Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome

Study Overview
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Brief Summary
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This is a placebo-controlled clinical trial to assess whether Guanfacine Extended Release (GXR) reduces aggression and self injurious behavior in individuals with Prader Willi Syndrome (PWS). In addition, the study will establish the safety of GXR with a specific focus on metabolic effects.

Detailed Description
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Prader-Willi syndrome is a genetic disorder due to loss of function of specific genes. In newborns, symptoms include weak muscles, poor feeding, and slow development. Beginning in childhood, the person becomes constantly hungry, which often leads to obesity and type 2 diabetes. Aggression, oppositional behavior, and temper tantrums frequently occur in patients with PWS. PWS also has a high prevalence of self-injury, repetitive behavior, impulsivity, over-activity, and mild to moderate learning disability. Guanfacine Extended Release (GXR), the investigational drug in this study would be the first study to evaluate the drug in patients with Prader Willi Syndrome. Investigational means it is not approved by the Food and Drug Administration (FDA) to treat Prader Willi Syndrome. However, Guanfacine Extended Released (GXR) is an FDA approved drug used to treat children and adolescents with hypertension and attention deficit hyperactivity disorder (ADHD). GXR is thought to respond to parts of the brain that lead to strengthening working memory, reducing distraction, improving attention and impulse control. GXR is generally considered safe for children as long as it is used according to the dosing instructions (up to 4mg) of a qualified medical professional. This randomized, double-blind, placebo-controlled clinical trial aims to determine whether guanfacine extended release (GXR) reduces aggression and self-injury compared to placebo in individuals with PWS with moderate to severe aggressive and/or self-injurious behavior. In addition, GXR's tolerability will be assessed by systematically evaluating and documenting adverse events.

Official Title
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A Double Blind, Placebo Controlled, Fixed-Flexible Dose Clinical Trial of Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome

Conditions
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Prader-Willi Syndrome, Aggression, Self-Injurious Behavior, Pathologic Processes, Behavioral Symptoms, Intellectual Disability, Neurobehavioral Manifestations, Neurologic Manifestations, Nervous System Diseases, Abnormalities, Multiple, Congenital Abnormalities, Chromosome Disorders, Genetic Diseases, Inborn, Obesity, Overnutrition, Nutrition Disorders, Antihypertensive Agents, Neurotransmitter Agents, Molecular Mechanisms of Pharmacological Action, Physiological Effects of Drugs, Skin-Picking

Intervention / Treatment
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* Drug: Guanfacine Extended Release
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PWS confirmed by genetic testing documentation Rating of moderate or above on the Clinical Global Impression- Severity Scale Exclusion Criteria: Subjects with positive pregnancy test, swallowing difficulty, and/or presenting with active psychosis or mania will be excluded Subjects currently taking guanfacine extended release Patients with lactose intolerance Individuals with pre-existing, clinically significant bradycardia (< 8 years: <64 bpm; 8 to 12 years: <59 bpm; 12 to 16 years: <53 bpm) or hypotension, defined as 5th percentile for height and gender,26 will be excluded from the study. Subjects receiving antipsychotic medications due to a documented history of psychosis or bipolar disorder will be allowed to continue taking the medication without dosage modification. Growth hormone, thyroid hormone replacement treatment, and non-psychiatric medicines will be allowed to continue. N-Acetyl Cysteine and anticonvulsant medication (only if prescribed for seizures) will be allowed to continue, with specific instructions to not make any dosage changes during the clinical trial.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 35 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Placebo<br> | Other: Placebo<br>* Placebo will be administered concurrently with GXR during trials.<br>|
| Experimental: GXR<br>Immediately following the 8-week blinded randomized trial, an 8-week open-label continuation phase will be pursued to further define efficacy and tolerability of GXR, and to establish its safety with specific focus on metabolic profile. | Drug: Guanfacine Extended Release<br>* Initial dose for all participants will be 1mg per day. If the medication is well tolerated, the dose can be raised to 2 mg until day 28 and increased to 3 mg for the remaining 4 weeks in the trial. The dose schedule will not be fixed., the treating clinician can delay a planned increase or lower the dose to manage adverse effects. At week 8 timepoint, the study will be unblinded.and subjects will continue treatment for 8 weeks.<br>* Other names: Intuniv;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression- Improvement change from baseline to week 16 | Clinical Global Impression-Improvement is a 7 item scale. A rating of 0=not assessed, 1= very much improved, 2= much improved, 3=minimally improved, 4= no change, 5= minimally worse, 6= much worse, and 7= very much worse. Scores after 4 indicate a decreasing health outcome. Positive clinical response will be determined by a rating of 1= very much improved or 2= Much improved at the end of the blinded trial. | 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A change in Aberrant Behavior Checklist from baseline to week 16 | Aberrant Behavior Checklist is a 58 item survey. Items are rated on 4 point scale, 0 indicates no problem, 3 indicates major problem. Higher scores are associated with greater severity. The scales are subdivided into 5 subscales: hyperactivity, lethargy, stereotypical behavior, irritability, and inappropriate speech. | 16 Weeks | 
| A change in Self-Injury Trauma Scale from baseline to week 16 | Self Injury Trauma Scale is divided into three parts. Part 1 is an observation of healed injuries and identifying self injurious behaviors. Part 2 is subdivided into three parts number, type, and severity. Number is based on the number of wounds 1=one wound (common in a mild cases but rare in a severe case) 2=two or four wounds (common) and 3=five or more wounds (rare). Type is categorical and used to differentiate between abrasion/laceration and contusion. Injury severity is scored on a 3 item scale. 1 represents the least severe option and 3 represents the most severe option. Injury severity is broken down between type. Part 3 is the Estimate of Current Risk. It is assessed on a subjective basis with labels such as mild, moderate, and severe accompanied by descriptions of the observed state of the anatomy. Higher scores are associated with greater severity. | 16 Weeks | 
| A change in Modified Overt Aggression Scale from baseline to week 16 | Modified Overt Aggression Scale is a four-part behavior rating scale used to evaluate and document the frequency and severity of aggressive episodes. The rating scale is made up of four categories: verbal aggression, aggression against objects, aggression against self, and aggression against others. Each part is rated on a 5 point scale, 0 indicates no aggression, 4 indicates the most aggressive option. Higher scores are associated with greater severity. | 16 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adrenergic alpha-2 Receptor Agonist, Guanfacine, Adrenergic alpha-Agonists, Adrenergic Agonists, Adrenergic Agents