A Study to Examine the Effect of Tesofensine and Metoprolol on the 24-hour Mean Heart Rate

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

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

Study Overview

• Status: Completed
• Conditions: Phase 1
• Intervention / Treatment: Drug: Metoprolol Succinate 25 MG; Drug: Metoprolol Succinate 50 MG; Drug: Metoprolol Succinate 100 MG

Detailed Description

In this study, the dose-response relationship between tesofensine and metoprolol will be examined and thus the optimal dose of metoprolol to mitigate the effects of tesofensine on heart rate (HR) will be determined. HR is the primary endpoint because in the previous studies it has been shown to be the most affected safety endpoint by the effects of tesofensine.

After enrolment of 37 subjects, 2 Subjects (0115 and 0147) in dose cohort 2 experienced prolonged tachycardia (> 120 beats per minute (bpm) lasting for 30 min) documented in Holter Electrocardiogram (ECG) recording (a stopping criteria of the study). Therefore, the study was temporarily halted on 22 November 2018. Subsequent to the temporary halt, Saniona reviewed all the available data in January and February 2019 and determined that the results obtained from the completed participants were sufficiently robust to answer the questions for which the trial was designed. Therefore, Saniona decided to permanently end the trial on 20 February 2019.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Parexel International GmbH; Early Phase Clinical Unit Berlin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (Tesofensine 0.25mg); Tesofensine 0.25 mg once daily for 23 days (loading dose of 1.0 mg for the first 3 days), plus a single dose of 25 mg, 50 mg or 100 mg metoprolol extended release (ER) in random order on Day 15, Day 18 and Day 21, respectively.	Drug: Metoprolol Succinate 25 MG; 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.; Drug: Metoprolol Succinate 50 MG; 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.; Drug: Metoprolol Succinate 100 MG; 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.
Experimental: Cohort 2 (Tesofensine 0.50mg); Tesofensine 0.50 mg once daily for 23 days (loading dose of 2.0 mg for the first 3 days), plus a single dose of 25 mg, 50 mg or 100 mg metoprolol extended release (ER) in random order on Day 15, Day 18 and Day 21, respectively.	Drug: Metoprolol Succinate 25 MG; 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.; Drug: Metoprolol Succinate 50 MG; 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.; Drug: Metoprolol Succinate 100 MG; 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.
Experimental: Cohort 3 (Tesofensine 0.75mg); Tesofensine 0.75 mg (0.25 mg + 0.50 mg) once daily for 23 days (loading dose of 2.0 mg [4 tablets of 0.50 mg] for the first 5 days), plus a single dose of 25 mg, 50 mg or 100 mg metoprolol extended release (ER) in random order on Day 15, Day 18 and Day 21, respectively.	Drug: Metoprolol Succinate 25 MG; 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.; Drug: Metoprolol Succinate 50 MG; 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.; Drug: Metoprolol Succinate 100 MG; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose of Metoprolol Resulting in no Change in Mean Heart Rate Over 24 Hours (M24HR)	The dose of metoprolol which resulted in no change relative to baseline in mean heart rate over 24 hours (M24HR) for each respective dose of tesofensine was calculated from a dose response relationship with the log-dose of metoprolol as independent variable and change in M24HR induced by various doses of metoprolol given to subjects on steady-state dose of tesofensine as the dependent variable. The dose for no change in M24HR derived from above calculation and the corresponding 95% confidence interval (CI) is presented for each dose of tesofensine. The result in this endpoint is not an arithmetic mean, but the model derived estimated dose from the model. Mitigating dose was estimated using a linear regression modelling mean change from pre-tesofensine baseline (Day -1) of M24HR as a function of the log metoprolol dose.	Day -1 to Day 23

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Heart Rate Over 24 Hours (M24HR) at Baseline (Day -1) and Days 14, 17, 20 and 23	M24HR at Baseline (Day -1) and Days 14, 17, 20 and 23.	Baseline (Day -1), Days 14, 17, 20 and 23
Mean Heart Rate Over 24 Hours (M24HR) on Days 15, 18 or 21	M24HR following each of the 3 metoprolol doses (M24HR on Days 15, 18 or 21).	Days 15, 18, or 21
Change in Mean Heart Rate Over 24 Hours (M24HR) Between Pre-tesofensine Baseline (Day -1) and After Tesofensine Alone (Day 14, Day 17, Day 20 and Day 23)	Change in M24HR between pre-tesofensine baseline (Day -1) and after tesofensine alone (Day 14, Day 17, Day 20 and Day 23)	Baseline (Day -1), Day 14, Day 17, Day 20, Day 23
Change in Mean Heart Rate Over 24 Hours (M24HR) Values After Tesofensine Co-administered With Metoprolol	Change in M24HR values after tesofensine co-administered with metoprolol. As the three metoprolol doses were given in a random order these results are not reported as Day 15, Day 18 and Day 21 but instead as change from matched day.	Day 15, Day 18, Day 21
Maximum and Minimum Heart Rate of 24 Hours (HRmax and HRmin) Values After Tesofensine Alone (Day 14, Day 17, Day 20 and Day 23)	Maximum and minimum heart rate of 24 hours (HRmax and HRmin) values after tesofensine alone (Day 14, Day 17, Day 20 and Day 23)	Day 14, Day 17, Day 20 and Day 23
Maximum Heart Rate (HRmax) and Minimum Heart Rate (HRmin) Values After Tesofensine Co-administered With Metoprolol (Day 15, Day 18 and Day 21)		Day 15, Day 18, Day 21
Mean Heart Rate (HR) During a Designated Quiet Hour and a Designated Period After Tesofensine Alone (Day 14, Day 17, Day 20 and Day 23)		From 12 to 13 hours post-dose on Day 14, Day 17, Day 20 and Day 23
Mean Heart Rate (HR) During a Designated Quiet Hour and a Designated Period After Tesofensine Co-administered With Metoprolol (Day 15, Day 18 and Day 21)		From 12 to 13 hours post-dose on Day 15, Day 18, or Day 21
Heart Rate (HR) After at Least 10 Minutes Rest Before Each Pharmacokinetic (PK) Sampling Time Point or the Corresponding Time Point (Day -1, Day 13 [Pre-dose Only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23)		Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23
Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) Values After at Least 10 Minutes Rest Before Each PK Sampling Time Point or the Corresponding Time Point (Day -1, Day 13 [Pre-dose Only], Day 14, 15, 17, 18, 20, 21, 23)		Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23
Trough Concentration (Ctrough) of Tesofensine on Day 13, Day 14, Day 15, Day 18, Day 21 and Day 23		Pre-dose on Day 13, Day 14 and Day 23. Pre-dose on Day 15, Day 18 and Day 21 is listed as Metoprolol 25 mg, Metoprolol 50 mg and Metoprolol 100 mg since metoprolol was administered in randomized order.
Maximum Serum Concentration (Cmax) of Metoprolol on Day 15, Day 18, and Day 21		Day 15, Day 18 and Day 21
Time to Cmax (Tmax) of Metoprolol on Day 15, Day 18, and Day 21		Day 15, Day 18 and Day 21
Area Under the Concentration-time Curve From 0 to 24 h (AUC 0-24) of Metoprolol on Day 15, Day 18, and Day 21		Day 15, Day 18 and Day 21
Heart Rate (HR) Stratified by Metoprolol Concentration		Day before dosing (Days 14, 17, 20), dosing day (Days 15, 18, 21) and two days after dosing (Days 17, 20, 23)
Change From Baseline Mean Heart Rate Over 24 Hours (M24HR) by Metoprolol Dose	The difference in increase in M24HR caused by tesofensine alone (calculated as the difference between the M24HR at pre-tesofensine baseline and the mean of M24HR on Days 14, 17, 20 and 23) and the reduction in M24HR following each of the 3 metoprolol doses (M24HR on Day 15, 18 or 21).	From baseline to Day 23
Mean of Triplicated QT Interval	Mean of triplicated QT Interval	Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23
Use of Concomitant Medication From 30 Days Prior to Screening Until Day 50	Any medicinal product, prescribed or over-the-counter (OTC), including herbal and other non-traditional remedies, was considered a concomitant medication.	30 days prior to Screening until the Safety Follow-up phone call, up to Day 50

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2018
• Primary Completion (Actual): June 6, 2019
• Study Completion (Actual): June 6, 2019

Study Registration Dates

• First Submitted: March 12, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 5, 2018

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: June 8, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: 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: TM004

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
• product manufactured in and exported from the U.S.: No