Propranolol for Challenging Behaviors in Autism

• ClinicalTrials.gov Identifier: NCT04047355
• Recruitment Status: Recruiting
• First Posted: August 6, 2019
• Last Update Posted: August 6, 2019
• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: New Jersey Governor’s Council for Medical Research and Treatment of Autism; New York State Institute for Basic Research
• Information provided by (Responsible Party): Barbie Zimmerman-Bier, M.D., Rutgers, The State University of New Jersey

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Autism Spectrum Disorder; Developmental Disability; Aggression; Self-Injurious Behavior; Challenging Behavior	Drug: Propranolol	Phase 2

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 participant will then continue in the open label phase.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Pilot/Feasibility Study of the Use of High Dose Propranolol to Treat Severe and Chronic Challenging Behaviors in Adolescents and Adults With Autism Spectrum Disorders
• Estimated Study Start Date: September 2019
• Estimated Primary Completion Date: July 2021
• Estimated Study Completion Date: July 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group A: Propranolol first; Participants randomly assigned to this group will receive Propranolol first. After the washout period, they will receive Placebo. Propranolol will be given in liquid or pill form.	Drug: Propranolol; 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.; Other Name: Inderal
Placebo Comparator: Group B: Placebo first; Participants randomly assigned to this group will receive Placebo first. After the washout period, they will receive Propranolol. Placebo will look identical to the study drug Propranolol.	Drug: Propranolol; 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.; Other Name: Inderal

Outcome Measures

Primary Outcome Measures :

1. Change in Aberrant Behavior Checklist (ABC-C) [ Time Frame: Weekly through study completion, up to 7 months ]
   The ABC-C is a global behavior checklist that measures drug and other treatment effects in people with 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. The Irritability Subscale will serve as the primary dependent measure.

Secondary Outcome Measures :

1. Change in Clinical Global Impression Scale (CGI) [ Time Frame: Weekly through study completion, up to 7 months ]
   The CGI 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. On this scale, 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.
2. Change in Modified Overt Aggression Scale (IBR-MOAS) [ Time Frame: Weekly through study completion, up to 7 months ]
   The IBR-MOAS is a questionnaire that includes 5 types of aggression (verbal aggression towards self and others, physical aggression towards objects, self, and others) with four levels of severity for each type of aggression. Only the section assessing the 5 types of aggression will be used for repeat evaluations: Verbal aggression toward others, Verbal aggression toward self, Physical aggression against other people, Physical aggression against objects, Physical aggression against self. The frequency of occurrence of each items are as follows: 0 = Never (never happens); 1 = Rarely (averages about once a year to once a month); 2 = Sometimes (averages about several times a month to several times a week); 3 = Often (averages about daily to several times a day); and U (Used to happen but not this past year).
3. Change in Questions About Behavior Function (QABF) [ Time Frame: Weekly through study completion, up to 7 months ]
   The QABF is an indirect assessment of behavioral function for individuals with developmental disabilities. It contains 25 items. The QABF yields five behavioral function categories: Access to Attention, Escape from Demands, Physical, Access to Tangible, and Nonsocial (i.e., sensory or automatically-maintained). Each question is scored with frequency descriptors of Never, Rarely, Some, and Often. A function is endorsed if the score for a particular function is at or above 4 points or higher.
4. Change in Side Effects Survey [ Time Frame: Weekly through study completion, up to 7 months ]
   A questionnaire for measuring patient/caregiver-reported side effects of medication. This survey does not have psychometric properties.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 30 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: J. Helen Yoo, Ph.D.; 718-494-5295; JHelen.Yoo@opwdd.ny.gov

Contact: Eric London, M.D.; 718-494-3695; naarlondon@gmail.com

Locations

United States, New Jersey

Department of Pediatrics, Division of Pediatric Neurology, Robert Wood Johnson Medical School; Recruiting

New Brunswick, New Jersey, United States, 08901

Contact: Barbie Zimmerman-Bier, M.D.

Sponsors and Collaborators

Rutgers, The State University of New Jersey

New Jersey Governor’s Council for Medical Research and Treatment of Autism

New York State Institute for Basic Research

Investigators

• Principal Investigator: Barbie Zimmerman-Bier, M.D.; Rutgers, The State University of New Jersey

More Information

• Responsible Party: Barbie Zimmerman-Bier, M.D., Assistant Professor of Pediatrics, Rutgers, The State University of New Jersey
• ClinicalTrials.gov Identifier: NCT04047355
• Other Study ID Numbers: Pro20170001942; CAUT17 APL025 ( Other Grant/Funding Number: NJ Governor's Council )
• First Posted: August 6, 2019
• Last Update Posted: August 6, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Barbie Zimmerman-Bier, M.D., Rutgers, The State University of New Jersey:

Propranolol; Beta Blocker; Psychopharmacology; Inderal

Additional relevant MeSH terms:

Autistic Disorder; Autism Spectrum Disorder; Aggression; Developmental Disabilities; Self-Injurious Behavior; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders; Behavioral Symptoms; Propranolol; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents