Long-term Evaluation of Carbetocin Nasal Spray for Hyperphagia Management in Prader-Willi Syndrome: Safety and Tolerability Assessment

Trial ID: 2023-506201-19-00
Protocol: ACP-101-303
Sponsor: Acadia Pharmaceuticals Inc.

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Diseases & Conditions

Hyperphagia

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of long-term treatment with **carbetocin** nasal spray for the management of **hyperphagia** in individuals with Prader-Willi Syndrome (PWS). This is clinically relevant as hyperphagia is a significant challenge in PWS, often leading to severe obesity and associated complications. Ensuring the safety and tolerability of carbetocin could provide a viable therapeutic option for managing this condition.

Secondary objectives include investigating the benefits of long-term carbetocin treatment on various aspects of PWS, such as:

**Hyperphagia**
Overall PWS symptoms
Anxiousness
Environmental controls
Caregiver burden
Healthcare utilization

These secondary objectives aim to assess the broader impact of carbetocin on the quality of life and healthcare needs of individuals with PWS and their caregivers.

Participants

The clinical trial involves a total of **130 participants** diagnosed with **Prader-Willi Syndrome (PWS)**, specifically focusing on hyperphagia-related behavior. The study population includes both male and female subjects, encompassing an age range from children to adults. Participants were selected based on their completion of a prior study and the potential benefit from long-term treatment with carbetocin nasal spray, as assessed by the investigator. The trial includes a vulnerable population, requiring informed consent from legal authorized representatives (LARs) for minors or those under guardianship. Participants must live with a caregiver capable of adhering to study procedures and attending all study visits. Caregivers are required to have sufficient language skills and the ability to manage study drug logistics. Lifestyle considerations include the requirement for female participants of childbearing potential to use effective contraception and for male participants to use condoms if sexually active. The trial aims to evaluate the safety and tolerability of the treatment over an extended period.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and tolerability of long-term treatment with **carbetocin** nasal spray for managing hyperphagia in individuals with Prader-Willi Syndrome (PWS). This is a Phase III, open-label extension study, which follows a non-randomized, single-arm design. The trial is expected to span approximately three years, with an estimated end date in July 2028. Participants who have completed the Week 12 or end-of-treatment visit of the antecedent study and meet all entry criteria are eligible for inclusion. The study will involve multiple visits, including an initial screening visit, regular follow-up visits, and a final end-of-study visit.

Participants will be required to attend scheduled study visits throughout the trial duration. The initial screening visit will confirm eligibility based on the inclusion criteria, such as informed consent and the ability to benefit from long-term treatment with carbetocin. Follow-up visits will be conducted to monitor treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and other safety assessments. The primary endpoints include the incidence of TEAEs, SAEs, and withdrawals due to adverse events. Secondary endpoints will assess changes in hyperphagia-related behaviors and caregiver burden using various questionnaires.

The expected length of participant involvement is up to 36 months, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must live with a caregiver who can adhere to study procedures and attend all study visits. Caregivers will be responsible for receiving and storing the study drug and must have sufficient language skills to complete assessments. The study drug, administered via an intranasal pump device, will be provided to participants, and caregivers will be trained in its use. Participants of childbearing potential must adhere to contraceptive guidelines throughout the study and for a specified period thereafter.

Treatment

The clinical trial involves the administration of **Carbetocin Nasal Spray**, a chemically synthesized peptide and oxytocin analogue, for the treatment of hyperphagia in Prader-Willi Syndrome. The pharmaceutical form of the experimental medication is a **nasal spray, solution**, and it is administered via **intranasal use**. The maximum daily dose of Carbetocin Nasal Spray is 9.6 mg, with the same amount being the maximum total dose. The treatment period extends up to 36 weeks. The spray is delivered using the Aptar CPS Nasal Spray Pump, which is mounted on the vial as an integral device component for administering the medicinal product. The product is not a paediatric formulation and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the long-term safety and tolerability of Carbetocin Nasal Spray. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted under the sponsorship of ACADIA PHARMACEUTICALS, with the product identified by the sponsor product code ACP-101.

Efficacy

Efficacy in this clinical trial will be assessed using a range of secondary endpoints designed to evaluate the impact of **Carbetocin Nasal Spray** on hyperphagia in individuals with Prader-Willi Syndrome (PWS). The primary focus will be on changes in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score, which will be measured from Baseline to each subsequent visit. Additionally, the Clinical Global Impression–Severity (CGI-S) score for PWS will be evaluated for changes from Baseline to each visit, providing insight into the severity of the condition over time.

Other secondary endpoints include the percentage of subjects showing a treatment response, defined as an improvement of at least 8 points from Baseline on the HQ-CT. The PWS Anxiousness and Distress Behaviors Questionnaire (PADQ) score will also be monitored for changes from Baseline to each visit. The Clinical Global Impression – Change (CGI-C) for PWS score will be assessed at each visit to determine overall changes in the condition. Furthermore, the CGI-S for hyperphagia in PWS score, Food Safe Zone score, and Zarit Burden Interview (ZBI) score will be evaluated for changes from Baseline to each visit. The PWS-specific Healthcare Resource Use and Caregiver Burden Questionnaire (PWS-HRUQ) will also be used to assess changes from Baseline to each visit.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Informed consent prior to the conduct of any study procedures is required as follows: a) For subjects who are minors: written informed consent will be obtained from the LAR (or LARs where local regulations require) or from the minor him/herself if deemed able by the Investigator per local regulations. When consent is obtained from the LAR, the subject should provide written or oral assent if deemed able by the Investigator, and according to local regulations. b) For subjects who are of legal age of consent: written informed consent will be obtained from the subject if the subject is not under guardianship and is deemed able by the Investigator. If the subject is under guardianship or deemed not able to provide consent, the subject should provide written or verbal assent if deemed able by the Investigator, and a written informed consent will be obtained from the subject’s LAR(s) according to local regulations. c) The subject’s caregiver provides written consent to participate as an informant in study assessments. The caregiver may or may not be an LAR.
Has completed the Week 12/EOT visit of the antecedent study.
Met all entry criteria for the antecedent study.
May benefit from long-term treatment with open-label carbetocin in the judgment of the Investigator.
Lives with a caregiver who understands and is willing and able to adhere to study-related procedures and is willing to participate in all study visits. a) The subject must be under the caregiver’s consistent care and observation during the study when not attending school or day programs. b) The caregiver should be a family member of the subject or someone whose association with the subject is the equivalent of a family relation OR The caregiver is not a family member but has cared for the subject for at least 6 months and plans to continue to care for the subject during this study and spends time with the subject at least 5 days per week. c) The caregiver must have sufficient language skills to complete the assessments in the language of the assessments and be able to utilize electronic media for study visits and questionnaires. Caregivers will be trained to use the electronic media by which assessments are completed and respond in the local language.
Caregiver is able to receive study drug shipments, where permitted, and store study drug per instructions during the study.
Caregiver is able to snap the intranasal pump device onto the study drug vial.
This criterion for female subjects varies depending on the location of the subject’s clinical site due to local regulatory requirements (or requests). a) In the EU: If female, must not be pregnant or breastfeeding. Subjects of childbearing potential should abstain from sexual activity for the duration of the study and for at least 30 days thereafter. If a subject is sexually active or becomes sexually active during the study, she must use a highly effective contraceptive method per Clinical Trials Facilitation and Coordination Group (CTFG) recommendations (Appendix B). The contraceptive method should be used for at least 1 month prior to Baseline, throughout the study, and for at least 30 days thereafter. b) In the UK: If the subject is female, she must not be pregnant or breastfeeding. Subjects of childbearing potential (including subjects who reach menarche during the study) should abstain from sexual activity for the duration of the study and for at least 30 days thereafter. If a subject is sexually active or becomes sexually active during the study, she must use an intrauterine device (IUD) plus barrier method (diaphragm, cap, or sponge with spermicide), OR she must use one of these acceptable methods of contraception and her partner must use a condom for at least 1 month prior to Baseline, throughout the study, and for at least 30 days thereafter. A female is considered of childbearing potential following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. c. In North America: If the subject is female, she must not be pregnant or breastfeeding. Subjects of childbearing potential should abstain from sexual activity for the duration of the study and for at least 30 days thereafter. If a subject is sexually active or becomes sexually active during the study, she must use a non-user-dependent method of contraception (e.g., IUD or implant) or a user-dependent hormonal method of contraception (e.g., injection, oral, transdermal, or intravaginal). The contraceptive method should be used for at least 1 month prior to Baseline, throughout the study, and for at least 30 days thereafter.
This criterion for male subjects varies depending on the location of the subject’s clinical site due to local regulatory requirements (or requests). a) In the EU: If male and sexually active, must use a condom (even if vasectomized) from the time of Baseline until 90 days after the last dose of study drug. The male subject’s female partner must use a highly effective contraceptive method per CTFG recommendations (Appendix B). The female partner’s contraceptive method should be used for at least 1 month prior to Baseline, throughout the study, and for at least 30 days thereafter; OR the male subject must not have a female partner of childbearing potential. Male subjects must also agree to not donate sperm from the time of Baseline until 90 days after the last dose of study drug. b. In the UK: If the subject is male and sexually active, he must use a condom (even if vasectomized) from the time of Baseline until 90 days after the last dose of study drug. The male subject’s female partner must use either an IUD or a barrier method (e.g., diaphragm, cap, or sponge with spermicide; a female condom in combination with a male condom is not acceptable); OR the male subject must not have a female partner of childbearing potential. Subjects must also agree not to donate sperm from the time of Baseline until 90 days after the last dose of study drug. c. In North America: If the subject is male and sexually active, he must use a condom (even if vasectomized) from the time of Baseline until 90 days after the last dose of study drug. The male subject’s female partner must use either a non-user dependent method of contraception (e.g., IUD or implant) or a user dependent hormonal method of contraception (e.g., injection, oral, transdermal, or intravaginal). The female partner’s contraceptive method should be used for at least 1 month prior to Baseline, throughout the study, and for at least 30 days thereafter; OR the male subject must not have a female partner of childbearing potential. Subject must also agree not to donate sperm from the time of Baseline until 90 days after the last dose of study drug. b. In the UK: If the subject is male and sexually active, he must use a condom (even if vasectomized) from the time of Baseline until 90 days after the last dose of study drug. The male subject’s female partner must use either an IUD or a barrier method (e.g., diaphragm, cap, or sponge with spermicide; a female condom in combination with a male condom is not acceptable); OR the male subject must not have a female partner of childbearing potential. Subjects must also agree not to donate sperm from the time of Baseline until 90 days after the last dose of study drug. c) In North America: If the subject is male and sexually active, he must use a condom (even if vasectomized) from the time of Baseline until 90 days after the last dose of study drug. The male subject’s female partner must use either a non-user dependent method of contraception (e.g., IUD or implant) or a user dependent hormonal method of contraception (e.g., injection, oral, transdermal, or intravaginal). The female partner’s contraceptive method should be used for at least 1 month prior to Baseline, throughout the study, and for at least 30 days thereafter; OR the male subject must not have a female partner of childbearing potential. Subject must also agree not to donate sperm from the time of Baseline until 90 days after the last dose of study drug.

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Exclusion Criteria

Has a history of, or current, cerebrovascular disease, brain trauma, epilepsy, or frequent migraines. A history of febrile seizures is not exclusionary.
Has active psychotic symptoms, a history of psychotic symptoms, or a psychotic disorder.
Has a history of suicide attempt or inpatient psychiatric hospitalization.
Has any of the following: a) QTcF interval of >450 ms at Baseline (before dosing); b) History of a risk factor for torsades de pointes (e.g., heart failure or family history of long QT syndrome); c) History of clinically significant QT prolongation that is deemed to put the subject at increased risk of clinically significant QT prolongation; d) Has any other clinically significant finding on ECG at Baseline (before dosing).
Is judged by the Investigator or the Medical Monitor to be inappropriate for the study for any reason.
In France only: Is under court protection, not affiliated to a social security system, or a protected adult under French law (Art. L. 1121-6, Art. L. 1121-8, Art. L. 1121-8-1).