Phase 3 Study of Intranasal Carbetocin (LV-101) in Patients With Prader-Willi Syndrome

This is a Phase 3 randomized, double-blind study with an 8-week, placebo-controlled period designed to test the effectiveness, safety, and tolerability of LV-101 in participants with PWS.

Effectiveness will be measured using both caregiver-reported and clinician-reported measures of hyperphagia (extreme hunger), obsessive and compulsive behaviors, and anxiety. Safety and tolerability will be measured by adverse events, laboratory tests, and physical exams.

After the 8-week placebo-controlled period, there will be a long-term follow-up period of 56 weeks and an optional extension period after study week 64 during which all participants will receive active treatment with LV-101. At Week 8, participants who were randomized to placebo in the placebo-controlled period will be randomized to one of the two LV-101 doses, administered three times per day before meals.

• 3.2 mg intranasal carbetocin (Drug), also known as LV-101: three times per day with meals
• 9.6 mg intranasal carbetocin (Drug), also known as LV-101: three times per day with meals
• placebo (Drug): three times per day with meals

Primary outcomes

• Hyperphagia Behavior [Baseline to Week 8]: Change in hyperphagia (extreme hunger) as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score versus placebo. Score range: 0-36; higher scores mean a worse outcome. Reduction in score indicates improvement.
• Obsessive and Compulsive Behaviors [baseline to Week 8]: Change in obsessive and compulsive behaviors as measured by the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) Total Score versus placebo. Score range: 0-40; higher scores mean a worse outcome. Reduction in score indicates improvement.

Secondary outcomes

• Anxiety [Baseline to Week 8]: Change in participant anxiety as measured by the PWS Anxiety and Distress Questionnaire (PADQ) Total Score versus placebo. Score range: 0-56; higher scores mean a worse outcome. Reduction in score indicates improvement.
• Global Impression [Week 8]: Clinical Global Impression of Change (CGI-C) score versus placebo. Score range: 1-7; higher scores mean a worse outcome. Reduction in score indicates improvement.
• Hyperphagia Behavior (Subset) [Baseline to Week 8]: Change in hyperphagia as measured by the change in specified subsets of HQ-CT questions versus placebo. Score range: 0-24; higher scores mean a worse outcome. Reduction in score indicates improvement.

Sex: All, ages: 7 Years to 18 Years

Inclusion Criteria:

* Genetically-confirmed Prader-Willi syndrome
* Provide voluntary, written informed consent (parent(s) / legal guardian(s) of participant); provide voluntary, written assent (participants, as appropriate)
* PWS Nutritional Phase 3 (hyperphagic, rarely feels full)

Exclusion Criteria:

* Living in a group home
* Genetically diagnosed Schaaf-Yang syndrome or other genetic, hormonal, or chromosomal cognitive impairment
* New food-related interventions, including environment or dietary restrictions, within 1 month of screening
* Dose of any allowed chronic concomitant medications or supplements that have not been stable for ≥3 months prior to the study or is not expected to remain stable while participating in the study; adjustments in growth hormone dose ≤10% are not exclusionary
* Presence of cardiovascular disorders, epilepsy, frequent migraines, or severe asthma
* More than 3 episodes of sinusitis in the 12 months prior to Screening Visit or presence of nasal diseases that may affect deposition of intranasal medication
* Unwilling to abstain from nasal saline, other nasal irrigation, or other intranasal medications for 2 weeks prior to the Baseline visit and during the 8-week, placebo-controlled period of the study
* Use of weight loss medication, oxytocin, carbetocin, or vasopressin in the 6 months prior to screening
* Participation in an interventional research study involving another investigational medication or device in the 6 months prior to screening or during the study
* Based on the judgment of the Investigator, is unsuitable for the study for any reason, including but not limited to unstable medical condition, inability to comply with the protocol, or other risk to subject or to the integrity of the study

Participant flow

Outcome results

• Hyperphagia Behavior (Primary), Least squares mean, score on a scale: 9.6 mg of LV-101 -3.439 (-5.304 to -1.575); 3.2 mg of LV-101 -5.372 (-7.259 to -3.486); Placebo -2.237 (-4.095 to -0.378) (p 0.3493)
• Obsessive and Compulsive Behaviors (Primary), Least squares mean, score on a scale: 9.6 mg of LV-101 -2.968 (-4.667 to -1.268); 3.2 mg of LV-101 -3.123 (-4.843 to -1.403); Placebo -2.360 (-4.046 to -0.674) (p 0.6001)
• Anxiety (Secondary), Least squares mean, score on a scale: 9.6 mg of LV-101 -4.306 (-6.797 to -1.815); 3.2 mg of LV-101 -8.301 (-10.790 to -5.811); Placebo -4.489 (-6.942 to -2.037) (p 0.9144)
• Global Impression (Secondary), Least squares mean, score on a scale: 9.6 mg of LV-101 3.582 (3.250 to 3.913); 3.2 mg of LV-101 3.395 (3.057 to 3.733); Placebo 3.893 (3.562 to 4.225) (p 0.1598)
• Hyperphagia Behavior (Subset) (Secondary), Least squares mean, score on a scale: 9.6 mg of LV-101 -3.295 (-4.667 to -1.922); 3.2 mg of LV-101 -4.621 (-6.010 to -3.233); Placebo -2.209 (-3.577 to -0.841) (p 0.2479)

Adverse events

Time frame: 8-week placebo-controlled period

Other adverse events by term

Limitations and caveats: The COVID-19 pandemic began affecting this study in early March 2020 by substantially impacting the ability to safely enroll clinical study subjects, by requiring remote visits and monitoring, and by dramatically changing daily routines and social environments in this sensitive PWS population. Levo held new screening and enrollment in March 2020, and subsequently closed screening and enrollment in May 2020, resulting in the enrollment of 130 subjects instead of the 175 subjects planned.

• Results publication: Roof E, Strong TV, Stafford DEJ, Singh D, Roy SM, Doshi D, Zhang Y, Salvucci A, Youakim JM, McCandless SE; COMPASS PWS Investigators. Carbetocin Nasal Spray for the Treatment of Hyperphagia in Prader-Willi Syndrome: Results From the Randomized, Placebo-Controlled, Phase 3 Compass PWS Study. Clin Ther. 2026 Jul 22:S0149-2918(26)00234-1. doi: 10.1016/j.clinthera.2026.06.019. Online ahead of print. PMID 42486751
• Results publication: Roof E, Deal CL, McCandless SE, Cowan RL, Miller JL, Hamilton JK, Roeder ER, McCormack SE, Roshan Lal TR, Abdul-Latif HD, Haqq AM, Obrynba KS, Torchen LC, Vidmar AP, Viskochil DH, Chanoine JP, Lam CKL, Pierce MJ, Williams LL, Bird LM, Butler MG, Jensen DE, Myers SE, Oatman OJ, Baskaran C, Chalmers LJ, Fu C, Alos N, McLean SD, Shah A, Whitman BY, Blumenstein BA, Leonard SF, Ernest JP, Cormier JW, Cotter SP, Ryman DC. Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial. J Clin Endocrinol Metab. 2023 Jun 16;108(7):1696-1708. doi: 10.1210/clinem/dgad015. PMID 36633570

• Study Protocol (PDF, 2019-06-19)
• Statistical Analysis Plan (PDF, 2020-07-08)