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

NCT03488719 | Completed Phase 1 Results

• 1 other identifier: TM004
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Phase 1

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (18)

• Mean Heart Rate Over 24 Hours (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

  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)

  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

  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)

  Day 14, Day 17, Day 20 and Day 23

Study Arms (3)

Cohort 1 (Tesofensine 0.25mg)

EXPERIMENTAL

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; Drug: Metoprolol Succinate 50 MG; Drug: Metoprolol Succinate 100 MG

Cohort 2 (Tesofensine 0.50mg)

EXPERIMENTAL

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; Drug: Metoprolol Succinate 50 MG; Drug: Metoprolol Succinate 100 MG

Cohort 3 (Tesofensine 0.75mg)

EXPERIMENTAL

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; Drug: Metoprolol Succinate 50 MG; Drug: Metoprolol Succinate 100 MG

Interventions

Metoprolol Succinate 25 MG DRUG

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.

Cohort 1 (Tesofensine 0.25mg); Cohort 2 (Tesofensine 0.50mg); Cohort 3 (Tesofensine 0.75mg)

Metoprolol Succinate 50 MG DRUG

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.

Cohort 1 (Tesofensine 0.25mg); Cohort 2 (Tesofensine 0.50mg); Cohort 3 (Tesofensine 0.75mg)

Metoprolol Succinate 100 MG DRUG

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.

Cohort 1 (Tesofensine 0.25mg); Cohort 2 (Tesofensine 0.50mg); Cohort 3 (Tesofensine 0.75mg)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• Male and female subjects between 18 to 60 years of age, inclusive, at Screening.
• Overweight and obese subjects with a body mass index (BMI) between ≥ 27 and \< 40 kg/m2 at Screening but otherwise healthy.
• 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.
• 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).
• Hemoglobin A1c (HbA1c) \< 6.5% at Screening.
• Subject was willing to adhere to the contraception requirements details.

You may not qualify if:

• 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.
• Subject had any disorder that would interfere with the absorption, distribution, metabolism or excretion of drugs.
• 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.
• 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)
• 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.
• Had a creatinine value exceeding the ULN.
• 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.
• 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.
• Subject had history of alcohol and/or illicit drug abuse within 2 years of entry.
• Subject had positive urine drug test (e.g., cocaine, amphetamines, barbiturates, opiates, benzodiazepines, cannabinoids) or alcohol test at Screening or at admission.
• 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.
• 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.
• 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.

Sponsors & Collaborators

• Saniona: lead

Study Sites (1)

Parexel International GmbH; Early Phase Clinical Unit Berlin

Berlin, 14050, Germany

Location

MeSH Terms

Interventions

Metoprolol

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Results Point of Contact

• Title: Janus Schreiber Larsen
• Organization: Saniona A/S

janus.larsen@saniona.com

+45 7070 5225

Study Officials

• Kim Krogsgaard, MD, DMSc

  Saniona

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Tesofensine dosing will be performed open-label. Metoprolol dosing will be performed "single-blind".
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: March 12, 2018
• First Posted: April 5, 2018
• Study Start: July 11, 2018
• Primary Completion: June 6, 2019
• Study Completion: June 6, 2019
• Last Updated: February 9, 2024
• Results First Posted: February 9, 2024

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)