Phase 3 Randomized Double-Blind Placebo-Controlled Study of Carbetocin Nasal Spray for Hyperphagia in Prader-Willi Syndrome

Trial ID: 2023-506200-24-00
Protocol: ACP-101-302
Sponsor: Acadia Pharmaceuticals Inc.

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Diseases & Conditions

Hyperphagia

Objectives

The primary objective of this study is to evaluate the **efficacy** of carbetocin nasal spray compared to placebo in reducing **hyperphagia** in individuals with Prader-Willi Syndrome (PWS). Hyperphagia, characterized by an insatiable appetite, is a significant clinical concern in PWS, often leading to obesity and associated comorbidities. Addressing hyperphagia can improve quality of life and reduce health risks in affected individuals.

Secondary objectives include investigating the efficacy of carbetocin versus placebo on overall Prader-Willi Syndrome symptoms and specifically on hyperphagia within this population. These objectives aim to provide a comprehensive understanding of carbetocin's potential therapeutic benefits in managing PWS-related symptoms.

Participants

The clinical trial involves a total of **85 participants** diagnosed with **Prader-Willi Syndrome (PWS)**, specifically focusing on hyperphagia-related behavior. The study population includes both male and female subjects, ranging in age from 5 to 30 years. Participants were selected based on their documented disease-causing mutation and increased appetite with decreased satiety, consistent with PWS Nutritional Phase 3. The trial includes individuals who live with a caregiver capable of adhering to study-related procedures. Participants are required to have a stable dose of any allowed chronic concomitant medications for at least three months prior to the screening visit. The trial population is characterized by a vulnerable group, necessitating informed consent from legally acceptable representatives for minors or those under guardianship. Lifestyle considerations include the requirement for female participants of childbearing potential to use highly effective contraceptive methods, and male participants to use condoms if sexually active. The study aims to evaluate the efficacy of carbetocin nasal spray compared to a placebo in managing hyperphagia symptoms in this specific population.

Plans and Procedures

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy of **Carbetocin Nasal Spray** in treating hyperphagia associated with **Prader-Willi Syndrome** (PWS). The trial aims to compare the effects of Carbetocin Nasal Spray against a placebo over a 12-week period. Participants will be randomly assigned to receive either the active treatment or placebo, ensuring that neither the participants nor the investigators know which treatment is being administered, thus maintaining the double-blind nature of the study.

The trial will commence with a screening visit to determine participant eligibility based on specific inclusion criteria, such as age range (5 to 30 years), documented PWS, and stable medication use. Following successful screening, eligible participants will enter the baseline phase, where initial assessments will be conducted. The primary endpoint is the change in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score from baseline to Week 12. Secondary endpoints include changes in the Clinical Global Impression–Severity (CGI-S) score and the Clinical Global Impression–Change (CGI-C) score for PWS at Week 12.

Participants will attend regular follow-up visits throughout the study to monitor safety, efficacy, and adherence to the treatment regimen. These visits will include assessments of hyperphagia symptoms, overall health, and any adverse events. The end-of-study visit will occur at the conclusion of the 12-week treatment period, where final evaluations will be conducted to assess the overall impact of the treatment.

The expected duration of participant involvement is approximately 12 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial is scheduled to begin recruitment in July 2024, with an estimated completion date in April 2025. Participants and their caregivers must adhere to study protocols, including the use of effective contraceptive methods for the duration of the study and a specified period thereafter, to ensure the integrity and safety of the trial.

Treatment

The clinical trial involves the administration of **Carbetocin Nasal Spray**, an experimental medication developed by ACADIA PHARMACEUTICALS. This pharmaceutical product is formulated as a **nasal spray, solution** and is intended for **intranasal use**. The active substance in the medication is **carbetocin**, a chemically synthesized peptide and an analogue of **oxytocin**. The maximum daily dose of carbetocin is 9.6 mg, with a total treatment period not exceeding 12 weeks. The administration device used is the Aptar CPS Nasal Spray Pump, which is mounted on the vial as an integral component for delivering the medicinal product. The trial aims to assess the efficacy of carbetocin in treating hyperphagia in individuals with Prader-Willi Syndrome.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the carbetocin nasal spray in appearance and administration method, ensuring that neither the participants nor the investigators can distinguish between the active treatment and the placebo. The placebo is provided in a 2 ml vial, matching the concentration and volume of the carbetocin solution, but without any active pharmaceutical ingredient. This design allows for an unbiased assessment of the carbetocin's therapeutic effects compared to the placebo.

Efficacy

The efficacy of the treatment in this clinical trial will be assessed using several parameters. The primary endpoint is the change from Baseline in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score at Week 12. Secondary endpoints include the change from Baseline in the Clinical Global Impression–Severity (CGI-S) score for Prader-Willi Syndrome (PWS) at Week 12, the Clinical Global Impression–Change (CGI-C) score for PWS at Week 12, the percentage of subjects with a treatment response defined as an improvement from Baseline of at least 8 points based on the HQ-CT at Week 12, and the change from Baseline in the CGI-S score for hyperphagia in PWS at Week 12.

The efficacy parameters will be measured and collected at specified timepoints, including Baseline and Week 12. The HQ-CT and CGI-S are validated scales used to evaluate symptom improvement and severity, respectively. The analysis will focus on the comparison of these scores between the treatment group receiving **Carbetocin** Nasal Spray and the placebo group. The assessments will be conducted in a double-blind manner to ensure objectivity and reliability of the results.

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 legally acceptable representative (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 a LAR.
Is a male or female 5 to 30 years of age, inclusive, at Screening.
Has PWS with a documented disease-causing mutation.
Has increased appetite with decreased satiety accompanied by food seeking (consistent with PWS Nutritional Phase 3).
Has an HQ-CT score of ≥13 at Screening and Baseline.
Has a CGI-S for hyperphagia in PWS score of ≥4 at Screening and Baseline.
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, plans to continue to care for the subject during this study, and spends time with the subject 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 (IN) pump device onto the study drug vial.
Caregiver agrees to request and provide medical records to the investigative site.
Has been on a stable dose of any allowed chronic concomitant medications for at least 3 months prior to the Screening visit. Adjustments in growth hormone dose or medication changes that are not clinically significant in the judgment of the Investigator (i.e., having no reasonable possibility of causing changes in mood, behavior, or appetite, or otherwise affecting study endpoints) are allowed. If the medication was discontinued, the discontinuation occurred at least 2 weeks or 5 half-lives (whichever is greater) prior to Screening.
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 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 highly effective contraceptive method per Clinical Trials Facilitation and Coordination Group (CTFG) recommendations. 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 the subject is male and sexually active, he must use a condom (even if vasectomized) from the time of Screening 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. 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 Screening 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 Screening 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 Screening 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 Screening 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 Screening until 90 days after the last dose of study drug.

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Exclusion Criteria

Is genetically diagnosed with Schaaf-Yang syndrome or another genetic, hormonal, or chromosomal cognitive impairment besides PWS.
Has another nasal disorder that may affect deposition of IN medication.
Has known hypersensitivity to any component of study drug.
Has been diagnosed with cancer (except managed basal cell carcinoma or squamous cell carcinoma of the skin).
Has had clinically significant irritability or agitation, requiring initiation of antipsychotic medication, within the 6 months prior to the Screening visit.
Has used prostaglandins, prostaglandin analogues, or prostaglandin agonists in the 3 months prior to the Baseline visit. Inhibitors of prostaglandin synthesis, such as nonsteroidal anti-inflammatory drugs, are not exclusionary.
Has started a glucagon-like peptide 1 (GLP-1) agonist within the 6 months prior to the Screening visit. Treatment with GLP-1 agonist is allowed if the subject has been taking it for more than 6 months prior to Screening.
Has used oxytocin, desmopressin (DDAVP), tesofensine, diazoxide choline, melanocortin-4 receptor (MC4R) agonists (e.g., setmelanotide), or any medication approved to treat hyperphagia within 6 months prior to the Baseline visit.
Has active psychotic symptoms, a history of psychotic symptoms, or a psychotic disorder.
Has a history of suicide attempt or inpatient psychiatric hospitalization.
Has new food-related interventions, including environment or dietary restrictions, within 1 month prior to the Screening visit or during the Screening period (i.e., before the Baseline visit).
Has an active upper respiratory infection at the Screening visit or the Baseline visit.
Has participated in an interventional research study involving another investigational medication or device in the 6 months prior to the Screening visit.
Has a history of or current abuse of/dependence on alcohol or illicit drugs.
Has a clinically significant abnormal laboratory value at Screening. Laboratory testing may be repeated during the Screening period with agreement of the Medical Monitor.
Has serum potassium below the normal range (according to the central laboratory) at Screening. Serum potassium may be repeated during the Screening period with the agreement of the Medical Monitor.
Has a clinically significant thyroid function test result at Screening (as measured by thyroid stimulating hormone [TSH] and reflex free thyroxine [T4]). If TSH is abnormal and the reflex free T4 is normal, the subject may be randomized.
Has clinically significant abnormality in vital signs at Screening or Baseline.
Has any of the following: a. QTcF interval of >450 ms at Screening or 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 Screening or Baseline (before dosing)
Has a positive pregnancy test at Screening.
Is an employee or is a family member of an employee of Acadia Pharmaceuticals Inc.
Is judged by the Investigator or the Medical Monitor to be inappropriate for the study for any reason.
Has any clinically significant cardiovascular disorder, renal, hepatic, gastrointestinal, or respiratory disease, including severe asthma.
Has a history of, or current, cerebrovascular disease, brain trauma, epilepsy, or frequent migraines. A history of febrile seizures is not exclusionary.
Has significant, uncorrected visual or uncorrected hearing impairment.
Has had major surgery within 1 month of the Screening visit or planning to have surgery during the study.
Has had nasal surgery within 1 month of Screening visit or planning to have nasal surgery during the study.
Is unwilling to abstain from nasal saline, other nasal irrigation, and other IN medications medications (including IN vaccines) within two hours before or after administration of study drug during the Screening period and through the treatment period of the study.
Has had more than three episodes of sinusitis in the 12 months prior to the Baseline visit.
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).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Jul 2024	14
France	Not Recruiting	01 Jul 2024	5
Germany	Not Recruiting	01 Jul 2024	28
Italy	Not Recruiting	01 Jul 2024	30
Spain	Not Recruiting	01 Jul 2024	21