EPE; Comissão de Ética do Centro Hospitalar de Setúbal, EPE: Romania; National Drug & Medical Devices Agency; National Ethics Committee: Turkey; Central IRB within MoH: Ukraine; Central Ethics Committee of Ministry of Health of Ukraine: Venezuela; RA: Instituto Nacional de Higiene "Rafael Rangel"; Comité de Bioética Hospital Universitario de Caracas; Centro Nacional de Bioética de Venezuela; Instituto Autónomo Hospital Universitario de Los Andes; Comisión de Ética del Hospital Vargas.
Investigators will perform the study in accordance with the regulations and guidelines governing medical practice and ethics in their country and in accordance with currently acceptable techniques. Patients and caregivers will authorise the collection, use and disclosure of their personal data by the investigator and by those persons who need that information for the purposes of the study. Study data will be stored in a computer database, maintaining confidentiality in accordance with local laws for data protection.