Intranasal Oxytocin vs. Placebo for the Treatment of Hyperphagia in Prader-Willi Syndrome

Change in Repetitive Behavior from baseline was determined using the Repetitive Behavior Scale Revised (RBS-R) score. The RBS-R is a 44-item form used to measure the full spectrum of repetitive behavior of participants. The child's parent will choose a score that describes how much of a problem the behavior has been over the last month on a 4-point scale ranging from 0 ("Behavior does not occur") to 3 ("Behavior occurs and is severe problem"). The final question asks participants to "lump together" all behaviors described in the RBS-R, and provide a rating (0-100) for how much of a problem these repetitive behaviors are overall: 1 ("Not a problem at all") to 100 ("As bad as you can imagine"). For purposes of this outcome, a change in group mean score from baseline is summarized. A negative score is indicative of a decrease in the frequency and severity of behavioral problems; whereas, a positive score is indicative of an increase in the frequency and severity of behavioral problems.

Change in Rigid Behavior from baseline was assessed using the Montefiore-Einstein Rigidity Scale-Revised-Prader-Willi Syndrome (MERS-R-PWS). The MERS-R-PWS is designed to assess 3 domains of rigid behavior in children with PWS: 1. Behavioral Rigidity (e.g., insistence on sameness, things must be done his/her way, etc.) 2. Cognitive Rigidity (e.g., special interests, inflexible adherence to rules, etc.) 3. Protest (in response to deviation from rigidity (e.g., verbal objection, tantrum, physical aggression). Four items are rated on a 5-point scale ranging from 0 ("No/None") to 4 ("Extreme/Extremely difficult") for each of the 3 domains. The domains are added yielding a possible Total Domain Score which could range from 0-48. For purposes of this outcome measure, a change in group mean score from baseline is summarized. A negative score is indicative of a decrease in rigid behaviors from baseline; whereas, a positive score is indicative of an increase in rigid behavior from baseline.

Change in body weight from baseline was determined by obtaining the participant's body weight, in kilograms, using a regularly calibrated scale. Change in body weights from baseline are summarized by study arm using basic descriptive statistics. A negative result indicates a decrease in body weight from baseline and may be associated with improved health-related outcomes including a decrease in hyperphagia.

Body composition, in particular fat mass, was assessed using bioelectrical impedance analysis (BIA). BIA was conducted with equipment and oversight provided by the Einstein-Mount Sinai Diabetes Research Center. The equipment measured resistance in ohms which represents the resistance to a small alternating current passing through the body. These values are converted to body fat percentages using built-in software, after calibrating for variables, for purposes of reporting. Percentages are summarized by study arm using basic descriptive statistics.

Change in BMI from baseline will be calculated by dividing the participant's weight in kilograms by their height in meters squared (kg/m^2). Change in mean BMI from baseline will summarized and reported using basic descriptive statistics. A negative BMI score may be indicative of a decrease in hyperphagia from baseline; whereas, a positive BMI score may be indicative of an increase in hyperphagia when compared to baseline.

Change in QOL/Caregiver burden was assessed using the 7-item Physical Health domain subscale of the WHOQOL-BREF questionnaire. The questionnaire was completed by the parent/caregiver and quantified the burden placed on the caregiver/family by the PWS disorder. Each item of the Physical Health domain was scored on a 5-point ordinal scale ranging from 1-5, for an overall possible raw scoring range of 7-35. A mean overall Physical Health score was calculated by summing the scores from the seven items (response values for 2 of the items are inversely-coded) and dividing by the total # of questions (7) for an algebraic mean. A transformed scale score was obtained by subtracting 7 (lowest possible score) from the raw score and dividing by 28 (possible raw score range). For purposes of this outcome measure change from baseline was reported. Increases in Physical Health scores from baseline were associated with higher physical health QOL and reduced caregiver physical burden.

Change in QOL/caregiver burden was assessed using the abbreviated WHOQOL-BREF. The WHOQOL-BREF measures 4 broad domains: Physical Health, Health, Social Relationships, and Environment. The questionnaire was completed by the parent/caregiver quantified the burden placed on the caregiver/family by the PWS disorder. For the Psychological Health domain (6 questions), responses were assigned to corresponding predefined scores ranging from 1-5 points. A mean overall Psychological Health score was calculated by summing the scores from 5 of the questions (#s 5, 6, 7, 11, and 19) and inverting the response value from Question #26 and adding it to the sum of the other 5 scores and dividing by the total number of questions (6). This result was multiplied by 4 to get a final Psychological Health domain score. Raw scoring ranges from 6-30; however, for purposes of this outcome measure change from baseline was reported. Positive values were associated with higher QOL and reduced caregiver burden.

Change in QOL and caregiver burden was assessed using the abbreviated WHOQOL-BREF. The WHOQOL-BREF measures 4 broad domains: Physical Health, Psychological Health, Social Relationships, and Environment. The questionnaire was completed by the parent/caregiver and quantified the burden placed on the caregiver/family by the PWS disorder. For the Social Relationships domain (3 questions), responses were assigned to corresponding predefined scores ranging from 1-5 points. A mean overall Social Relationships score was calculated by summing the 3 scores (#s 20, 21, and 22) and dividing by the total number of questions (3). This result was multiplied by 4 to get a final Social Relationships domain score. Social Relationships raw scoring ranges from 3-15; however, for purposes of this outcome measure change from baseline was reported. Positive values were associated with higher QOL and reduced caregiver burden.

Change in QOL and caregiver burden was assessed using the abbreviated WHOQOL-BREF. The WHOQOL-BREF is comprised of 26 items which measure 4 broad domains: Physical Health, Psychological Health, Social Relationships, and Environment. The questionnaire was completed by the parent/caregiver and quantified the burden placed on the caregiver/family by the PWS disorder. For the Environment domain (8 questions), responses were assigned to corresponding predefined scores ranging from 1-5 points. A mean overall Environment score was calculated by summing the scores from the 8 questions (#s 8, 9, 12, 13, 14, 23, 24, and 25) and dividing by the total number of questions (8). This result was multiplied by 4 to get a final Environmental domain score. Environment raw scoring ranges from 8-40; however, for purposes of this outcome measure change from baseline was reported. Positive values were associated with higher QOL and reduced caregiver burden.

Change in Caregiver Strain from baseline was assessed using the Caregiver Strain Questionnaire (CSQ). The CSQ is a 21-item measure of self-reported strain experienced by caregivers/families of youth with emotional problems. Responses to the CSQ are measured on a 5-point Likert scale measuring the impact of strain ranging from 1 = ("Not at all") to 5 = ("very much") for an overall possible scoring range of 21-105. For purposes of this outcome measure, a change in group mean score from baseline is summarized. A negative score is indicative of decreased caregiver/family strain from baseline; whereas, a positive score is indicative of increased caregiver/family strain from baseline.

Change in Aberrant Behavior from baseline was assessed using the Aberrant Behavior Checklist-Irritability 15-item subscale (ABC-I). The ABC-I subscale was completed by the caregiver on behalf of the child. At the suggestion of the FDA, the ABC-I subscale was included as a prospective assessment for suicidal ideation and behavior and inform investigators of trends toward increased irritability and disruptive behavior. ABC-I measures behavior on a 4-point severity scale where 0 = no problem at all, 1 = behavior is a problem but in a slight degree, 2 = problem is moderately serious, and 3 = problem is severe in degree, for an overall scoring range of 0-45. For purposes of this outcome, a change in group mean score from baseline is summarized. A negative ABC-I score is indicative of overall decreased irritability and disruptive behavior from baseline, whereas a positive ABC-I score is indicative of overall increased irritability and disruptive behavior from baseline.

Change in Salivary Oxytocin concentration levels from baseline were to have been collected. Salivary samples were to have been collected using the Oragene-Discover collection kit (ORG-500). If able, participants were to have spit saliva directly into the collection tube during an in office or remote visit, and subsequently transported to the clinical site during visit and later processed and submitted for analysis. Change in group mean concentrations from baseline was to have been summarized by study arm using basic descriptive statistics. Increases in concentrations of salivary oxytocin are generally correlated with central nervous system effects and an improvement in these symptoms.

CGI-I is a clinician rated global measure of improvement that requires the clinician to assess how much the patient's illness has improved or worsened relative to baseline at the beginning of the intervention. The CGI-I consists of one query which is rated on a 7-point scale: "Compared to the patient's condition at admission [prior to medication initiation], this patient's condition is: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment." Scores are summarized by study arm using basic descriptive statistics.