| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Prader Willi syndrome is genetic condition that affects many parts and organ system of the body |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036476 |
| E.1.2 | Term | Prader-Willi syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of the study are:
• To examine the efficacy of Tesomet over 16 weeks on hyperphagia in adult and adolescent subjects with PWS and to inform the dose selections for the Phase 3 study; and
• To assess the safety and tolerability of Tesomet over 16 weeks in adult and adolescent subjects with PWS.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To examine the efficacy of Tesomet on body weight in adult and adolescent subjects with PWS;
• To examine the efficacy of Tesomet on hyperphagia based on Caregivers’ Global Impressions of Hyperphagia Severity and Change in adult and adolescent subjects with PWS;
• To examine the efficacy of Tesomet on overall health based on Clinicians’ Global Impressions of PWS Severity and Change in adult and adolescent subjects with PWS;
• To examine the effects of Tesomet on heart rate (HR) and blood pressure (BP) in adult and adolescent subjects with PWS; and
• To examine the pharmacokinetic (PK) profile of tesofensine and metoprolol in adult and adolescent subjects with PWS. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject and their legally authorized representative (ie, parent, legal guardian) and the caregiver must be willing to sign and receive a copy of their respective informed consent form(s) (ICF) after the nature and risk of study participation have been fully explained;
a. Informed consent(s) [and assent(s) for subjects below the legal age of consent when applicable] signed by the subject, parent, or legal guardian, as appropriate, prior to the initiation of any study procedures; and
b. informed consent(s) from the caregiver, signed prior to the initiation of any study procedures;
2. Confirmed genetic diagnosis of PWS via the central laboratory (Note: past genetic documentation is acceptable for enrollment with confirmatory methylation test done in parallel);
3. Female and male subjects aged 13 to 65 years at the time of informed consent;
4. Female subjects of non-childbearing potential (WONCBP); defined as follows: surgically sterile (ie, had a hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy ≥6 months prior to the first dose of study drug); or Postmenopausal (no menses) for at least 1 year prior to the first dose of study drug. Postmenopausal status must be confirmed by follicle-stimulating hormone (FSH) testing at screening;
5. Body mass index (BMI) within the following range at Screening:
a. Female and male subjects 18 to 65 years of age: 27 to 60 kg/m2; or
b. Female and male subjects 13 to 17 years of age with a BMI 85th percentile for age and sex;
6. Documented stable body weight (gain/loss <10%) for at least 90 days prior to Screening;
7. Total Hyperphagia Questionnaire for Clinical Trials (HQ-CT, Appendix A) score of >=13 at both Screening and at Baseline (prior to randomization) with no more than ± 3 points difference between scores;
8. A score of 4 (moderately ill) or higher on the Clinical Global Impression of PWS Severity scale (CGIS, Appendix A) as assessed by the Clinician at Screening and at Baseline;
9. Subjects must have a consistent and reliable caregiver, able and willing to be trained and comply with study requirements, and should spend at least 4 waking hours/day for a minimum of 5 days a week with this caregiver for at least 6 months prior to Screening with no planned changes in caregiver and/or duration of time spent with the caregiver throughout study participation;
10. Normal lipid profile as per central laboratory normal ranges at Screening or, if elevated, (ie, outside normal ranges, per the central laboratory), the subject is well managed on a stable dose of lipid-lowering medication(s) for >=90 days prior to Screening and during the study;
11. Growth hormone and sex hormones are allowed, but the subject must be on a stable dose of these medications 90 days prior to Screening with no plans for dose modification during the course of the study;
12. Type 2 diabetes mellitus (T2DM) is allowed, provided that all of the following criteria are met:
a. Hemoglobin A1c (HbA1c) <8.5% at Screening;
b. Subjects being treated for T2DM must have been on a stable dose of anti-diabetic medication for >= 90 days prior to Screening;
13. Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline;
14. Females of childbearing potential and males must be willing to use a highly effective form of birth control from Screening until 90 days after their last dose of study drug;
15. Male subjects must agree not to donate sperm from the first dose until 90 days after the last dose of study drug. |
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| E.4 | Principal exclusion criteria |
1. Use of any prohibited medication
2. Planned change of residency during the course of the study
3. Genotypic CYP2D6-poor metabolizers and CYP2D6 ultra-rapid metabolizers as confirmed by the central laboratory at Screening
4. Sitting BP that meets the following criteria after 5 minutes of rest at Screening:
a. Adult subjects with systolic BP >= 145 mmHg or <100 mmHg; or
b. Adult subjects with diastolic BP >= 95 mmHg or <70 mmHg; or
c. Adolescent subjects with a systolic or diastolic BP >=95th percentile for age and sex;
5. HR >= 95 bpm or <50 bpm at Screening and at Baseline
6. Corrected QT interval using Fridericia's formula >450 msec for males and >470 msec for females at Screening (by central read)
7. Hypersensitivity or contraindication to tesofensine or metoprolol
8. Type 1 diabetes mellitus
9. History of dementia
10. History of bulimia or anorexia nervosa
11. Subject has a rare hereditary problem of fructose intolerance, glucose galactose malabsorption, or sucrase-isomaltose insufficiency
12. History of clinically significant cardiac disorders as determined by the Investigator including, but not limited to, arrhythmia, myocardial infarction, prolonged QT syndrome, cardiomyopathy, New York Heart Association classification level II or greater heart failure, or decompensated heart failure as determined by the Investigator
13. Medical history of stroke or transient ischemic attack
14. Subjects who, in the Investigator’s judgment, are actively suicidal and therefore deemed to be at significant risk for suicide, or:
a. Subjects who answer “yes” to Question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS); or
b. Subjects who answer "yes" to Question 5 of the C-SSRS (Active Suicidal Ideation with Specific Plan and Intent) on the "Suicidal Ideation" portion of the C-SSRS or
c. Subjects who answer "yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the "Suicidal Behavior" portion of the C-SSRS; and the ideation or behavior occurred within 2 years prior to Screening;
15. Subjects who experience any of the following active clinical symptoms within 90 days prior to Screening, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and clinical judgment supported by the Brief Psychiatric Rating Scale (BPRS) administered centrally:
a. Delusions; b. Hallucinations; c. Major depressive disorder; d. Hypomania; or e. Suicidality;
16. Subjects who answer “yes” to the self-mutilation/self-injury question in the C-SSRS at Screening and/or Baseline
17. Participation in another interventional study within 90 days prior to Screening or any prior participation in a tesofensine or Tesomet clinical study
18. Uncontrolled endocrine disorders
19. Underlying liver impairment as evidenced by abnormal liver function test results at Screening, including alanine aminotransferase or aspartate aminotransferase abnormalities >3 x the upper limit of normal, or total bilirubin >1.5 x the upper limit of normal (except in cases of diagnosed Gilbert’s Syndrome)
20. Underlying kidney impairment, defined as estimated glomerular filtration rate <= 60 mL/min/1.73 m2 (using the Schwartz equation), as determined by Screening laboratory assessments performed by the central laboratory
21. Planned major surgery which, in the Investigator’s opinion, will interfere significantly with subject safety or compliance
22. Subjects with a history of substance abuse, including cannabinoids and/or alcohol use disorders, as per DSM-5, or a positive urine drug test (including amphetamines, cocaine, opiates, phencyclidine, tetrahydrocannabinol, barbiturates, and benzodiazepines) at Screening;
23. Subjects who have co-existing, medical condition or recent systemic infection that, in the opinion of the Investigator, could impact the safety of the subject. Each case will be evaluated individually with the Medical Monitor
24. Any subject who has had a confirmed COVID-19 infection within 90 days of screening
25. Subject received COVID-19 vaccine less than 2 weeks before baseline or subject is scheduled for a COVID-19 vaccination that will take place during their participation in the study except for booster vaccinations
26. Contact with an individual with COVID-19 infection within 14 days prior to screening, or between screening and the baseline visit
27. Subjects who have allergy to bovine-derived products, or are unable to ingest bovine-derived products due to dietary or cultural reasons
28. Subject has new onset eye pain (within 6 months prior to baseline) that is clinically unresolved, unstable and has not been medically evaluated prior to Screening
29. Subject has unstable or worsening vision within 6 months prior to baseline (one or both eyes), photophobia, or diplopia and has not been medically evaluated prior to Screening
30. History of asthma with an acute asthma exacerbation within the last 2 years |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy endpoint : The primary efficacy endpoint is the change in total HQ-CT score from Baseline to Week 16.
Safety endpoints:
• The incidence of treatment-emergent adverse events (TEAEs) of special interest (secondary endpoint);
• The incidence of TEAEs and treatment-emergent serious adverse events (TESAEs);
• The incidence of MACE;
• Laboratory evaluation (chemistry and hematology) results at Baseline and at all site visits;
• Vital sign measurements at Baseline and at Week 8 and Week 16;
• ECG assessments at Baseline and at Week 8 and Week 16;
•Physical examination findings at Baseline and at Week 8 and Week 16;
• C-SSRS administered by a trained rater at Baseline and at all visits; and
• The Aberrant Behavior Checklist (ABC) completed by the caregiver at Baseline and at all visits to assess the change in behavior. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• The change in body weight (%) from Baseline to Week 16;
• The change in the Caregiver Global Impression of Hyperphagia Severity scale (CaGI-H-S) from Baseline to Week 16;
• The proportion of responses to the Caregiver Global Impression of Hyperphagia Change scale (CaGI-H-C) at Week 16;
• The change in the Clinical Global Impression of PWS Severity scale (CGIS) from Baseline to Week 16; and
• The proportion of responses to the Clinician Global Impression of PWS Change scale (CGIC) at Week 16.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Ireland |
| Italy |
| New Zealand |
| Spain |
| Sweden |
| United Kingdom |
| United States |
| France |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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