Prader-Willi Syndrome
Conditions
Keywords
PWS, Prader- Willi Syndrome, Irritability, CBDV, Cannabinoids
Brief summary
This study aims to examine the feasibility and safety of cannabidivarin (CBDV) as a treatment for children and young adults with PWS.
Detailed description
This clinical research trial aims to study the feasibility and safety of cannabidivarin (CBDV), in children and young adults with Prader-Willi Syndrome (PWS). CBDV has effects independent of Cannabinoid Receptor Type 1 (CB1) and Cannabinoid Receptor Type 2 (CB2) receptor activation and a good safety profile. This proposal addresses the Foundation for Prader Willi Research's PWS Research Plan: Program 1, Clinical Care Research: seeks to evaluate treatments that aim to reduce behavioral symptoms, such as irritability, in order to improve the quality of life of both the individual with PWS and their families. GW Pharmaceuticals (since acquired by Jazz Pharmaceuticals) will provide the CBDV drug and matching placebo.
Interventions
DRUGCBDV Compound
CBDV is obtained from the Cannabis sativa L. plant and contains a negligible quantity (less than 0.2%) of Tetrahydrocannabinol (THC).
DRUGPlacebo
Placebo oral solution contains matching excipients.
Sponsors
Eric Hollander
Foundation for Prader-Willi Research
GW Pharmaceuticals Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or Female outpatients aged 5 to 30 years. 2. Diagnosis of PWS confirmed by genetic testing and patient medical records and history. 3. Stable pharmacologic, educational, behavioral and/or dietary interventions for 4 weeks prior to the study start, and for the duration of the study. 4. Have a physical exam and laboratory results that are within the norms for PWS 5. Presence of a parent/caregiver/guardian that is able to consent for their participation and complete assessments regarding the patient's development and behavior throughout the study. Child Assent will be obtained if the subject is 7 years of age or older and has the mental capacity to understand and sign a written assent form and/or give verbal assent. 6. Score on the Clinical Global Impression Scale Severity (CGI-S) ≥ 4 (moderate severity) at baseline. 7. Score of ≥18 on the Aberrant Behavior Checklist-Irritability (ABC-I) at baseline. 8. Agree not to drive or operate machinery.
Exclusion criteria
1. Exposure to any investigational agent in the 30 days prior to randomization. 2. Prior chronic treatment with CBD or CBDV. 3. Positive testing for THC or other drugs of abuse via urine testing at the screening visit or baseline visits upon repeat confirmation testing. 4. History of Drug Abuse Disorder including Cannabis Use Disorder 5. A primary psychiatric diagnosis other than PWS, including bipolar disorder, psychosis, schizophrenia, Post-Traumatic Stress Disorder (PTSD), or Major Depressive Disorder (MDD). These patients will be excluded due to potential confounding results. 6. A medical condition that severely impacts the subject's ability to participate in the study, interferes with the conduct of the study, confounds interpretation of study results or endangers the subject's well-being (including but not limited to hepatic or renal impairment and cardiovascular disease). 7. Known or suspected allergy to CBDV or excipients used in the formulation (i.e. sesame). 8. Clinical indications of renal, pancreatic, or hematologic dysfunction as evidenced by values above upper limits of normal for Blood Urea Nitrogen (BUN)/creatinine, values twice the upper limit of normal for serum lipase and amylase, platelets \<80,000 /microliter, white blood cell (WBC)\<3.0 103 /microliter or \> 2x Upper Limit of Normal (UNL) values of aspartate aminotransferase (AST) or alanine aminotransferase (ALT). 9. ECG abnormality at baseline screening or clinically significant postural drop in systolic blood pressure at screening. If the initial screening ECG shows a Bazett's corrected QT interval (QTcB) of greater than 460 msec, then 2 additional ECGs will be conducted in the same sitting, 5 minutes apart. If not recognized at screening, then a full triplicate repeat showing an average QTcB of 460 msec or less to meet all inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Irritability Based on Aberrant Behavior Checklist-Irritability (ABC-I) Subscale | Baseline, Week 4, Week 8, Week 12 | Irritability will be assessed using the Aberrant Behavior Checklist-Irritability Subscale (ABC-I). The ABC-I is a well-characterized outcome that is accepted by the FDA for the purpose of labeling and is one of the best and most validated outcome measures in the developmental disabilities. The ABC-Irritability subscale consists of 15 questions that address the presence of irritability, aggression, tantrums and/or self-injury. Each item is rated on a scale ranging from 0 ("Not at all a problem") to 3 ("Severe problem"), resulting in a total score range of 0-45, such that higher ABC-I scores are indicative of more severe behavioral problems. Subjects must score an 18 or higher at screening to be included in the study. ABC-I scores for Week 4, Week 8, and Week 12 are summarized in the table by study arm using descriptive statistics. Baseline results for this outcome can be found in the Baseline Characteristics module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Repetitive Behavior Based on the Repetitive Behavior Scale-Revised (RBS-R). | Baseline, Week 4, Week 8, Week 12 | Repetitive behavior will be evaluated using the RBS-R. RBS-R is a 43-item self-report questionnaire used to measure the breadth or repetitive behaviors in children, adolescents, and adults with ASD. The RBS-R consists of 6 subscales: Stereotyped Behavior, Self-injurious Behavior, Compulsive Behavior, Ritualistic Behavior, Sameness Behavior, and Restricted Behavior that have no overlap of item content. Each of the 43 items are rated on a 4-point Likert scale ranging from 0 ("Behavior does not occur") to 3 ("Behavior occurs and is a severe problem"), yielding an overall scoring range of 0-129, such that higher scores are associated with increased severity of the problem behavior. RBS-R scores for Week 4, Week 8, and Week 12 are summarized in the table by study arm using descriptive statistics. Baseline results for this outcome can be found in the Baseline Characteristics module. |
| Repetitive Behaviors Based on Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) | Baseline, Week 4, Week 8, Week 12 | Obsessive-compulsive symptoms will be assessed using the CY-BOCS. The CY-BOCS is 10-item clinician-rated measure designed to assess the severity of obsessive-compulsive symptoms in children/adolescents over the prior week. It consists of 5 primary sections: Time, Distress, Interference, Resistance, and Control of Symptoms. The 10 items are rated on a scale from 0 ("No symptoms") to 4 ("Extreme symptoms"), for an overall possible range of 0-40, with higher scores indicative of greater severity of symptoms. CY-BOCS scores for Week 4, Week 8, and Week 12 are summarized by study arm using descriptive statistics. Baseline results for this outcome can be found in the Baseline Characteristics module. |
| Hyperphagia | Baseline, Week 4, Week 8, Week 12 | Hyperphagia will be assessed using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). The HQ-CT is a 9-item caregiver-reported measure of the frequency and intensity of food-seeking behaviors in participants with Prader-Willi Syndrome (PWS) over the prior two-week period. The 9 items are graded on a Likert scale ranging from 0 ("No Hyperphagia") to 4 ("Most severe hyperphagia"), yielding an overall possible scoring range of 0-36, with higher scores indicating greater, more severe hyperphagia. HQ-CT scores for Week 4, Week 8, and Week 12 are summarized by study arm using descriptive statistics. Baseline results for this outcome can be found in the Baseline Characteristics module. |
| Global Functioning | Week 4, Week 8, Week 12 | Global Functioning will be assessed using the Clinical Global Impression Scale - Improvement (CGI-I). The CGI-I is a global assessment which measures the change in a participant's illness severity, relative to a baseline, considering all symptoms, behaviors, and functional impairment. It consists of a 7-point clinician-rated scale as follows: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. such that higher scores are indicative of worsening global function. CGI-I scores for Week 4, Week 8, and Week 12 are summarized by study arm using basic descriptive statistics. |
| Caregiver Strain | Baseline, Week 4, Week 8, Week 12 | Caregiver Strain will be evaluated using the Caregiver Strain Questionnaire (CSQ). The CSQ is a 21-item self-report questionnaire, consisting of 3 subscales, developed to assess caregiver strain/stress for families with a child living with an emotional or behavioral disorder. Items 1-11 assess Objective Strain. Items 12, 16-18, and 20-21 assess Subjective Internalized Strain. Items 13-15, and 19 assess Subjective Externalize Strain. All CSQ items are rated from 1 ("Not at all a problem") to 5 ("Very much a problem"). Scores are calculated by averaging items within each subscale to handle missing data and calculating a Global Score by summing the 3 subscale means for a total possible scale range of 3-15. Higher Global Scores are associated with increased Caregiver Strain. Global results scores for Week 4, Week 8, and Week 12 are summarized by study arm using descriptive statistics. Baseline results for this outcome can be found in the Baseline Characteristics module. |
| Rigid Behavior - Based on the Montefiore-Einstein Rigidity Scale-Revised-Prader-Willi Syndrome Scale (MERS-R-PWS) | Week 12 | Rigid behavior will be assessed based using the MERS-R-PWS. The MERS-R-PWS is a clinician-rated scale designed to assess 3 domains of rigid behavior in individuals with PWS: Behavioral Rigidity (e.g., Insistence on sameness, things must be done in his/her way, etc.) Cognitive Rigidity (e.g., Special interests, inflexible adherence to rules, etc.) Protest (in response to deviation from rigidity; e.g., tantrum, irritability, arguing) Each domain consists of 4 items rated on a 5-point scale ranging from 0 ("No/None/Not difficult") to 4 ("Extreme/Extremely Difficult"), yielding a range of 0-16. Scores at Week 12 will only be completed for subjects who display rigid behaviors at baseline, week 4, week 8 and week 12. A total MERS-R-PWS score (0-48) is obtained by summing subscale score. Individual subscale scores (0-16) are also summarized. Higher MERS-R-PWS scores are indicative of greater rigidity within each domain and overall rigidity. |
| Sleep Quality | Baseline through Week 12 | Sleep quality will be assessed using ActiGraph GT9X-BT® activity monitors. Successfully screened patients will receive the actigraphy device prior to the onsite baseline visit and will record a minimum of three days of baseline activity data prior to study initiation. The ActiGraph GT9X-BT activity monitors are a well validated activity and sleep monitoring device widely utilized in clinical trials and health research. For this study the ActiGraph monitors will measure: Sleep Latency (the time it takes to fall asleep), Total Sleep Time (the total amount of time spent asleep), and sleep efficiency (percentage of time in bed actually spent sleeping). Sleep data is captured automatically via cloud service. All parameters will be reported in hours/minutes and summarized by study arm. |
| Aberrant Behavior | Baseline, Week 4, Week 8, Week 12 | Aberrant Behavior will be assessed using the Aberrant Behavior Checklist (ABC). The ABC is a 58-item informative rating instrument used to measure maladaptive behaviors in individuals with developmental disabilities and ASD which resolves into 5 subscales: Irritability (15 items); Lethargy/Social withdrawal (16 items); Stereotypic behavior (7 items); Hyperactivity/noncompliance (16 items); and Inappropriate speech (4 items). The ABC is completed by a parent/caregiver who knows the participant well. The ABC measures behavior on a 4-point Likert severity scale: (0 = "Not all a problem," 1 = "Slight problem," 2 = "Moderately serious problem," and 3 = "Severe problem"). Scores for 4 of the 5 subscales are reported below (ABC-I results reported as part of the primary outcome). Higher ABC subscale scores indicate greater behavioral severity/dysfunction of that subscale. Week 4, Week 8, and Week 12 scores are summarized by study arm. See Baseline Characteristics module for baseline data. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATOREric Hollander, MD
Montefiore Medical Center/Albert Einstein College of Medicine
Baseline characteristics
| Characteristic | — |
|---|---|
| Aberrant Behavior - Aberrant Behavior Checklist (ABC) | 53.3 score on a scale STANDARD_DEVIATION 9.02 |
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 19.3 years STANDARD_DEVIATION 8.14 |
| Behavioral Rigidity based on the MERS - Behavioral Rigidity domain subscale | 9.50 score on a scale STANDARD_DEVIATION 3.15 |
| Caregiver Strain based on the Caregiver Strain Questionnaire (CSQ) | 7.05 score on a scale STANDARD_DEVIATION 2.44 |
| Cognitive Rigidity based on the MERS - Cognitive Rigidity domain subscale | 10.3 score on a scale STANDARD_DEVIATION 3.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Hyperactivity/Noncompliance based on the ABC-Hyperactivity subscale | 20.3 score on a scale STANDARD_DEVIATION 3.22 |
| Hyperphagia based on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) | 17.3 score on a scale STANDARD_DEVIATION 4.73 |
| Inappropriate Speech based on the ABC-Inappropriate Speech subscale | 2.67 score on a scale STANDARD_DEVIATION 2.31 |
| Irritability Based on Aberrant Behavior Checklist-Irritability Subscale (ABC-I) | 22.3 score on a scale STANDARD_DEVIATION 6.66 |
| Lethargy/Social withdrawal based on the ABC-Lethargy-Social Withdrawal subscale | 4.00 score on a scale STANDARD_DEVIATION 2 |
| Obsessive Compulsive based on the Children's Yale Brown Obsessive Compulsive Scale (CY-BOCS) | 12.67 score on a scale STANDARD_DEVIATION 1.97 |
| Protest behavior based on the MERS - Protest Domain subscale | 9.50 score on a scale STANDARD_DEVIATION 2.26 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 6 participants |
| Repetitive Behavior based on the Repetitive Behavior Scale-Revised (RBS-R) | 29.7 score on a scale STANDARD_DEVIATION 23.9 |
| Rigid Behavior - Montefiore Einstein Rigidity Scale-Revised-Prader-Willi Syndrome (MERS-R-PWS) | 28.33 score on a scale STANDARD_DEVIATION 8.33 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
| Stereotypic behavior based on the ABC-Stereotypic Behavior subscale | 3.00 score on a scale STANDARD_DEVIATION 2.28 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 1 / 3 | 0 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
None listed