Co-administration of Tesofensine/Metoprolol in Subjects With Prader-Willi Syndrome (PWS) (2016-003694-18)

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.

Study Overview

• Status: Completed
• Conditions: Confirmed Genetic Diagnosis of Prader-Willi Syndrome
• Intervention / Treatment: Drug: Tesofensine/Metoprolol; Drug: Placebos

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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia, 150 06
    • Motol University Hospital
• Hungary
  • Budapest, Hungary, H-1094
    • Semmelweis University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 28 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tesofensine/Metoprolol; Tesofensine + metoprolol administered once a day, in the morning with a meal	Drug: Tesofensine/Metoprolol; Study medication will be administered for 91 days.; Other Names: Tesofensine; Metoprolol
Placebo Comparator: Tesofensine/Metoprolol placebo; Placebo tablets matching tesofensine + metoprolol administered once a day, in the morning with meal	Drug: Placebos; Study medication will be administered for 91 days.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to End of Treatment in Mean Body Weight	Change from baseline to end of treatment in body weight [kg]. LOCF.	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.	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.	DB Step 1: Day 29; DB Step 2: Day 29; OLE I: Day 120; OLE II: Day 210
Change From Baseline to End of Treatment in Fat- and Fat Free Mass (%) by Dual X-ray Absorptiometry (DEXA)	Change from baseline to end of treatment in fat- and fat free mass (%) by dual X-ray absorptiometry (DEXA). Observed values.	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 Bone Mineral Density (BMD) by Dual X-ray Absorptiometry (DEXA)	Change from baseline to end of treatment in BMD by dual X-ray absorptiometry (DEXA). Observed values.	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 Bone Mineral Content (BMC) by Dual X-ray Absorptiometry (DEXA)	Change from baseline to end of treatment in BMC by dual X-ray absorptiometry (DEXA). Observed values.	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 Heart Rate (HR)	Change from baseline to end of treatment in HR (bpm). LOCF.	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 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Change from baseline to end of treatment in SBP (mmHg) and DBP (mmHg). LOCF.	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	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
Change From Baseline to End of Treatment in PR Interval	Change from baseline to end of treatment in PR interval. Observed values.	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 Electrocardiogram (ECG) Parameters	Change from baseline to end of treatment in ECG parameters - QRS duration, QT interval, QTcF and QTcB	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	Change from baseline to end of treatment in HbA1c (%). LOCF.	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	Change from baseline to end of treatment in insulin (mIU/L). LOCF.	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, Triglycerides, Low-density Lipoprotein (LDL) and High-density Lipoprotein (HDL) Cholesterol	Change from baseline to end of treatment in fasting pl. glucose (mmol/L), triglycerides (mmol/L), LDL and HDL cholesterol (mmol/L). LOCF.	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 (AE) and Serious Adverse Events (SAE)	Number of subjects with Adverse Events and Serious 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

Collaborators and Investigators

• Sponsor: Saniona
• Investigators: Study Director: Kim Krogsgaard, MD, DMSc, Saniona

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2017
• Primary Completion (Actual): July 22, 2019
• Study Completion (Actual): July 22, 2019

Study Registration Dates

• First Submitted: April 3, 2017
• First Submitted That Met QC Criteria: May 10, 2017
• First Posted (Actual): May 11, 2017

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Overnutrition; Nutrition Disorders; Overweight; Genetic Diseases, Inborn; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Obesity; Syndrome; Prader-Willi Syndrome; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol
• Other Study ID Numbers: TM002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No