Co-administration of Tesofensine/Metoprolol in Subjects With Prader-Willi Syndrome (PWS)

A Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose, Multi-Center Safety and Efficacy Study of Co-Administration of Tesofensine/Metoprolol for 12 Weeks in Adult and Adolescent Patients With Prader-Willi Syndrome (PWS), Followed by Two Open Label 12 Weeks Extension Periods for Adolescent Patients

Two-centre, double-blind, placebo-controlled, randomized, and multiple-dose clinical study followed by two open label extension periods.

Two-centre, double-blind, placebo-controlled, randomized, and multiple-dose clinical study. Study medication will be administered for 91 days. The study will be conducted in two steps:

• Step 1 - 9 adult subjects with PWS was treated.
• Sponsor review - following the completion of the treatment of the adult subjects, unblinded efficacy, safety, Pharmacokinetic (PK) data as well as all data from the study in subjects with type 2 diabetes (TM001) will be reviewed by sponsor and an interim analysis will be done. Following competent authority positive opinion regarding the interim analysis and unblinded data the study will proceed to:
• Step 2 - 9 adolescent subjects with PWS was treated.
• OLE (Open Label Extension) I - Participation in a 12-week OLE I was offered to subjects who completed Step 2. 8 subjects entered OLE I.
• OLE (Open Label Extension) II - Participation in a 12-week OLE II was offered to subjects who completed OLE I. 6 subjects continued to OLE II.

Inclusion Criteria:

1. Males and females with a confirmed genetic diagnosis of Prader-Willi syndrome

2. Age:

   1. Step 1: Adults aged 18-30
   2. Step 2: Adolescents aged 12-17

3. Body Mass Index (BMI):

   1. Step 1: Adults with ≥25 kg/m2
   2. Step 2: Children with a BMI >85th percentile for the same age and sex

4. Normal Blood Pressure (BP) or well managed hypertension (only if dose of BP medication(s) has been stable for >2 months)

5. Normal lipid profile or well managed dyslipidemia (only if dose of lipid-lowering medication(s) has been stable for >2 months)

6. Growth hormone is allowed; but patient must be on stable dose of growth hormone >2 months

7. Type 2 diabetes is allowed, but the following criteria must be met:

   1. HbA1c <10.0 % not being managed with insulin within the past 3 months
   2. Patients taking GLP-1 analogues (e.g. exenatide, liraglutide) must have been on stable dose for >3 months
   3. Fasting plasma glucose <11.0 mmol/l

Exclusion Criteria:

1. BP:

   1. Step 1: Adults with >140/90
   2. Step 2: Adolescents with ≥95th percentile for gender, age, and height

2. Heart Rate (HR) ≥ 90, <50 bpm

3. Hypersensitivity to tesofensine/metoprolol

4. Type 1 diabetes

5. Heart failure New York Heart Association (NYHA) level II or greater, decompensated heart failure

6. Previous myocardial infarction or stroke

7. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other DSM-III disorders, or any other psychiatric condition, which in the investigator's opinion will interfere significantly with study compliance

8. History of major depressive disorder or suicidality

9. Any clinically significant cardiac arrhythmia

10. Treatment with calcium channel blockers and beta blockers

11. Concomitant use of monoaminooxidase inhibitors

12. Bulimia or anorexia nervosa

13. Any agent used for weight loss in the past 3 months

14. Untreated hypo- or hyperthyroidism

15. Clinically significant liver (>3x ULN (Upper Limit of Normal range)) and/or kidney impairment

16. More than 5% weight loss within the last 3 months

17. Any other clinically meaningful condition, in the opinion of the investigator, which would make participation potentially unsafe

18. Contraindications to administration of metoprolol per current Summary of Product Characteristics