Long-term Antipsychotic Pediatric Safety Trial

Weight, Body Clinical Trial

— LAPS  

Official title:

Pediatric Trials Network Long-term Antipsychotic Pediatric Safety Trial (LAPS) NICHD-2016-LAP01 Phase 4 Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03522168
• Other study ID #: Pro00084468
• Status: Completed
• Start date: January 10, 2019
• Est. completion date: November 21, 2023

Study information

• Verified date: February 2024
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Main LAP01 study: The purpose is to evaluate the long-term pathologic weight changes associated with multi-year risperidone or aripiprazole therapy in 3 - <18-year-old children, who have varying durations of prior antipsychotic drug exposure from the start of study Month 0 (M0). This is critical because children appear to have greater vulnerability to antipsychotic-associated weight gain than adults, and obesity has significant effects on morbidity and mortality.

An additional sub-study (registry sub-study) was added via a protocol amendment. This registry sub-study is optional for participants and only participants who participate in the main study are eligible if they were 6 to less than 18 years of age at the time of the M0 visit. Participants who consent to this registry sub-study will participate in yearly in-person visits and complete monthly assessments remotely over the course of two additional years from the time of their final visit of the main LAP01 study.

Description:

Main LAP01 study: Prospective, multi-site, Phase 4, longitudinal observational study designed to systematically collect robust longitudinal post-marketing safety and quality of life data about multi-year pediatric treatment with risperidone or aripiprazole. Screening may occur for up to 37 days prior to enrollment. Assessments will occur at in-person visits planned at months 0, 6, 12, 18 and 24, and at unscheduled, in-person visits that study staff request when the participant switches or stops antipsychotic monotherapy with risperidone or aripiprazole, adds or stops treatment with a weight modifying agent, becomes pregnant, chooses to withdraw from the study prematurely or, has an ongoing Serious Adverse Event (SAE) that requires further assessment. Monthly remote interim contacts occurring between in-person visits will monitor for changes (other than dose related) in antipsychotic therapy or weight modifying treatments, potential SAEs, and potential pregnancy. The participant, his/her parent/guardian, and the participant's personal psychotropic-prescribing medical provider (PPPMP) will make any and all decisions related to antipsychotic medications, any other medications, and the participant's current mental state, developmental/psychiatric condition, and level of risk for potential harm to self or others independent of the study procedures and assessments. Study staff (SS) will share with the participant's PPPMP all lab results and changes in the participant's AEs or clinical presentation, which the study medical clinician (SMC) considers medically concerning based on the participant's assessment during in-person visits. If an emergency safety concern is evident during an in-person visit, the SMC will immediately assess the participant, following medical standard-of-care procedures, to determine whether the participant is safe to leave the clinic or requires additional emergency care. If new or worsening symptoms are reported by the participant or parent/guardian during remote interim contacts, the participant and/or parent/guardian will be instructed to contact the PPPMP directly.

Registry sub-study: Participants who choose to participate will consent via a mobile application (Pattern Health) and will measure their height and weight at home monthly (also collected through the Pattern Health mobile application). One questionnaire will be completed every 6 months via the Pattern Health mobile application. Yearly in-person visits will be conducted to obtain in-clinic height, weight, vital signs and review concomitant medications.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 509
• Est. completion date: November 21, 2023
• Est. primary completion date: November 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 18 Years

Eligibility

Main Study

Inclusion Criteria:

1. Parent/guardian has provided informed consent

2. Participant has provided assent if developmentally appropriate and as required by the institutional review board (IRB)

3. 3 - <18 years of age inclusive at time of M0 visit

4. Participant, when developmentally appropriate, and parent/guardian are:

1. Willing to authorize exchange of information between the SS and the participant's PPPMP and/or other significant medical provider

2. Affirm participant's use at M0 visit of either risperidone or aripiprazole mono-antipsychotic therapy as prescribed by participant's PPPMP

5. Based on their age at the time of M0 visit, participant is receiving aripiprazole or risperidone at the dose and for the diagnoses as listed below:

1. Participants ages 3 - < 6 years can have any diagnosis and any dose

2. Participants ages = 6 - <18 years at the doses and for the diagnoses listed below

Labeled Indications (Closely Related Disorders)

Aripiprazole 2-30 mg/day

• Irritability associated with autistic disorder:

(Irritability in autism spectrum disorder) - Treatment of Tourette's disorder:

(Tourette's disorder, persistent (chronic) motor or vocal tic disorder)

• Bipolar mania/acute treatment of manic and mixed episodes associated with Bipolar l disorder: (Bipolar spectrum disorders including disruptive mood dysregulation disorder)

• Schizophrenia: (Schizophrenia spectrum disorders including schizoaffective disorder, psychosis not otherwise specified, and delusional disorder)

Risperidone 0.25-6 mg/day - Irritability associated with autistic disorder:

(Irritability in autism spectrum disorder)

• Bipolar Mania: (Bipolar spectrum disorders including disruptive mood dysregulation disorder)

• Schizophrenia: (Schizophrenia spectrum disorders including schizoaffective disorder, psychosis not otherwise specified, and delusional disorder)

• MYCITE® (aripiprazole) and all forms of injectables are not permitted in this study

6. Guardian anticipates risperidone or aripiprazole treatment will continue for =6 months

Exclusion Criteria:

1. History of prior or current diagnosis of an eating disorder or meets diagnostic criteria for an eating disorder as described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and determined by psychiatric exam

2. Pre-existing or suspected major medical, metabolic, or genetic condition that is expected to be associated with weight, cardiovascular, neuromotor, or endocrine problems

3. Known or self-reported pregnancy

4. Taking antipsychotic medication other than either risperidone or aripiprazole at the time of M0 visit

5. Contraindications to participation in the study in the opinion of the SMC

6. Unwilling or unable to provide back-up family contact information

Registry Sub-Study

Inclusion Criteria:

1. Enrolled in LAPS Trial

2. Access to a personal mobile device (with Bluetooth capability and data or internet access) and willing to use it for the purposes of this study

3. Parent/guardian/LAR/participant has provided informed consent

4. Participant has provided assent/consent if developmentally appropriate and as required by the institutional review board (IRB)

5. Participant was part of the 6 to <18 year-old group in the LAPS Trial

Exclusion Criteria:

1. Participant has completed the M24 LAPS Trial Visit

Related Conditions & MeSH terms

• Body Weight
• Weight, Body

Intervention

Drug:
• Risperidone
Medications prescribed as standard of care for Schizophrenia, Bipolar mania/acute treatment of manic and mixed episodes associated with Bipolar I disorder, Tourette's disorder, persistent (chronic) motor or vocal tic disorder and Irritability associated with autistic disorder
• Aripiprazole
Medications prescribed as standard of care for Schizophrenia, Bipolar mania/acute treatment of manic and mixed episodes associated with Bipolar I disorder, Tourette's disorder, persistent (chronic) motor or vocal tic disorder and Irritability associated with autistic disorder

Locations

Country	Name	City	State
United States	Kennedy Krieger Institute	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Montefiore Medical Center, Albert Einstein College of Medicine	Bronx	New York
United States	University of Cincinnati	Cincinnati	Ohio
United States	Harmonex Neuroscience Research	Dothan	Alabama
United States	Duke Child and Family Study Center	Durham	North Carolina
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Pine Rest Christian Mental Health Services	Grand Rapids	Michigan
United States	Behavioral Health Hospital Oupatient Clinic	Greensboro	North Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	OM Research	Lancaster	California
United States	Massachusetts General Hospital, Lurie Center for Autism	Lexington	Massachusetts
United States	Arkansas Children's Research Institute	Little Rock	Arkansas
United States	UCLA Semel Institute	Los Angeles	California
United States	Le Bonheur Children's Hospital	Memphis	Tennessee
United States	Southwest Autism Research & Resource Center	Phoenix	Arizona
United States	Carolina Partners in Mental HealthCare, PLLC	Raleigh	North Carolina
United States	Avera McKennan University Psychiatry Associates	Sioux Falls	South Dakota
United States	Beacon Medical Group	South Bend	Indiana
United States	Neuropsychiatric Associates	Woodstock	Vermont
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	The Emmes Company, LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Registry Sub-Study: Weight and height	Concordance between weight and height collected over time from R0 LAPS Registry to R24 LAPS Registry in-person visits and mobile data	Up to 24 months
Other	Registry Sub-Study: Demographics, Measurements and Vital Signs, Lab Measurements, Clinical data	Describe extraction and transfer completeness of proposed data elements (e.g. blank fields versus error fields).; Describe if extracted measurements, vital signs, and lab values are within the expected biological range.; Describe concordance of extracted height and weight values with height and weight values obtained from in-person study visits.; Describe the format and usability of extracted data.	Up to 24 months
Primary	Main Trial: Change in BMI z-score	Longitudinally, evaluate the long term pathologic weight changes associated with multi- year risperidone or aripiprazole therapy over a period of 24 months in children ages 3 -<18 years with varying durations of prior antipsychotic drug exposure at the M0 visit. The primary analysis will focus on changes in the modified Body Mass Index (BMI) z- score in children 6 - <18 years old from M0 visit over 24 months of follow up.	Baseline, 24 months
Primary	Registry Sub-Study: Modified Body Mass Index (BMI) z-score	Evaluate the long-term pathologic weight changes associated with multi-year risperidone or aripiprazole therapy over a period of 24 to 50 months in children who were 6 to <18 years of age at the time of LAPS Trial enrollment	Up to 24 months
Secondary	Main Trial: Measure of weight change	Change in BMI category and Modified BMI z-score increase of =1.0 unit from M0	Baseline, 24 months
Secondary	Main Trial: Metabolic measures associated with risk of diabetes and cardiovascular disease	Clinical laboratory evaluations for high-sensitivity C-reactive protein (hs-CRP); hemoglobin A1c (Hgb A1c); Presence of acanthosis nigricans or, in females only, hirsuitism on physical exam	Baseline, 24 months
Secondary	Main Trial: Prolactin related outcomes	Clinical laboratory evaluation of serum prolactin; Incidence of gynecomastia in males on physical exam	Baseline, 24 months
Secondary	Main Trial: Uniformly Elicited Events of Special Interest	A standardized semi-structured interview will be used by the SMC to assess events of special interest in all participants at every in-person visit [56]. The form queries for potential hospitalizations, emergency department visits, and urgent care visits and for pregnancy. The form also evaluates frequent or especially concerning adverse effects seen with antipsychotics including behavioral events. Targeted symptoms are: Sedation, Increased sleep, Problems with attention, thinking or learning Insomnia, Arrhythmias, Light-headedness (Orthostasis vs Vertigo), Seizures, Increased appetite, Decreased appetite, Tics, Tremors, Parkinsonian symptoms, Akathisia, Drooling, Dyskinesia, Polydipsia, Polyuria, Enuresis, Galactorrhea, Amenorrhea, Sexual dysfunction/anorgasmia, Diabetes, Fractures Menorrhagia, Lack of satiety	Baseline, 24 months
Secondary	Main Trial: Adverse effects	Serious adverse events Adverse events (AEs) of mild (grade 1) severity and related to risperidone or aripiprazole All adverse events of moderate (grade 2) severity or greater regardless of relatedness to risperidone or aripiprazole	Baseline, 24 months
Secondary	Main Trial: Suicidality	Assessed using DASS	Baseline, 24 months
Secondary	Main Trial: Neuromotor effects	Abnormal Involuntary Movement Scale (AIMS) Simpson Angus Extrapyramidal Symptoms Scale (SAS)	Baseline, 24 months
Secondary	Main Trial: AEs (Adverse Events)	Elicited AEs, including AEs of mild (grade 1) and related to risperidone or aripiprazole, and all AEs of moderate (grade 2) or greater and clinically significant changes in suicidality.	Baseline, 24 months
Secondary	Main Trial: Pediatric Quality of Life Inventory	Relationship of risperidone or aripiprazole therapy to adaptive functioning and quality of life as assessed by the Pediatric Quality of Life Inventory (PedsQL, 23 item), and changes in the intensity or frequency of pre-existing behavioral problems indicated at M0 (baseline). The 23-item PedsQL Generic Core Scales were designed to measure the core dimensions of health as delineated by the World Health Organization in individuals aged 2 years and older. The main scales include physical functioning, emotional functioning, social functioning, and school functioning. Summary scores can also be utilized to measure change over time on a five point scale for 0 = "Never a Problem" to 5 = "Almost Always a Problem". The guardian will be asked to complete the parent version for reporting on their child's quality of life.	Baseline, 24 months
Secondary	Main Trial: School and Work Questionnaire (SWQ)	Relationship of risperidone or aripiprazole therapy with age-appropriate skip patterns, school promotions and graduations, changes in school supports, type of living situations, romantic relationships, arrests, and types and extent of employment during the interval since the prior assessment.	Baseline, 24 months
Secondary	Main Trial: Caregiver Strain Questionnaire (CSQ)	Relationship of risperidone or aripiprazole therapy to adaptive functioning and quality of life as assessed ) by the Caregiver Strain Questionnaire (CSQ) and changes in the intensity or frequency of pre-existing behavioral problems indicated at M0 (baseline). This is a 21-item questionnaire with a categorical scale ranging from 1 (not at all a problem) to 5 (very much a problem) that assesses the caregiver's quality of life. It asks specifically about the caregiver's quality of life by assessing the impact of caring for a child with emotional and behavioral problems. The questions include information about disruption of family life and relationships; demands on time; negative, mental, and physical health effects for any family member; financial strain; feelings of sacrifice; disruption of social/community life; worry/guilt; fatigue/strain; and embarrassment.	Baseline, 24 months
Secondary	Main Trial: Delighted-Terrible Faces Scale (DTFS)	Relationship of risperidone or aripiprazole therapy to adaptive functioning and quality of life as assessed by the Delighted-Terrible Faces Scale (DTFS) and changes in the intensity or frequency of pre-existing behavioral problems indicated at M0 (baseline). The DTFS is a uni-dimensional, single item scale that will be used to assess the participant's perceived life quality. Faces expressing various feelings are depicted, and the participant is asked which face comes closest to expressing how he/she feels about his/her life over the past month. The participant can then select from the range of seven categorical faces depicting from one-delighted to seven-terrible expressions. This scale is included because it can be easily completed by participants with limited verbal and cognitive abilities as well as by very young children.	Baseline, 24 months
Secondary	Main Trial: PK CL/F	CL/F, apparent total clearance of the drug from plasma after oral administration at steady state	24 months
Secondary	Main Trial: PK Vss/F	Vss/F, apparent volume of distribution at steady state after non-intravenous administration at steady state	24 months
Secondary	Main Trial: PK AUCss	AUCss, area under the curve at steady state	24 months
Secondary	Main Trial: PK Cmax	Cmax, maximum concentration at steady state	24 months
Secondary	Main Trial: PK Tmax	Tmax, time of maximum concentration at steady state	24 months
Secondary	Main Trial: PK T1/2	T1/2, half-life at steady state	24 months
Secondary	Registry Sub-Study: Parent/guardian/former guardian/LAR completed Pediatric Quality of Life Inventory (PedsQL, 23 item) survey.	Change in PedsQL outcomes over time from M0 LAPS Trial in-person visit to R24 LAPS Registry mobile data collection	Up to 24 months