Prader-Willi Syndrome

The main questions the VNS4PWS study seeks to answer are: (1) is tVNS treatment safe in people with PWS, (2) is tVNS treatment acceptable to people with PWS, and (3) is tVNS an effective treatment to reduce temper outbursts in people with PWS. Participants will wear the tVNS device daily for 4 hours over a period of 9 months. Two different doses of tVNS will be compared. During the final three months of the trial, the effect of stopping treatment will be studied. After the first year of the study, participants will have the opportunity to continue on to a 1-year open label extension period during which active tVNS treatment will be resumed.

The study will consist of an up to 45-day Screening/Baseline Period, a Double-Blind Treatment Period, and an optional Open-Label Extension Period. After completion of all Baseline assessments, patients who meet all eligibility criteria will be randomized 1:1 to receive once daily pitolisant or matching placebo. During the Double-Blind Treatment Period, in-person visits will be at Day 29, Day 57, and Day 77. Patients who do not elect to enter the Open-Label Extension Period will have follow-up visits 15 days and 30 days after the final dose of study drug. During the optional Open-Label Extension Period, in-person visits will be at Day 113, Day 260, and Day 441. Patients will have follow-up visits 15 days and 30 days after the final dose of pitolisant.

This is a first-in-human and first-in-patient, 4-part study that includes the evaluation of safety, tolerability, and PK of: single ascending doses (SAD) of RM-718 weekly (RM-718) in healthy subjects 18 to 55 years of age with obesity (Part A), multiple ascending doses (MAD) of RM-718 in healthy subjects 18 to 55 years of age with obesity (Part B), MAD of RM-718 in patients 12 to 65 years of age with HO (Part C), and MAD of RM-718 in patients with PWS (Part D). Cohorts in Parts A and B are double-blind, placebo-controlled, and randomized 2:1 (4 subjects receive RM-718, 2 subjects receive placebo). Part C evaluates open-label dose escalation in patients 12 to 65 years of age with HO. Part D evaluates open-label dose escalation in patients 12 to 65 years of age. Study participants will receive: 1 weekly dose of either RM-718 or placebo in Part A, 4 weekly doses of either RM-718 or placebo in Part B,16 weekly doses of open-label RM-718 in Part C, and 26 weekly doses of RM-718 in Part D. Study drug (RM-718 or placebo) doses are administered weekly via subcutaneous injection.

Energy balance parameters (dietary intake and energy expenditure) are influenced by gonadal hormones, such as estradiol and progesterone that fluctuate across the menstrual cycle in pre-menopausal women. Dietary intake varies across the menstrual cycle, with higher self-reported energy intake in the luteal phase. However, it is unclear how physiological and behavioral parameters such as appetite, resting metabolic rate, body composition, physical activity, or premenstrual symptoms relate to energy intake fluctuations. Furthermore, only two studies have measured free-living objective dietary intake across the menstrual cycle, neither of which have measured other aspects of energy balance in detail. This study will help address these knowledge gaps by characterizing several aspects of energy balance in both laboratory and free-living settings in healthy pre-menstrual women across the menstrual cycle. Twenty-three women (for complete data on n=18) aged 18-35 without major comorbidities and with normal menstrual cycles will be enrolled in an observational trial. In addition to a baseline visit to measure body composition, participants will undergo two 4.5-hour study visits, one of which will occur in the follicular phase and the other in the luteal phase (as confirmed with multiple low-burden methods including self-reported menstrual cycle history and urinary luteinizing hormone). Participants will be given a two-day run-in diet prior to each study day to ensure energy balance. On each study day visit, participants will undergo a resting metabolic rate test followed by a series of fasting saliva samples quantitatively pooled to measure estradiol and progesterone. Following collection of fasted ratings of appetite, participants will be provided with a standard breakfast meal. Appetite ratings will be repeated 30, 60, 90, 120, 150, and 180 minutes after the meal. Questionnaires related to eating behavior will also be completed during this time. After the 180-minute timepoint, participants will be provided with a buffet-like lunch meal with instructions to eat as much or as little as they would like; this will allow measurement of ad libitum dietary intake at a single meal. To assess free-living ad libitum dietary intake, participants will receive three days of food boxes tailored to their preferences, with uneaten food returned at the end of the three-day period. After each study visit, participants will be asked to record their dietary intake and appetite (three days) and wear and activity monitor (seven days). Differences in outcomes between visits will be assessed using paired samples t-tests and relationships among variables will be assessed via Pearson correlations. This study will provide preliminary evidence of the factors associated with dietary intake fluctuations across the menstrual cycle and provide essential preliminary data that could inform future weight management and health-promotion strategies.

The goal of this clinical trial is to learn if ARD-101 works to treat hyperphagia-related behavior in patients with Prader-Willi syndrome (PWS). It will also teach us about the safety of ARD-101. The main questions it aims to answer are: * Does ARD-101 improve the total score of the HQCT-9 (hyperphagia questionnaire for clinical trials, 9 questions)? * What medical problems do participants have when taking ARD-101? Researchers will compare ARD-101 to a placebo (a look-alike substance that contains no drug) to see if ARD-101 works to treat hyperphagia in PWS subjects. Eligible participants will: * Take ARD-101 or a placebo every day for 12 weeks. * Visit the clinic or have a tele-visit once every 2 to 4 weeks during dosing and then have a tele-visit 4 weeks after stopping the ARD-101 or placebo. * Patients/Caregivers will keep a daily diary. Participants who complete the study may be eligible to enter an open-label extension study where everyone will receive ARD-101.

Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder (NDD) with genetic origin linked to chromosomal damage in the 15q11-q13 region and characterised by hypothalamic dysfunction. At the psychiatric level, patients with PWS display difficulties in social interaction, mild to moderate intellectual deficit, major eating disorders, mood disorders and autistic manifestations, including hypo-/hyper-reactivity to sensory stimuli. While the International Classification (DSM-5) lists PWS as one of the genetic causes of Autism Spectrum Disorder (ASD), little is known about the interaction between autistic traits, sensory features and PWS. To date, assessment and diagnosis of ASD in PWS remains exceptional in standard care in France, despite the obvious importance of correct assessment for early identification and intervention. In this context, the CASSPER study aims to identify the specificity of PWS in terms of autistic symptomatology and sensory characteristics. The CASSPER study is in line with the recommendations of the French National Health Authority (HAS) for early and appropriate guidance of children with PWS. In addition, almost all children with PWS under the age of 5 have received early treatment with oxytocin (OT). As the neuromodulatory effect of OT treatment and the involvement of this neurohormone in the development of attachment, social interaction and sensory processing may explain a difference in autistic symptomatology, this parameter will be included in the analyses. The CASSPER study aims to fill gaps in our knowledge of PWS and its care and could be useful more generally to improve our understanding of autistic manifestations in NDD of genetic origin.

This study uses a noninvasive technique called transcranial magnetic stimulation (TMS) to study hyperphagia and satiety in Prader-Willi syndrome. TMS is a noninvasive way of stimulating the brain, using a magnetic field to change activity in the brain. The magnetic field is produced by a coil that is held next to the scalp. In this study, the investigators will be stimulating the brain to learn more about how TMS might improve hyperphagia in Prader-Willi syndrome.

The STIM-PRADER study aims to assess the effectiveness of auricular vagal neuromodulation therapy (aVNT) on emotional, behavioral, and cognitive domains impaired in Prader-Willi Syndrome (PWS). Currently, no treatment exists that addresses the multiple alterations associated with this rare neurodevelopmental disorder that significantly impact patients and their families. We will investigate the effects of daily, four-hour aVNT stimulation over a nine-month period on (a) emotion regulation, including assessing the persistence of effects following stimulation; (b) executive functions, including inhibition, flexibility, planning, and updating information in memory; (c) hyperphagia; (d) depression; (e) quality of life; (e) and the threshold at which effects on these dimensions can be observed. We will conduct a longitudinal multicenter parallel randomized controlled single-blind exploratory trial. Twenty-four adults with PWS and 24 caregivers will be randomly assigned to receive either active or sham stimulation under identical conditions (four hours per day, seven days per week over nine months). The primary outcome, focusing on emotional control, will be assessed every two weeks for both participants and caregivers. Secondary outcomes (executive functions, hyperphagia, depression, and quality of life) will be measured at four time points: pre-intervention, at three months, six months, and at nine months. As this is the first multicenter randomized controlled trial investigating the effects of aVNT as a treatment in PWS patients, we anticipate witnessing improved emotional regulation and reduced eating disorders, along with enhancements in executive functions and quality of life in the active stimulation group. The findings from this project could support the development of broader therapeutic approaches for other conditions in which behavioral disorders and emotional processing deficits affect patients and their caregivers.

This study will include adults aged 18-70 years with a BMI \>19 kg/m², both with and without prior bariatric surgery. Those with bariatric surgery must have experienced clinically significant weight regain (\>10% of maximum weight lost) within 1 to 5 years post-surgery. Participants will complete three initial clinical visits before beginning a 12-week high-intensity interval training (HIIT) program, followed by three post-training clinical visits. During visit 1, participants will undergo anthropometric assessments, baseline blood draw, oral glucose tolerance test, psychometric evaluations, and complete an MRI safety screening. At visit 2, participants will complete a resting metabolic rate assessment and a VO₂peak test. During visit 3, participants will have another baseline blood draw and undergo a functional MRI (fMRI). The HIIT program will consist of four weekly 28-minute sessions conducted at the Joslin Diabetes and at home. Each exercise session will include a 3-minute warm-up, six rounds of 40 seconds high-intensity followed by 3 minutes of moderate intensity, and will conclude with a 3-minute cool-down. After completing the 12-week program, participants will return for clinical visits 4-6, repeating all baseline assessments.

Overview: Investigators will conduct a randomized, single-blind cross-over study in adults with and without obesity. The study consists of one screening/baseline visit, plus two 4.5-hour in-lab appetite visits: one with the exogenous ketone supplement and one without. After the baseline/screening visit, individuals will be randomized to either placebo/ketone or ketone/placebo study visit order in a 1:1 manner using online software (http://www.randomization.com). A washout period of at least 7 days will occur between study visits. For females, every attempt will be made to book these visits in the same menstrual cycle phase (according to self-reported menstrual cycle history) or estimated phase (for individuals not taking hormonal contraceptives or with a hormonal IUD). Screening and baseline visit (\~1 hour): Individuals who consent to enroll in the study will be scheduled for a \~1 hour visit to confirm eligibility, measure body composition, and review study day procedures. Height and weight will be collected to confirm eligibility. Participants will also complete questionnaires to collect data on basic demographics and medical history, menstrual cycle history (for females), food preferences for the run-in and study day diets, screening for disordered eating (EATS-26) and alcohol or drug abuse (CAGE). Data on participant's fat mass (FM), fat-free mass (FFM), body fat percent and bone mineral density will be collected using a full body dual X-ray absorptiometry (DEXA; Hologic Model A). Body composition variables will be expressed in absolute terms and controlling for height (e.g. FM index: FM \[kg\]/height \[m2\]); FFM will also be expressed in relation to FM (FM:FFM). Run-in energy balanced diet A 1-day energy-balanced run-in diet will be provided to each participant prior to each study day. Diets will be modified according to participant preferences and the same diet will be given on the second run-in day. The caloric value of the diet will be determined using the 2023 dietary reference intake equations with self-identified activity factor (collected at the screening and baseline visit), and will have a macronutrient composition of 50% carbohydrate, 30% fat, and 20% protein. This baseline dietary control period will ensure energy balance and weight maintenance prior to each study day. All meals will be prepared by a third-party dietary meal prep company in Kelowna. Study visit days (\~4.5-5 hours) Participants will be asked to refrain from food and calorie- or caffeine-containing beverages for at least 12 hours, alcohol for at least 24 hours, and vigorous-intensity exercise for at least 48 hours before each study visit. Each study day visit will be scheduled to start sometime between 7 - 9:30am, depending on scheduling availability and usual participant wake time; both visits will be scheduled at approximately the same time. All study day procedures will be conducted on the first floor of RHS in the following order: * Body weight on a digital scale, measured without shoes or heavy clothing items * Resting metabolic rate will be measured for 15-20 minutes after a period of 25-30 minutes of quiet rest using an indirect calorimeter metabolic cart with face mask (ParvoMedics TrueOne 240). This test measures oxygen consumed and to estimate resting metabolic rate (in kilocalories/day). During the test, participants breathe normally through a facemask, while relaxed but not falling asleep. * The following procedures will be completed after the resting metabolic rate test, but before breakfast (timepoint '-5'; fasted sample) and 60, 120, and 180 minutes after breakfast is consumed: * Serial blood sampling: First, a 22-gauge intravenous (IV) catheter will be placed in the antecubital area of the arm or dorsal side of the hand. For each timepoint, two 3-mL tubes (pretreated ethylenediaminetetraacetic acid \[EDTA\]) labeled with the participant's study ID, study number, date, and time will be collected. 0.6 mg AEBSF inhibitor will be immediately added to one sample and 0 μL Dipeptidyl peptidase-IV inhibitor and 0.05 mL of aprotinin will be added to the other sample. These samples will be immediately placed on ice stored in a -80 freezer until analyses. The following appetite hormones will be assessed: acylated ghrelin, PYY (radioimmunoassay), GLP-1 (7-36), leptin, and insulin (enzyme-linked immunoassay \[ELISA\]). * Circulating concentrations of glucose and D-β-hydroxybutyrate (ketone) concentrations will be collected using a glucose and ketone monitoring system (Fora 6 Connect). * Appetite ratings will be completed using visual analogue scale (VAS) questions about hunger, fullness, prospective food consumption, and desire to eat on a sliding scale on a university-owned iPad. Questions will be from Flint et al. (In J Obes 2000; 24:38-48) and are standard procedure in the greater appetite literature. * Additional 30-minute assessments of postprandial energy expenditure and fuel utilization will be collected using indirect calorimetry after the 30, 90, and 120-minute time points. Postprandial energy expenditure assessments will be expressed relative to the resting metabolic rate values. * Standard breakfast meal: Participants will be given a standard breakfast meal consisting of a protein bar, juice, and mixed nuts (or similar substitutes, in case of food intolerances/allergies). The energy content of the breakfast in both conditions (ketone and placebo) will be designed to meet 25% of each individual's estimated total energy requirements (calculated from the 2023 Dietary Reference Intake equations). In the placebo condition, the macronutrient composition of 50% carbohydrate, 30% fat and 20% protein. In the ketone condition, 70 kcal of carbohydrate will be removed from the breakfast and replaced with the 70-kcal Ketone-IQ supplement. Participants will have up to 20 minutes to consume this meal in a private and quiet location and may not use personal devices, computers, or read during this time to avoid the influence of external stimuli on dietary intake. * Exogenous ketone and placebo supplements will be delivered in liquid form and consumed orally with the breakfast meal. Both drinks will be diluted to 500mL with a commercially available calorie-free drink (Mio; Kraft-Heinz, Chicago, IL). The ketone supplement (R-1,3-butanediol \[HVMN Ketone 2.0\]) and taste-matched calorie-free placebo will be provided by HVMN. * Ad libitum dietary intake at a single lunch meal: At the end of the 180-minute time point, participants will be offered a buffet-style lunch with pre-weighed food items, including: pre-packaged spaghetti with sauce (e.g., Stouffers or similar), dinner rolls, butter, fresh fruit, salad or steamed vegetables, cookies, chips, juice, granola bars, and regular and diet soda. Participants will be asked to consume as much or as little as they like, until comfortably full, and can request more of any item. The meal will be consumed in isolation with no distractions or and the use of computers or mobile phones. At the end of the buffet meal, leftover food will be weighed, and absolute energy and macronutrient intake will be determined by calculating the weighed difference of each food item before and after each meal. Post-study day visit dietary intake assessment • Ad libitum dietary intake: Participants will be provided with 1.5 days of meals and snacks to begin consuming after the study day visit. Participants will be instructed to eat as little or as much as they would like in free-living settings. Meals will be provided by a local meal delivery service and supplemented with snacks and beverages purchased by the study team. The content of the provided food will be identical between visits and be determined according to participant's reported eating habits, excluding both top-rated foods and disliked ones to avoid over- and under- consumption. Participants will be asked to only eat the food provided and return empty containers and remaining food at the end of the 1.5-day period. They will be provided with a paper form and food scale to record any foods that were consumed that were not provided.