Aggression, Autism Spectrum Disorder, Challenging Behavior, Developmental Disability, Self-Injurious Behavior
Conditions
Keywords
Propranolol, Beta Blocker, Psychopharmacology, Inderal
Brief summary
Severe challenging behaviors such as aggression and self-injury can cause significant morbidity and decrease the quality of life for individuals with Autism Spectrum Disorders (ASD). There are only two medications (Risperdal and Abilify) rigorously studied and FDA-approved for the treatment of irritability in individuals with ASD. These medications are not always successful and have many short and long-term side effects. Well-designed studies demonstrating efficacy and safety of alternative medication treatment choices are needed. There is preliminary evidence that high-dose propranolol can be effective in individuals with ASD who display severe aggression and have not responded to antipsychotics or mood stabilizers. Concerns regarding the safety of high dose propranolol have limited its clinical application. Well-designed clinical trials demonstrating the efficacy and safety of high dose propranolol will have significant effects on clinical practice and improve the physical and behavioral quality of life for an underserved subset of individuals with ASD. This study will pilot the safety and efficacy of high dose propranolol. The investigators will randomly assign participants to either propranolol or to placebo later crossing each participant over to the other group. As propranolol can cause changes in blood pressure and heart function, each participant will complete initial comprehensive testing to monitor cardiac safety throughout the study. The investigators will be utilizing telemedicine and computer based telemetry to minimize the burden of office visits on the individual and family.
Detailed description
This is a randomized, double blind, placebo controlled crossover study. A complete cardiac exam will be conducted by the pediatric cardiology team at the Robert Wood Johnson Medical School. All participants will remain on their existing, pre-study medication throughout all phases of the study. Once admitted to the study, a baseline period will begin. During the baseline period, cognitive and adaptive information will be collected. The participant will then be randomly assigned to propranolol (Phase A) or placebo (Phase B). The titration schedule will be flexible and the dose can be held steady for an extended period. Dose reduction to manage side effects are allowed at any time. Each week the family will complete behavioral forms online and meet with the study psychiatrist via telemedicine. Following the initial Phase (A or B), participants will undergo a washout period (whether propranolol or placebo). Then, they will crossover to the other Phase (A or B). Upon completion of the crossover phase, the study blind will be broken. The participants then had the option of enrolling in an open label study.
Interventions
DRUGPropranolol
Propranolol is a beta-blocker used to treat high blood pressure, irregular heartbeats, and tremors. It is used after a heart attack and to prevent migraine headaches and chest pain. It is also used off-label for anxiety and PTSD.
Sponsors
New Jersey Governor's Council for Medical Research and Treatment of Autism
New York State Institute for Basic Research
Rutgers, The State University of New Jersey
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
1. Males and females between the ages of 12-30 years and is a resident in the state of New Jersey. 2. Diagnosis of autism conducted by a clinician with confirmation using the Autism Diagnostic Observation Schedule (ADOS) or the Social Communication Questionnaire (SCQ). 3. At least one of the following challenging behaviors. 1. Self-injurious behaviors (e.g., hitting one's self, head banging or banging of other body parts causing some degree of tissue damage); 2. Physical aggression towards others (e.g., hitting, kicking, pushing, or throwing objects at others); 3. Disruptive behaviors including property destruction during anger episodes, excessive screaming which interferes with functioning; and 4. The challenging behaviors are generally (but not necessarily exclusively) associated with a congruent affect (i.e. anger or rage when aggressing) as determined by the study psychiatrist. 4. Pharmacologic treatment with at least two psychotropic including one antipsychotic medication has yielded inadequate outcome (partial improvement on one or more medications is acceptable for the study). 5. Clinical Global Impression Severity scale score of 6 or 7. 6. Aberrant Behavior Checklist--Community Irritability scale score at or above 18. 7. Medical and cardiac clearance.
Exclusion criteria
1. Asthma or any history of asthma or any disorder involving bronchoconstriction. 2. Cardiac Diseases in which the use of propranolol at high doses would be contraindicated. 3. Uncontrolled Seizure disorder (participant had a seizure within the past year and/or changes in seizure medication in the previous six months). 4. Diabetes or a history of ketoacidosis. 5. Any other medical disorder or medication which would contraindicate the use of propranolol. 6. History of allergy or adverse reaction to propranolol. 7. Pregnancy. 8. Medication exclusions include clonidine/guanfacine / digoxin or other medications affecting blood pressure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aberrant Behavior Checklist--Community (ABC-C) Irritability Subscale Scores | Titration schedule varied based on individual response; it was not predetermined. On average, Placebo was 8 wks and Propranolol was 11 wks, including titration. The last Baseline score and the last scores from Placebo and Propranolol phases were analyzed. | The Aberrant Behavior Checklist--Community (ABC-C) is a behavior checklist that measures drug and other treatment effects in people with intellectual and developmental disabilities. It is made up of five subscales, including Irritability, Lethargy, Inappropriate Speech, Hyperactivity, and Stereotypy based on 58 items that describe various behavioral problems. Each item is scored on a Likert scale: 1 = not at all a problem, to 3 = problem is severe in degree. The Irritability Subscale served as the primary dependent measure. The minimum score on the Irritability Subscale is 0 and the maximum score is 45. Lower scores represent better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression Improvement (CGI-I) Scale | Titration schedule varied based on individual response; it was not predetermined. On average, Placebo was 8 wks and Propranolol was 11 wks, including titration. The last Baseline score and the last scores from Placebo and Propranolol phases were analyzed. | The Clinical Global Impression Improvement (CGI-I) scale is used by the study psychiatrist to judge the overall clinical condition relative to baseline using the same scale as the CGI-S. The study psychiatrist will rate the improvement from baseline. The CGI consists of a 7-point subjective scale assessing symptom. Lower scores represent better outcomes. Scores of 1, 2, and 3 represent normal, some presence of symptoms, and mild behavior, respectively. A score of 4 represents moderate behavior. Scores of 5, 6, and 7 represent marked, severe, and among the most severe behavior, respectively. |
Countries
United States
Participant flow
Pre-assignment details
This was a crossover study. 6 subjects underwent both experimental phases (i.e., crossover design). 3 subjects underwent Propranolol first, then Placebo while the remaining 3 subjects underwent Placebo first, then Propranolol.
Participants by arm
| Arm | Count |
|---|---|
| Group A: First Propranolol, Then Placebo Participants randomly assigned to this group received Propranolol first. After the washout period, they received Placebo. | 3 |
| Group B: First Placebo, Then Propranolol Participants randomly assigned to this group received Placebo first. After the washout period, they received Propranolol. | 3 |
| Total | 6 |
Baseline characteristics
| Characteristic | Group A: First Propranolol, Then Placebo | Total | Group B: First Placebo, Then Propranolol |
|---|---|---|---|
| Age, Continuous | 15 years | 15 years | 15 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment United States | 3 participants | 6 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 5 |
| other Total, other adverse events | 2 / 6 | 0 / 6 | 0 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 5 |
Outcome results
Primary
Aberrant Behavior Checklist--Community (ABC-C) Irritability Subscale Scores
The Aberrant Behavior Checklist--Community (ABC-C) is a behavior checklist that measures drug and other treatment effects in people with intellectual and developmental disabilities. It is made up of five subscales, including Irritability, Lethargy, Inappropriate Speech, Hyperactivity, and Stereotypy based on 58 items that describe various behavioral problems. Each item is scored on a Likert scale: 1 = not at all a problem, to 3 = problem is severe in degree. The Irritability Subscale served as the primary dependent measure. The minimum score on the Irritability Subscale is 0 and the maximum score is 45. Lower scores represent better outcome.
Time frame: Titration schedule varied based on individual response; it was not predetermined. On average, Placebo was 8 wks and Propranolol was 11 wks, including titration. The last Baseline score and the last scores from Placebo and Propranolol phases were analyzed.
Population: Participants served as their own controls. Each participant received both Propranolol and Placebo. The treatment order was randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Propranolol Phase | Aberrant Behavior Checklist--Community (ABC-C) Irritability Subscale Scores | 14.0 score on a scale |
| Placebo Phase | Aberrant Behavior Checklist--Community (ABC-C) Irritability Subscale Scores | 18.50 score on a scale |
Comparison: A post-hoc power analysis was conducted using G\*Power, v. 3.1, to determine the achieved power for the Wilcoxon signed-rank test for matched pairs.p-value: 0.12Wilcoxon (Mann-Whitney)
Secondary
Clinical Global Impression Improvement (CGI-I) Scale
The Clinical Global Impression Improvement (CGI-I) scale is used by the study psychiatrist to judge the overall clinical condition relative to baseline using the same scale as the CGI-S. The study psychiatrist will rate the improvement from baseline. The CGI consists of a 7-point subjective scale assessing symptom. Lower scores represent better outcomes. Scores of 1, 2, and 3 represent normal, some presence of symptoms, and mild behavior, respectively. A score of 4 represents moderate behavior. Scores of 5, 6, and 7 represent marked, severe, and among the most severe behavior, respectively.
Time frame: Titration schedule varied based on individual response; it was not predetermined. On average, Placebo was 8 wks and Propranolol was 11 wks, including titration. The last Baseline score and the last scores from Placebo and Propranolol phases were analyzed.
Population: Participants served as their own controls. Each participant received both Propranolol and Placebo. The treatment order was randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Propranolol Phase | Clinical Global Impression Improvement (CGI-I) Scale | 2.00 score on a scale |
| Placebo Phase | Clinical Global Impression Improvement (CGI-I) Scale | 5.50 score on a scale |
Comparison: A post-hoc power analysis was conducted using G\*Power, v. 3.1, to determine the achieved power for the Wilcoxon signed-rank test for matched pairs.p-value: 0.07Wilcoxon (Mann-Whitney)