48 Weeks, Study to Evaluate Overall Safety and Tolerability of Co-administration of Tesofensine and Metoprolol in Subjects With Hypothalamic Injury-induced Obesity (HIO)

Study Overview
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Brief Summary
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Double-blind, randomized, placebo-controlled, single- center study followed by an open-label extension period. • The study will have two parts: Part 1: 24 weeks double-blind treatment, followed by Part 2: 24 weeks open-label extension - all subjects still participating at the end of Part 1 will be given an option to continue for additional 24 weeks on the active drug if evaluated eligible by the Investigator

Detailed Description
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Part 1 - the double-blind part: The active medication arm will be given co-administration of 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks. The placebo arm will receive matching placebo tablets. Part 2 - the open-label extension part: All active participants at the end of the double-blind part will be given the active medication 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks.

Official Title
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A 24-week Phase 2, Double-blind, Randomized, Placebo- Controlled, Single-center Safety and Efficacy Study to Evaluate Overall Safety and Tolerability of Co-administration of Tesofensine and Metoprolol in Subjects With Hypothalamic Injury-induced Obesity (HIO), and With a 24-week Open-label Extension, in Total 48 Weeks

Conditions
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Hypothalamic Injury-induced Obesity (HIO)

Intervention / Treatment
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* Drug: Tesofensine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities Males and females, aged 18-75 Confirmed diagnosis of HIO BMI ≥27 kg/m2 (where overweight is related to the HIO) Exclusion Criteria: BP ≥160/90 mmHg HR ≥ 90, <50 bpm Type 1 diabetes, Cushings disease, acromegaly, hypophysitis, infiltrative diseases or Prader-Willi syndrome Heart failure New York Heart Association (NYHA) level II or greater, decompensated heart failure Previous myocardial infarction or stroke within the last 5 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: active arm<br>The active medication arm will be given co-administration of 0.5 mg tesofensine/50 mg metoprolol daily for 24 weeks. | Drug: Tesofensine<br>* During Part 1 subjects will be randomized to treatment with co-administration of 0.5 mg tesofensine/50mg metoprolol (active medication)<br>|
| Placebo Comparator: placebo arm<br>The placebo arm will receive matching placebo tablets. | Drug: Placebo<br>* During Part 1 subjects will be randomized to matching placebo treatment with co-administration of 0.5 mg tesofensine/50mg metoprolol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of treatment emergent adverse events | Number and percentage of adverse events in each of the two treatment arms | from Baseline to week 24 | 
| Severity of treatment emergent adverse events | Number and percentage of mild, moderate and severe adverse events in each of the two treatment arms | from Baseline to week 24 | 
| Frequency and type of serious adverse events | Number, percentage and type of serious adverse events in each of the two treatment arms | from Baseline to week 24 | 
| Safety as assessed by systolic blood pressure [mmHg] | Systolic blood pressure in mmHg measured at each visit in each of the two treatment arms | from Baseline to week 24 | 
| Safety as assessed by diastolic blood pressure [mmHg] | Diastolic blood pressure in mmHg measured at each visit in each of the two treatment arms | from Baseline to week 24 | 
| Safety as assessed by heart rate [b/min] | Heart rate measured in bpm at each visit in each of the two treatment arms | from Baseline to week 24 | 
| Safety as assessed by hematology parameters | Number and percentage of deviations from normal range for hemoglobin, platelet counts, white cells count, differential counts at baseline, week 14 and week 24 in each of the two treatment arms | from Baseline to week 24 | 
| Safety as assessed by electrolytes and creatinine | Number and percentage of deviations from normal range for sodium, potassium, creatinine at each visit in each of the two treatment arms | from Baseline to week 24 | 
| Safety as assessed by liver and kidney function tests | Number and percentage of deviations from normal range for gamma glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, glomerular filtration rate and urea at baseline, week 14 and week 24 in each of the two treatment arms | from Baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite satiety score (CSS) | Change in satiety and appetite using the CSS from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48 measured at each visit for each of the two treatment arms Full name of the scale: composite satiety score (CSS), sometimes referred to as appetite suppression score. Range of values is 0-100; lower the value, hungrier a person is. CSS = (satiety + fullness + [100 - hunger] + [100 - prospective food consumption]) / 4. The four variables included are measured by visual analog scales (0-100 mm) | from baseline to week 48 | 
| Body weight | Change in body weight from baseline to week 24, from baseline to 48 and from week 24 to week 48 measured at each visit for each of the two treatment arms | from baseline to week 48 | 
| Body composition - fat mass | Change in body fat mass as measured in kg by DXA scan measured at baseline, week 24 and week 48 for each of the two treatment arms | from baseline to week 48 | 
| Body composition - lean body mass | Change in lean body mass as measured in kg by DXA scan measured at baseline, week 24 and week 48 for each of the two treatment arms | from baseline to week 24, from baseline to week 48 and from week 24 to week 48 | 
| Glycemic control - HbA1c | Change in HbA1c from baseline to week 24, baseline to week 48 and week 24 to week 48 measured at baseline, week 14, week 24, week 36 and week 48 for each of the two treatment arms | from baseline to week 48 | 
| Glycemic control - Fasting Plasma Glucose | Change in fasting plasma glucose from baseline to week 24, baseline to week 48 and week 24 to wee 48 measured at each visit for each of the two treatments arms | from baseline to week 48 |