Clinical trial NCT03149445: Co-administration of Tesofensine/Metoprolol in Subjects With Prader-Willi Syndrome (PWS)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Confirmed Genetic Diagnosis of Prader-Willi Syndrome
Lead sponsor: Saniona
Sponsor class: INDUSTRY
First posted: 2017-05-11
Enrollment: 18
Sex: ALL
Minimum age (years): 12
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two-centre, double-blind, placebo-controlled, randomized, and multiple-dose clinical study.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percent Change From Baseline to End of Treatment in Mean Body Weight
timeFrame: 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:
measure: Change From Baseline to End of Treatment in Mean Body Weight
timeFrame: 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
measure: Change From Baseline to End of Treatment in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Score
timeFrame: 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
measure: Steady State Concentrations of Tesofensine and Metoprolol as Measured by Trough Values
timeFrame: DB Step 1: Day 29; DB Step 2: Day 29; OLE I: Day 120; OLE II: Day 210
measure: Change From Baseline to End of Treatment in Fat- and Fat Free Mass (%) by Dual X-ray Absorptiometry (DEXA)
timeFrame: 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
measure: Change From Baseline to End of Treatment in Bone Mineral Density (BMD) by Dual X-ray Absorptiometry (DEXA)
timeFrame: 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
measure: Change From Baseline to End of Treatment in Bone Mineral Content (BMC) by Dual X-ray Absorptiometry (DEXA)
timeFrame: 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
measure: Change From Baseline to End of Treatment in Heart Rate (HR)
timeFrame: 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
measure: Change From Baseline to End of Treatment in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: 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
measure: Total Number of Adverse Events
timeFrame: 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
measure: Change From Baseline to End of Treatment in PR Interval
timeFrame: 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
measure: Change From Baseline to End of Treatment in Electrocardiogram (ECG) Parameters
timeFrame: 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
measure: Change From Baseline to End of Treatment in HbA1c
timeFrame: 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
measure: Change From Baseline to End of Treatment in Insulin
timeFrame: 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
measure: Change From Baseline to End of Treatment in Fasting pl. Glucose, Triglycerides, Low-density Lipoprotein (LDL) and High-density Lipoprotein (HDL) Cholesterol
timeFrame: 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
measure: Number of Subjects With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: 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
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: Motol University Hospital
city: Budapest
country: Hungary
facility: Semmelweis University
Study officials:
affiliation: Saniona
name: Kim Krogsgaard, MD, DMSc
role: STUDY_DIRECTOR
References: