Monitoring of Metabolic Adverse Events of Second Generation Antipsychotics in a Naive Pediatric Population

Study Overview
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Brief Summary
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Introduction: Second Generation Antipsychotics (SGAs) are widely used in the pediatric population. It is currently established that SGAs may induce undesirable metabolic adverse events (AEs) such as weight gain, metabolic changes in blood lipids or glucose with risk of potential cardiovascular morbidity and mortality. The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in children (CAMESA) has published recommendations for monitoring the metabolic AEs of SGAs in the pediatric population. Factors that may be associated with the onset of SGA's metabolic AEs and long term consequences are less studied in the literature. The objectives of our research are to evaluate some factors that can influence the development of the SGA's metabolic AEs, and to study clinical adherence to CAMESA guidelines. Methods and analysis: The MEMAS study (Monitoring des Effets Métaboliques des Antipsychotiques de Seconde Génération) design is a multicenter, prospective, longitudinal observational study with repeated measures of metabolic monitoring up to 24 months of follow-up. Two recruiting centers have been selected for patients under 18 years of age, previously naïve of antipsychotics, starting an SGA or who have started an SGA for less than 4 weeks regardless of the diagnosis that motivated the prescription. Assessments are performed at inclusion and during follow-up for anthropometric measures (AM), blood pressure (BP) and blood tests (BT) at baseline and 1, 2, 3, 6, 9, 12 and 24 months of follow-up. Ethics and dissemination: The study protocol was approved by the Centre Hospitalier Universitaire (CHU) Sainte-Justine's Research Ethics Board (MP-21-2016-1201) in 2016 and obtained institutional suitability for the Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'Île-de-Montréal (CIUSSS NIM) Research Center in May 2018. For all participants, written consent will be obtained from parents/caregivers as well as the participant's assent in order to enable their participation in this research project. The results of this research will be published.

Detailed Description
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Objectives The primary objective is to study selected factors that can influence the development of the SGA's metabolic AEs such as the main diagnosis for which the SGA is prescribed, comorbidities, type and dose of AP, metabolic family history (siblings, parents, parents' siblings, grandparents) and the patient's characteristics (age, height, ethnicity, weight, puberty status). We hypothesize that factors such as younger age of exposure, SGA type, higher SGA doses, lower BMI, non-white ethnic status, hospitalization status at baseline and longer treatment duration will be associated with greater weight gain and, potentially, more cardio-metabolic complications. The secondary objective is to evaluate the clinical adherence to CAMESA guidelines for monitoring of SGAs metabolic AEs in current practice. We hypothesize that the monitoring rates will be low. Trial design The MEMAS study design is a multicenter, prospective, longitudinal observational study with repeated measures of metabolic monitoring up to 24 months of follow-up. Two recruiting centers have been selected. Recruitment started in January 2017 at CHU Sainte-Justine Hospital and in May 2018 at CIUSSS NIM including the Rivière-des-Prairies (HSM RDP) and Albert-Prévost Mental Health Hospitals (HSM AP). Patients have been included for up to 4 weeks after the initiation of SGA treatment (baseline). Patients will be assured a safe follow-up on their pharmacotherapy. Adherence to the proposed follow-up calendar by the CAMESA guidelines will allow for the detection and the early management of potential cardiometabolic AEs of SGAs. Assessments are performed at inclusion and during follow-up for anthropometric measures (AM), blood pressure (BP) and blood tests (BT) at baseline and 1, 2, 3, 6, 9, 12 and 24 months of follow-up. Participation in this study does not lead to any additional risk to current medical practices. Study participation will end when the patient reaches the end of their 24-month follow-up or earlier if the SGA treatment is discontinued. The prescription of SGA (including dose adjustments, end of treatment, switches and comedications) by the treating psychiatrist is clinically naturalistic. However, during this study, if measured parameters reach what is considered a critical value, the psychiatrist will be notified by the nurse or a member of the research team so that the patient can be referred to a specialist in order to have the proper intervention recommended by the CAMESA guidelines (Ho et al., 2011; Raffin et al., 2014). Measures All anticipated measurements during the follow-up are : Demographic and clinical baseline data, Adherence to treatment, Anthropometric measures (AM), Blood pressure, Blood tests, and The MEMAS questionnaire on lifestyle habits and stages of puberty. Blood tests are performed on site for patients included at HSM AP or Sainte-Justine Hospital whenever possible. For patients included at HSM RDP, blood samples are performed in a local community service center (CLSC) or elsewhere, depending on available resources. Data collection process In each recruitment center, nurses monitor the participant's studied variables according to the CAMESA calendar. Data is collected and coded from participant's medical records by a member of the research team. All data is anonymized and preserved in the participant's research file. All of the collected information will be kept confidential unless authorized by the participant or his caregiver or an exception from the law. The computerized data will be kept on a password protected file and the paper questionnaires will be kept in a locked space. The data collected will be kept for seven years after the end of the study. After this period of time, it will be safely deleted or destroyed by shredding. The parameters collected for the metabolic monitoring of each SGA-treated participant during follow-up were based on the recommendations of CAMESA guidelines as well as on other, more recent, clinical landmark studies (Nielsen et al., 2014; Pringsheim et al., 2011; Raffin et al., 2014; Rubin et al., 2015). This clinical research project does not require any further investigation compared to the standards of best practice. Statistical analysis Number of subjects required A number of 60 participants per recruitment center was calculated, for a total of 120 participants. The sample size has been estimated based on previous studies, with available data for four SGAs (risperidone, aripiprazole, quetiapine, olanzapine) and treatment duration up to 12 months (Correll et al., 2009; Findling et al., 2010; Marcus et al., 2011; Findling et al., 2013; Arango et al., 2014; Ronsley et al., 2015). For the estimation of the sample size, the BMI-z score was chosen as the primary dependent variable which is a good reflection of the metabolic changes related to weight gain. ANOVA one-way test was used with compared groups being olanzapine (O), risperidone (R), quetiapine (Q) and aripiprazole (A) with an expected distribution of subjects per group of 1:3:2:2 respectively, the power of 0.80 and an alpha of 0.05. The means to be compared were calculated using the BMI-z score at different times ((BMI-z 3 months + BMI-z 6 months + BMI-z 12 months) / 3); these means are as follow: 0.90 (O), 0.68 (R), 0.52 (Q) and 0.32 (A), with the standard deviation (SD) between 0.20 and 0.60. In the absence of an established size effect for the BMI-z score change, we varied the effect size (d) between 0.31 and 0.93, which resulted in an estimated sample size between 24 and 120 subjects. The sample size of our study was calculated as follows (Desu & Raghavarao, 1990): a one-way ANOVA study, sample sizes of 15, 45, 30, and 30 are obtained from the 4 groups whose means are to be compared. The total sample of 120 subjects achieves 80% power to detect differences among the means versus the alternative of equal means using an F test with a 0.05 significance level. The size of the variation in the means is represented by their standard deviation which is 0.19. The common standard deviation within a group is assumed to be 0.60. The effect size is 0.31. Participants will be recruited from the outpatient and inpatient mental health settings of CHU Ste-Justine and CIUSSS NIM. Thus, annually, the estimated number of patients newly treated with an SGA at CHU Sainte-Justine is approximately 30-40 at the Child and Adolescent Mental Health Outpatient Clinic, 5-10 at Gilles de la Tourette Syndrome Outpatient Clinic, 20 at Child and Adolescent Psychiatric Inpatient Unit (6-17 year old) and at CIUSSS NIM, 30-40 at the Child and Adolescent Psychiatric Inpatient Units (6-17 year olds) and 40 at the Outpatient Mental Health Clinics. Thus, considering a sample size of 120 subjects, we believe that the clinical reality will allow a realistic enrollment of approximately 60 subjects at CHU Sainte-Justine and 60 subjects at CIUSSS NIM. Scheduled analyzes Some analyzes will be provided. Mean changes in AM (weight, BMI-z score, waist circumference), fasting glucose, lipids, and blood pressure will be calculated over time for each SGA group. The percentage of patients in each group who meet one of the following conditions will be calculated: an increase of at least 0.5 in BMI-z score or of more than 7% in weight from baseline over time; developing obesity, metabolic syndrome, hyperglycemia, type 2 diabetes or insulin resistance over time according to the previously mentioned criteria (Measures paragraph). Comparison of baseline values between groups will be considered; chi-square test will be used for categorical variables while a Mann-Whitney U test will be used for continuous variables. This method accounts for multiple comparisons. Comparison between SGAs use in mono- (single AP) vs poly-therapy (combination of two or more APs) will be done. Descriptive analysis will be performed for the sociodemographic variables using percentages, means, medians, ratios and frequencies. A separated analysis will be conducted for the subgroup of participants who received a pharmacological treatment in order to treat the SGAs' cardiometabolic AEs. Thus, only the data available before this pharmacological treatment will be included in the main analysis. Incidence of the metabolic complications will be calculated as the proportion of new-onset metabolic complications at each time point divided by the number of patients with available data. A separate analysis will evaluate the impact of the pharmacological treatment introduced to treat the SGA's cardiometabolic AEs; comparisons will be done with the remaining participants.

Official Title
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Monitoring of Metabolic Adverse Events of Second Generation Antipsychotics in a Naive Pediatric Population Followed in Mental Health Outpatient and Inpatient Clinical Settings (MEMAS Prospective Study)

Conditions
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Adverse Drug Event

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients under 18 years of age, previously AP-naifs, starting an SGA or who started an SGA for less than 4 weeks, followed longitudinally at one of the selected recruiting center, regardless of the diagnosis that motivated the prescription of the SGA medication. Exclusion Criteria: diabetes, dyslipidemia, high blood pressure, thyroid dysfunction, hepatic disease, hyperprolactinemia, taking a medication to treat any of the above conditions before starting SGA treatment and pregnancy.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 24 months follow-up<br>Single-group study Patients have been included for up to 4 weeks after the initiation of Second Generation Antipsychotic (SGA) treatment (baseline) Patients under 18 years of age, previously naïve of antipsychotics, starting an SGA or who started an SGA treatment for less than 4 weeks, followed longitudinally at one of the selected recruiting centers, regardless of the diagnosis that motivated the prescription. Comedications and combination of APs are allowed, as this is an observational study. The exclusion criteria are the following: participants diagnosed before or at the baseline with diabetes, dyslipidemia, high blood pressure, thyroid dysfunction, hepatic disease, a disorder that can lead to hyperprolactinemia or another disorder that may interfere with the development of the side effects studied in this research, participants taking a drug intended to treat one of the conditions mentioned above before starting the SGA treatment, and pregnancy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant's demographic informations | Sex, age, ethnic group, socioeconomic status will be collected | At baseline (inclusion) | 
| Participant's clinical informations | Several participant's clinical informations will be collected : recruitment center, inpatient or outpatient status, main diagnosis (DSM-5), comorbidities, second generation antipsychotic prescribed and its dosage, co-medication type and dosage. In order to create an equivalence between the doses of APs received, a conversion to an equivalent dose of chlorpromazine will be carried out according to published standards (Woods et al., 2003). | At baseline (inclusion) | 
| Family metabolic informations | Presence or not of obesity, dyslipidemia, diabetes and gestational diabetes, high blood pressure, cardiovascular disease in parents will be asked ; and reported weight (in kilograms) and height (in meters) of the parents will be collected (but not measured). | At baseline (inclusion) | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At baseline (inclusion) | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At 1 month of follow-up | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At 2 months of follow-up | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At 3 months of follow-up | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At 6 months of follow-up | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At 9 months of follow-up | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At 12 months of follow-up | 
| Evaluation of Adherence to second generation antipsychotic treatment | Compliance will be indirectly estimated by the nurse and/or the treating psychiatrist at each measurement time of the CAMESA calendar, according to a voluntary declaration by the participants. The date of renewal of the psychotropic medication will also be verified using the Quebec medical record database (Dossier Santé Québec (DSQ)) and compared to the patient's declaration. The adherence will therefore be counted as the number of days of missed SGA dose per week or per month. | At 24 months of follow-up | 
| Assessment of change of Body Mass Index (BMI) at different times of the study | Assessment of weight and height will be taken using the same instruments and according to a standardized technique. Body Mass Index (BMI) will be calculated with the weight (kilograms) divided by the height squared (m2). Then, the BMI is standardized for sex and age according to the growth charts of the Centers for Disease Control (CDC) (Ogden et al., 2002) in order to obtain the BMI-z score. Significant weight gain is defined by a 0.5 increase in BMI-z score. Being overweight is defined by a BMI-z between the 85th and the 95th percentile. Obesity is defined by a BMI-z equal to or greater than the 95th percentile. | At baseline, at 1, 2, 3, 6, 9, 12 and 24 months of follow-up | 
| Assessment of change of waist circumference at different times of the study | Waist circumference (centimeters) will be taken using the same instruments and according to a standardized technique. The waist circumference percentiles will be calculated according to established Canadian standards for age and sex (Katzmarzyk et al., 2004). | At baseline, at 1, 2, 3, 6, 9, 12 and 24 months of follow-up | 
| Assessment of change of Blood pressure at different times of the study | Systolic and diastolic pressures will be assessed and considered abnormal when it is equal to or higher than the 90th percentile to follow pediatric standards (Cook et al. 2003; Weiss et al., 2004). | At baseline, at 1, 2, 3, 6, 9, 12 and 24 months of follow-up | 
| Assessment of change of fasting lipids level at different times of the study | The threshold values (mmol/L) for fasting lipids are those recommended by the National Cholesterol Education Program (NCEP, 1992), grouped into commonly used categories (Cook et al., 2003) : total cholesterol > 5.15; LDL >3.34; non-HDL cholesterol >3.73; HDL >1.04; triglycerides (0-9 years) >1.12; triglycerides >1.46 (10-19 years). | At baseline, at 3, 6, 12 and 24 months of follow-up | 
| Assessment of change of fasting glucose level at different times of the study | Laboratory testing includes fasting blood sugar. Diabetes will be defined according to the criteria (fasting glucose ≥ 0.7 mmol/L with confirmation by other test) established by the American Diabetes Association (ADA, 2004). | At baseline, at 3, 6, 12 and 24 months of follow-up | 
| Assessment of change of fasting insulinemia level at different times of the study | Laboratory testing includes fasting insulinemia level. Insulin resistance will be estimated with the Homeostasis Model Assessment Insulin - Resistance Index (HOMA-IR) = [Insulin (µUI/ml) x glucose (mg/dl)/405] (Matthews et al., 1985). The threshold value of 2.28 will define insulin resistance (Tresaco et al., 2005). | At baseline, at 3, 6, 12 and 24 months of follow-up | 
| Assessment of change of prolactin level at different times of the study | Laboratory testing includes prolactin level with normal range between 5 to 20 ng/mL. | At baseline, at 3, 12 and 24 months of follow-up | 
| Assessment of change of thyroid stimulating hormone (TSH) level at different times of the study | Laboratory testing includes thyroid stimulating hormone level with normal rate < 10 milliunits per liter (mU/L). | At baseline, at 6, 12 and 24 months of follow-up. | 
| Assessment of change of alanine aminotransferase (ALT) level at different times of the study | Laboratory testing includes alanine aminotransferase level with normal range between 5 to 40 U/L. | At baseline, at 6, 12 and 24 months of follow-up | 
| Assessment of change in responses to the physical activity MEMAS questionnaire at different times of the study | This self-questionnaire using a compilation of different validated items obtained from the United States Youth Risk Behavior Surveillance System (Brener et al, 2013), from Patient-centered Assessment and Counseling for Exercise + Nutrition, a 2-item validated questionnaire for adolescent physical activity (Hardie Murphy et al, 2015; Prochaska et al, 2001) and also include questions on the perception of self-efficacy during exercise (Motl et al, 2000). Screen time questions collect the number of hours spent during weekdays/ends (Schmitz et al, 2004). Items about transportation to school were adapted from the questionnaire of the Canadian branch of the Health Behavior in School-aged Children (Currie et al, 2010; Gropp et al, 2013). Time spent outdoors outside of school hours is evaluated by the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE)(LeBlanc et al, 2015; Katzmarzyk et al,2013), items are rated from 0 (strongly disagree) to 4 (very much agree). | At baseline, at 1, 3, 6, 12 and 24 months of follow-up | 
| Assessment of change in responses to the sleep MEMAS questionnaire at different times of the study | This part of the questionnaire compiles items on the duration (in number of hours) and quality of sleep (from  very good  =1 to  very bad  =4). Items were included since the literature seems to point out a link between lack of sleep and obesity (Chaput & Tremblay, 2012; Chen et al., 2008; Fatima et al., 2015; Patel & Hu, 2008). | At baseline, at 1, 3, 6, 12 and 24 months of follow-up | 
| Assessment of change in responses to the eating habits MEMAS questionnaire at different times of the study | Eating habits will be assessed using a Food Frequency Questionnaire from the Canadian branch of the Health Behavior in School-aged Children study (Currie et al., 2010; Vereecken & Maes, 2003) and culturally adapted by the ISCOLE team. These items are rated from 1 (no day a week) to 6 (5 days a week). Additional items concerning snacks while watching television (Van den Bulck & Van Mierlo, 2004), school meals (Johnson et al., 2014), meals from outside. These items are rated from 1 (no day a week) to 6 (5 days a week). Emotional hunger (Striegel-Moore et al., 1999) are also included. These items are rated from 1 ( never or almost never ) to 3 ( usually or always ). | At baseline, at 1, 3, 6, 12 and 24 months of follow-up | 
| Assessment of change of Tanner scores at different times of the study | Puberty status will be assessed using a questionnaire developed by Morris and Udry (1980) which includes illustrations of the five Tanner stages of pubertal development, accompanied by brief descriptions (stage 1 = no puberty, stade 2 = completed puberty). | At baseline, at 1, 3, 6, 12 and 24 months of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metabolic side effects, naïve pediatric population, second generation antipsychotics, predictive factors, monitoring