Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial

Author:

Roof Elizabeth1,Deal Cheri L2ORCID,McCandless Shawn E3ORCID,Cowan Ronald L4ORCID,Miller Jennifer L5,Hamilton Jill K67,Roeder Elizabeth R89ORCID,McCormack Shana E1011ORCID,Roshan Lal Tamanna R12ORCID,Abdul-Latif Hussein D13ORCID,Haqq Andrea M14ORCID,Obrynba Kathryn S1516ORCID,Torchen Laura C17ORCID,Vidmar Alaina P1819ORCID,Viskochil David H2021ORCID,Chanoine Jean-Pierre22ORCID,Lam Carol K L22,Pierce Melinda J23ORCID,Williams Laurel L24ORCID,Bird Lynne M2526ORCID,Butler Merlin G27ORCID,Jensen Diane E2829ORCID,Myers Susan E30,Oatman Oliver J31,Baskaran Charumathi3233,Chalmers Laura J34ORCID,Fu Cary1ORCID,Alos Nathalie2ORCID,McLean Scott D8,Shah Ajay24,Whitman Barbara Y30,Blumenstein Brent A35ORCID,Leonard Sarah F36,Ernest Jessica P36,Cormier Joseph W36,Cotter Sara P36,Ryman Davis C36ORCID

Affiliation:

1. Vanderbilt University , Nashville, TN 37240 , USA

2. Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche , Montréal, Québec H3T 1C5 , Canada

3. Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine and Children's Hospital Colorado , Aurora, CO 80309 , USA

4. Department of Psychiatry, The University of Tennessee Health Science Center College of Medicine , Memphis, TN 37996 , USA

5. Department of Pediatrics, University of Florida College of Medicine , Gainesville, FL 32611 , USA

6. Division of Endocrinology, The Hospital for Sick Children , Toronto M5G 1X8 , Canada

7. Department of Pediatrics, University of Toronto , Toronto M5G 1X8 , Canada

8. Department of Pediatrics, Baylor College of Medicine , San Antonio, TX 78207 , USA

9. Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA

10. Neuroendocrine Center, The Children's Hospital of Philadelphia Division of Endocrinology and Diabetes , Philadelphia, PA 19104 , USA

11. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104 , USA

12. Genetics and Metabolism, Children's National Hospital , Washington, DC 20010 , USA

13. Division of Pediatric Endocrinology and Diabetes, Children's of Alabama , Birmingham, AL 35233 , USA

14. Department of Pediatrics, University of Alberta , Edmonton, Alberta T6G 2R3 , Canada

15. Division of Endocrinology and Diabetes, Nationwide Children's Hospital , Columbus, OH 43205 , USA

16. Department of Pediatrics, The Ohio State University , Columbus, OH 43205 , USA

17. Division of Endocrinology, Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University , Chicago, IL 60208 , USA

18. Diabetes & Obesity Program, Center for Endocrinology, Diabetes and Metabolism, Children's Hospital Los Angeles Department of Pediatrics , Los Angeles, CA 90027 , USA

19. Keck School of Medicine of USC , Los Angeles, CA 90033 , USA

20. Department of Pediatrics, Division of Medical Genetics, The University of Utah School of Medicine , Salt Lake City, UT 84112 , USA

21. Shriners Hospital for Children , Salt Lake City, UT 84112 , USA

22. Department of Pediatrics, Endocrinology and Diabetes Unit, The University of British Columbia , Vancouver V6H 3V4 , Canada

23. Diabetes & Endocrinology, Children's Minnesota—St Paul , St Paul, MN 55404 , USA

24. Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine , Houston, TX 77030 , USA

25. Department of Pediatrics, University of California San Diego , San Diego, CA 92037 , USA

26. Rady Children's Hospital , San Diego, CA 92123 , USA

27. Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center , Kansas City, KS 66160 , USA

28. Children's Health Queensland Hospital and Health Services , South Brisbane, Queensland 4101 , Australia

29. Centre for Children's Health Research, University of Queensland , Brisbane, Queensland 4101 , Australia

30. Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Hospital , Saint Louis, MO 63104 , USA

31. Division of Endocrinology and Diabetes, Phoenix Children's Hospital , Phoenix, AZ 85016 , USA

32. Division of Endocrinology, Boston Children's Hospital , Boston, MA 02115 , USA

33. Department of Pediatrics, Harvard Medical School , Boston, MA 02115 , USA

34. Department of Pediatrics, The University of Oklahoma School of Community Medicine , Tulsa, OK 73117 , USA

35. Trial Architecture Consulting , Chevy Chase, MD 20814 , USA

36. Levo Therapeutics, Inc. , Skokie, IL 60077 , USA

Abstract

Abstract Context Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. Objective To evaluate safety and efficacy of intranasal carbetocin in PWS. Design Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. Setting Twenty-four ambulatory clinics at academic medical centers. Participants A total of 130 participants with PWS aged 7 to 18 years. Interventions Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. Main outcome measures Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). Results Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. Conclusions Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. Clinical Trials Registration Number NCT03649477

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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