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

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Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Confirmed Genetic Diagnosis of Prader-Willi Syndrome

Interventions

Tesofensine/MetoprololDRUG

Study medication will be administered for 91 days.

PlacebosDRUG

Study medication will be administered for 91 days.

Eligibility

Sex: ALLMin age: 12 YearsMax age: 30 Years

Medical Language ↔ Plain English

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

Locations (2)

Motol University Hospital

Prague, Czechia

Semmelweis University

Budapest, Hungary

Outcomes

Primary Outcomes

Percent Change From Baseline to End of Treatment in Mean Body Weight

Percent change from baseline to end of treatment in mean body weight. LOCF.

Time frame: DB Step 1: Day 1 to Day 91; DB Step 2: Day 1 to Day 91; OLE I: Day 91 to Day 181; OLE II: Day 181 to Day 271

Secondary Outcomes

Change From Baseline to End of Treatment in Mean Body Weight

Change from baseline to end of treatment in body weight \[kg\]. LOCF.

Time frame: DB Step 1: Day 1 to Day 91; DB Step 2: Day 1 to Day 91; OLE I: Day 91 to Day 181; OLE II: Day 181 to Day 271

Change From Baseline to End of Treatment in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Score

Change from baseline to end of treatment in HQ-CT score. LOCF. HQ-CT score was based upon a questionnaire with 9 items, each of them yielding a score between 0 and 4 resulting in a maximum HQ-CT score of 36. Change in HQ-CT answers (by question and in total) calculated as score at visit 2, 5, 9 or 14 minus score at screening visit 1 was analysed and presented using standard descriptive statistics (mean, median, standard deviation, minimum and maximum value). A decrease in total score indicates an improvement in hyperphagia. If less than three questions were answered by a subject, the missing answers were imputed by the mean score of all other available answers. In case of more than three missing answers, the total score was not calculated. For further information please refer to protocol appendix section 17.1.

Time frame: DB Step 1: Day 1 to Day 91; DB Step 2: Day 1 to Day 91; OLE I: Day 91 to Day 181; OLE II: Day 181 to Day 271

Steady State Concentrations of Tesofensine and Metoprolol as Measured by Trough Values

Steady state concentrations of tesofensine and metoprolol as measured by trough values. Observed values.

Time frame: DB Step 1: Day 29; DB Step 2: Day 29; OLE I: Day 120; OLE II: Day 210

Data from ClinicalTrials.gov

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