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

Phase 2

Completed

• Conditions: Confirmed Genetic Diagnosis of Prader-Willi Syndrome
• Interventions: Drug: Tesofensine/Metoprolol; Drug: Placebos

• Registration Number: NCT03149445
• Lead Sponsor: Saniona

Brief Summary

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

Detailed Description

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 Timeline

• Study Start: 2017-03-30
• Study First Submitted: 2017-04-03
• Study First Submitted QC: 2017-05-10
• Study First Posted: 2017-05-11
• Primary Completion: 2019-07-22
• Study Completion: 2019-07-22
• Results First Submitted: 2022-07-07
• Status Verified: 2024-02
• Results First Submitted QC: 2024-02-23
• Last Update Submitted: 2024-02-23
• Results First Posted: 2024-02-26
• Last Update Posted: 2024-02-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tesofensine/Metoprolol	Tesofensine/Metoprolol	Tesofensine + metoprolol administered once a day, in the morning with a meal
Tesofensine/Metoprolol placebo	Placebos	Placebo tablets matching tesofensine + metoprolol administered once a day, in the morning with meal

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline to End of Treatment in Mean Body Weight	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	Percent change from baseline to end of treatment in mean body weight. LOCF.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to End of Treatment in Mean Body Weight	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 body weight \[kg\]. LOCF.
Change From Baseline to End of Treatment in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Score	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 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.
Steady State Concentrations of Tesofensine and Metoprolol as Measured by Trough Values	DB Step 1: Day 29; DB Step 2: Day 29; OLE I: Day 120; OLE II: Day 210	Steady state concentrations of tesofensine and metoprolol as measured by trough values. Observed values.
Change From Baseline to End of Treatment in Fat- and Fat Free Mass (%) by Dual X-ray Absorptiometry (DEXA)	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 fat- and fat free mass (%) by dual X-ray absorptiometry (DEXA). Observed values.
Change From Baseline to End of Treatment in Bone Mineral Density (BMD) by Dual X-ray Absorptiometry (DEXA)	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 BMD by dual X-ray absorptiometry (DEXA). Observed values.
Change From Baseline to End of Treatment in Bone Mineral Content (BMC) by Dual X-ray Absorptiometry (DEXA)	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 BMC by dual X-ray absorptiometry (DEXA). Observed values.
Change From Baseline to End of Treatment in Heart Rate (HR)	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 HR (bpm). LOCF.
Change From Baseline to End of Treatment in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	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 SBP (mmHg) and DBP (mmHg). LOCF.
Total Number of Adverse Events	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	Total number of Adverse Events
Change From Baseline to End of Treatment in PR Interval	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 PR interval. Observed values.
Change From Baseline to End of Treatment in Electrocardiogram (ECG) Parameters	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 ECG parameters - QRS duration, QT interval, QTcF and QTcB
Change From Baseline to End of Treatment in HbA1c	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 HbA1c (%). LOCF.
Change From Baseline to End of Treatment in Insulin	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 insulin (mIU/L). LOCF.
Change From Baseline to End of Treatment in Fasting pl. Glucose, Triglycerides, Low-density Lipoprotein (LDL) and High-density Lipoprotein (HDL) Cholesterol	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 fasting pl. glucose (mmol/L), triglycerides (mmol/L), LDL and HDL cholesterol (mmol/L). LOCF.
Number of Subjects With Adverse Events (AE) and Serious Adverse Events (SAE)	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	Number of subjects with Adverse Events and Serious Adverse Events

Trial Locations

Locations (2)

Semmelweis University; 🇭🇺 Budapest, Hungary

Motol University Hospital; 🇨🇿 Prague, Czechia