A Study to Examine the Effect of Tesofensine and Metoprolol on the 24-hour Mean Heart Rate
Condition: Phase 1
Intervention: Metoprolol Succinate 25 MG; Metoprolol Succinate 50 MG; Metoprolol Succinate 100 MG
Intervention description: A single dose of 25 mg metoprolol ER in the morning of Day 15, Day 18 or Day 21 approximately 30 minutes after start of a standard breakfast and together with the tesofensine dose.; A single dose of 50 mg metoprolol ER in the morning of Day 15, Day 18 or Day 21 approximately 30 minutes after start of a standard breakfast and together with the tesofensine dose.; A single dose of 100 mg metoprolol ER in the morning of Day 15, Day 18 or Day 21, approximately 30 minutes after start of a standard breakfast and together with the tesofensine dose.
Intervention MeSH terms: Metoprolol
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Each subject will participate in a Screening Period (Day 28 to Day 3), a Baseline Period (Day -2 to Day -1) and a Treatment Period (Day 1 to Day 24) and will have two Follow-up phone calls (Day 30 and Day 50).
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: Tesofensine dosing will be performed open-label. Metoprolol dosing will be performed "single-blind".
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      A Phase 1 Study to Examine Pharmacodynamic Interaction Between Tesofensine and Metoprolol on
      24-hours Mean Heart Rate
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject voluntarily agreed to participate in this study and signed an Independent
             Ethics Committee (IEC)-approved informed consent prior to performing any of the
             Screening procedures.

          2. Male and female subjects between 18 to 60 years of age, inclusive, at Screening.

          3. Overweight and obese subjects with a body mass index (BMI) between ≥ 27 and < 40 kg/m2
             at Screening but otherwise healthy.

          4. Non-smokers (or other nicotine use) as determined by history (no nicotine use over the
             past 6 months) and by urine cotinine concentration (< 500 ng/mL) at Screening and
             admission.

          5. No clinically relevant deviation or finding in pre-study medical evaluation (medical
             history, physical examination, vital signs, 12-lead electrocardiogram (ECG) and
             clinical laboratory evaluations).

          6. Hemoglobin A1c (HbA1c) < 6.5% at Screening.

          7. Subject was willing to adhere to the contraception requirements details.

        Exclusion Criteria:

          1. Subject had history or evidence of any clinically significant cardiovascular,
             gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic (e.g.,
             diabetes, metabolic acidosis), urologic, pulmonary (e.g., asthma or chronic
             obstructive pulmonary disease), neurologic, dermatologic, psychiatric, renal, and/or
             other major disease or malignancy as judged by the Investigator.

          2. Subject had any disorder that would interfere with the absorption, distribution,
             metabolism or excretion of drugs.

          3. Subject had a clinically significant abnormality following the Investigator's review
             of the physical examination, ECG and clinical study protocol (CSP)-defined clinical
             laboratory tests at Screening or admission to the clinical unit or had any concurrent
             disease or condition that, in the opinion of the Investigator, would make the subject
             unsuitable for participation in the clinical study. One re-test was allowed, if (a)
             test result(s) was outside the limits.

          4. History or presence of liver disease or liver injury, as indicated by abnormal liver
             function tests including:

               -  Aspartate aminotransferase (AST) > 1.2 x upper limit of normal (ULN)

               -  Alanine aminotransferase (ALT) > 1.1 x upper limit of normal (ULN)

          5. Subject had a pulse < 50 or > 90 beats per minute (bpm); systolic blood pressure (SBP)
             < 90 mmHg or > 140 mmHg; diastolic blood pressure (DBP) < 50 mmHg or > 90 mmHg (using
             the mean of triplicate measurements) at Screening or admission. One re-test was
             allowed, if (a) test result(s) was outside these limits.

          6. History of any clinically significant cardiac arrhythmia. Subject had a corrected QT
             interval using Fridericia's formula (QTcF) interval > 450 msec or 2nd or 3rd degree
             atrioventricular (AV) block, high-grade sinoatrial block or PQ interval > 0.24 seconds
             at Screening (using the mean of triplicate measurements). If a mean ECG parameter of a
             triplicate ECG exceeded the limits above, an additional triplicate ECG could have been
             taken. If this also gave an abnormal result, the subject was excluded. Also, the
             following cardiac conditions led to exclusion of the subjects: Untreated heart failure
             (pulmonary oedema, impaired blood flow or hypotension) and continuous or intermittent
             treatment leading to an increased contractility of the heart muscle (beta-receptor
             agonism); sick sinus syndrome; cardiogenic shock; severe peripheral arterial
             circulatory disturbances.

          7. Had a creatinine value exceeding the ULN.

          8. Subject had a positive test for hepatitis B surface antigen (HBsAg), or hepatitis B
             core antibody (indicative of active hepatitis B), hepatitis A virus antibodies
             (immunoglobulin M), hepatitis C virus (HCV) antibodies or human immunodeficiency virus
             (HIV) type 1 and/or type 2 antibodies.

          9. Use of any prescribed or non-prescribed drugs (including vitamins, natural and herbal
             remedies, e.g., St. John's Wort) in the 2 weeks prior to admission or 5 half-lives of
             the drug, whichever was longer, except for the occasional use of paracetamol (up to 2
             g/day) or other non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal
             contraception for female subjects.

         10. Subject had history of alcohol and/or illicit drug abuse within 2 years of entry.

         11. Subject had positive urine drug test (e.g., cocaine, amphetamines, barbiturates,
             opiates, benzodiazepines, cannabinoids) or alcohol test at Screening or at admission.

         12. History of drinking > 168 g (males) and > 84 g (females) pure alcohol per week (10 g
             pure alcohol = 259 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%]
             within 3 months prior to admission to the clinical unit.

         13. Subject consumed more than 600 mg caffeine per day (e.g., more than 3 cups of coffee
             containing 200 mg caffeine per cup) within the 4 weeks before admission or the subject
             was unwilling to avoid consumption of coffee and caffeine-containing beverages within
             48 hours prior to admission until discharge from the clinical unit.

         14. Subject was unwilling to avoid use of alcohol or alcohol-containing foods, medications
             or beverages, within 48 hours prior to Screening and from admission until discharge
             from the clinical unit.

         15. Any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a
             transfusion of any blood or blood products within 60 days, or donated plasma within 7
             days prior to the admission to the clinical unit.

         16. Participation in any clinical study within 3 months or 5 half-lives of the drug,
             whichever was longer, prior to the expected date of IMP administration, or
             participation in more than 3 clinical studies within 12 months.

         17. Subject with a relevant history or with a present psychiatric disorder, including
             depression, suicidal ideation, or eating disorders (e.g., bulimia or anorexia
             nervosa). Subjects with a medical history of relevant psychiatric disorders or known
             and relevant family history or evidence of anxiety disorders or depression as judged
             by the Investigator using the Generalized Anxiety Disorder Assessment-7 (GAD-7) and
             Patient Health Questionnaire-9 (PHQ-9) at Screening. Any of the following led to
             exclusion of the subject:

               -  Subject had a GAD-7 mood scale score ≥ 10.

               -  Subject had a score ≥ 10 on the PHQ-9 questionnaire.

               -  Subject selected a response of "1, 2 or 3" to question number 9 on the PHQ-9
                  questionnaire regarding potential for suicidal thoughts or ideation (independent
                  of the total score of the PHQ-9).

         18. Use of any agent used for weight loss within the last 3 months.

         19. More than 5% weight loss within the last 3 months.

         20. Hypo- or hyperthyroidism.

         21. Subject was pregnant or lactating.

         22. Subject was unwilling to abstain from vigorous exercise from 48 hours prior to
             admission until discharge.

         23. Subject had a history of hypersensitivity to the Investigational medicinal products
             (IMPs) or any of the excipients or to medicinal products with similar chemical
             structures.

         24. Any contraindication for metoprolol, e.g., severe peripheral arterial disease,
             untreated pheochromocytoma, concomitant intravenous administration of calcium
             antagonists of verapamil and diltiazem, due to the risk of hypotension,
             atrioventricular (AV) conduction disturbances, or left ventricular insufficiency.

         25. Subject had lactose intolerance or a rare hereditary problem of fructose intolerance,
             glucose galactose malabsorption or sucrase isomaltase insufficiency.

         26. Subject was unable to understand and communicate in German language or to understand
             the protocol requirements, instructions and study-related restrictions, the nature,
             scope and possible consequences of the clinical study or was unlikely to comply with
             the study requirements; e.g., uncooperative attitude and improbability of completing
             the clinical study.

         27. Subject had previously been enrolled in this clinical study.

         28. Vulnerable subjects defined as individuals whose willingness to volunteer in a
             clinical study may be unduly influenced by the expectation, whether justified or not,
             of benefits associated with participation, or of a retaliatory response from senior
             members of a hierarchy in case of refusal to participate (e.g., persons in detention,
             minors and those incapable of giving consent).

         29. Subject was the Investigator or any Sub-Investigator, research assistant, pharmacist,
             study coordinator, other staff or relative thereof directly involved in the conduct of
             the study or employee of the Sponsor or Parexel.

         30. Poor or ultra-rapid cytochrome P450 2D6 (CYP2D6) metabolizer.