LAPS: Long-term Antipsychotic Pediatric Safety Trial
Study Details
Study Description
Brief 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) has been added via a protocol amendment. This registry sub-study is optional for participant and only participants who participating in the main part of the 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 three additional years from the time of their final visit of the main LAP01 study.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
Detailed 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 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, with the participant's PPPMP. 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. Participants may also provide access to their electronic health records via the use of a different mobile application (Pluto).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Risperidone group Rispridone, n=350, including 30 children 3 - <6 years old and 320 children 6 - <18 years old. ~50% - ~80% of the entire group will have <90 days of prior treatment with any antipsychotic. |
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
Other Names:
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| Aripiprazole group Aripiprazole group, n=350, including 30 children 3 - <6 years old and 320 children 6 - <18 years old. ~50% - ~80% of the entire group will have ≤90 days of prior treatment with any antipsychotic. |
Drug: 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
Other Names:
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Outcome Measures
Primary Outcome Measures
- Change in BMI z-score [Baseline, 24 months]
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.
Secondary Outcome Measures
- Measure of weight change [Baseline, 24 months]
Change in BMI category and Modified BMI z-score increase of ≥1.0 unit from M0
- Metabolic measures associated with risk of diabetes and cardiovascular disease [Baseline, 24 months]
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
- Prolactin related outcomes [Baseline, 24 months]
Clinical laboratory evaluation of serum prolactin; Incidence of gynecomastia in males on physical exam
- Uniformly Elicited Events of Special Interest [Baseline, 24 months]
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
- Adverse effects [Baseline, 24 months]
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
- Suicidality [Baseline, 24 months]
Assessed using DASS
- Neuromotor effects [Baseline, 24 months]
Abnormal Involuntary Movement Scale (AIMS) Simpson Angus Extrapyramidal Symptoms Scale (SAS)
- AEs (Adverse Events) [Baseline, 24 months]
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.
- Benefits - Pediatric Quality of Life Inventory [Baseline, 24 months]
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.
- Benefit - School and Work Questionnaire (SWQ) [Baseline, 24 months]
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.
- Benefits- Caregiver Strain Questionnaire (CSQ) [Baseline, 24 months]
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.
- Benefits - Delighted-Terrible Faces Scale (DTFS) [Baseline, 24 months]
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.
- PK CL/F [24 months]
CL/F, apparent total clearance of the drug from plasma after oral administration at steady state
- PK Vss/F [24 months]
Vss/F, apparent volume of distribution at steady state after non-intravenous administration at steady state
- PK AUCss [24 months]
AUCss, area under the curve at steady state
- PK Cmax [24 months]
Cmax, maximum concentration at steady state
- PK Tmax [24 months]
Tmax, time of maximum concentration at steady state
- PK T1/2 [24 months]
T1/2, half-life at steady state
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Parent/guardian has provided informed consent
-
Participant has provided assent if developmentally appropriate and as required by the institutional review board (IRB)
-
3 - <18 years of age inclusive at time of M0 visit
-
Participant, when developmentally appropriate, and parent/guardian are:
-
Willing to authorize exchange of information between the SS and the participant's PPPMP and/or other significant medical provider
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Affirm participant's use at M0 visit of either risperidone or aripiprazole mono-antipsychotic therapy as prescribed by participant's PPPMP
-
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:
-
Participants ages 3 - < 6 years can have any diagnosis and any dose
-
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)
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MYCITE® (aripiprazole) and all forms of injectables are not permitted in this study
- Guardian anticipates risperidone or aripiprazole treatment will continue for ≥6 months
Exclusion Criteria:
-
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
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Pre-existing or suspected major medical, metabolic, or genetic condition that is expected to be associated with weight, cardiovascular, neuromotor, or endocrine problems
-
Known or self-reported pregnancy
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Taking antipsychotic medication other than either risperidone or aripiprazole at the time of M0 visit
-
Contraindications to participation in the study in the opinion of the SMC
-
Unwilling or unable to provide back-up family contact information
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Harmonex Neuroscience Research | Dothan | Alabama | United States | 36303 |
| 2 | Southwest Autism Research & Resource Center | Phoenix | Arizona | United States | 85006 |
| 3 | Arkansas Children's Research Institute | Little Rock | Arkansas | United States | 72202 |
| 4 | OM Research | Lancaster | California | United States | 93594 |
| 5 | UCLA Semel Institute | Los Angeles | California | United States | 90024 |
| 6 | South Florida Behavioral Health Network | Hialeah | Florida | United States | 33012 |
| 7 | Clinical Trials Solution | Hialeah | Florida | United States | 33033 |
| 8 | South Florida Behavioral Health Network | Key Largo | Florida | United States | 33037 |
| 9 | South Florida Behavioral Health Network | Key West | Florida | United States | 33040 |
| 10 | South Florida Behavioral Health Network | Marathon | Florida | United States | 33050 |
| 11 | Scientific Clinical Research, Inc. | North Miami | Florida | United States | 33161 |
| 12 | IACT Health | Columbus | Georgia | United States | 31903 |
| 13 | Valley Healthcare System | Columbus | Georgia | United States | 31903 |
| 14 | IACT Health | Grayson | Georgia | United States | 30017 |
| 15 | Attalla Consultants, LLC dba Institute for Behavioral Medicine | Smyrna | Georgia | United States | 30082-2629 |
| 16 | Beacon Medical Group | South Bend | Indiana | United States | 46601 |
| 17 | Kennedy Krieger Institute | Baltimore | Maryland | United States | 21205 |
| 18 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
| 19 | Massachusetts General Hospital, Lurie Center for Autism | Lexington | Massachusetts | United States | 02421 |
| 20 | University of Massachusetts Medical School | Worcester | Massachusetts | United States | 01655 |
| 21 | Pine Rest Christian Mental Health Services | Grand Rapids | Michigan | United States | 49548 |
| 22 | University of Mississippi Medical Center | Jackson | Mississippi | United States | 39216 |
| 23 | Washington University School of Medicine | Saint Louis | Missouri | United States | 27710 |
| 24 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68131 |
| 25 | Montefiore Medical Center, Albert Einstein College of Medicine | Bronx | New York | United States | 10461 |
| 26 | Albert Einstein College of Medicine | Bronx | New York | United States | 10467 |
| 27 | Duke Child and Family Study Center | Durham | North Carolina | United States | 27705 |
| 28 | Behavioral Health Hospital Oupatient Clinic | Greensboro | North Carolina | United States | 27278 |
| 29 | Carolina Partners in Mental HealthCare, PLLC | Raleigh | North Carolina | United States | 27609 |
| 30 | University of Cincinnati | Cincinnati | Ohio | United States | 45219-2492 |
| 31 | Avera McKennan University Psychiatry Associates | Sioux Falls | South Dakota | United States | 57108 |
| 32 | Le Bonheur Children's Hospital | Memphis | Tennessee | United States | 38103 |
| 33 | BioBehavioral Research of Austin | Austin | Texas | United States | 78759 |
| 34 | Cook Children's Medical Center | Fort Worth | Texas | United States | 76104 |
| 35 | Baylor College of Medicine | Houston | Texas | United States | 77030 |
| 36 | Neuropsychiatric Associates | Woodstock | Vermont | United States | 05091 |
| 37 | University of Virginia | Charlottesville | Virginia | United States | 22903 |
Sponsors and Collaborators
- Duke University
- The Emmes Company, LLC
Investigators
- Principal Investigator: Linmarie Sikich, MD, Duke Clinical Research Institution (DCRI)
- Principal Investigator: Kevin Watt, MD, PhD, University of Utah
Study Documents (Full-Text)
More Information
Publications
None provided.- Pro00084468