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A Phase 1 Study to Examine Pharmacodynamic Interaction Between Tesofensine and Metoprolol on 24-hours Mean Heart Rate
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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:
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.
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.
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.
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.
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.
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:
Use of any agent used for weight loss within the last 3 months.
More than 5% weight loss within the last 3 months.
Hypo- or hyperthyroidism.
Subject was pregnant or lactating.
Subject was unwilling to abstain from vigorous exercise from 48 hours prior to admission until discharge.
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.
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.
Subject had lactose intolerance or a rare hereditary problem of fructose intolerance, glucose galactose malabsorption or sucrase isomaltase insufficiency.
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.
Subject had previously been enrolled in this clinical study.
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).
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.
Poor or ultra-rapid cytochrome P450 2D6 (CYP2D6) metabolizer.
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| Name | Affiliation | Role |
|---|---|---|
| Kim Krogsgaard, MD, DMSc | Saniona | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Parexel International GmbH; Early Phase Clinical Unit Berlin | Berlin | 14050 | Germany |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Cohort 2 (Tesofensine 0.50mg) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Pharmacodynamic (PD) Population: All randomized subjects with at least HR assessments (24 Hour Holter) on Baseline (Day -2 to -1) and on at least 2 Visits out of, Day 15, Day 18 and Day 21 without any major protocol deviations which could have influenced the PD parameters. | Posted | Mean | 95% Confidence Interval | mg | Day -1 to Day 23 |
From first dose of study drug through Day 50
Adverse events are reported per tesofensine dose group. Differentiation per metoprolol dose could not be delineated.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypomania | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lymphadenopathy | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Janus Schreiber Larsen | Saniona A/S | +45 7070 5225 | janus.larsen@saniona.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 14, 2018 | Mar 5, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 5, 2019 | Mar 11, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008790 | Metoprolol |
| ID | Term |
|---|---|
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
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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).
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Tesofensine dosing will be performed open-label. Metoprolol dosing will be performed "single-blind".
| 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. |
|
| 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. |
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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 |
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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Height | Mean | Standard Deviation | cm |
|
| Weight | Mean | Standard Deviation | kg |
|
| ID | Title | Description |
|---|---|---|
| OG000 | 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. |
| OG001 | 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. |
| OG002 | 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. |
|
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| Secondary | 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. | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | bpm | Baseline (Day -1), Days 14, 17, 20 and 23 |
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| Secondary | 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). | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | bpm | Days 15, 18, or 21 |
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| Secondary | 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) | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | bpm | Baseline (Day -1), Day 14, Day 17, Day 20, Day 23 |
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| Secondary | 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. | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | bpm | Day 15, Day 18, Day 21 |
|
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| Secondary | 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) | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | bpm | Day 14, Day 17, Day 20 and Day 23 |
|
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| Secondary | Maximum Heart Rate (HRmax) and Minimum Heart Rate (HRmin) Values After Tesofensine Co-administered With Metoprolol (Day 15, Day 18 and Day 21) | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at given time point. | Posted | Mean | Standard Deviation | bpm | Day 15, Day 18, Day 21 |
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| Secondary | 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) | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | bpm | From 12 to 13 hours post-dose on Day 14, Day 17, Day 20 and Day 23 |
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| Secondary | 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) | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at given time point. | Posted | Mean | Standard Deviation | bpm | From 12 to 13 hours post-dose on Day 15, Day 18, or Day 21 |
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| Secondary | 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) | All subjects included in the study and dosed with investigational medicinal product (IMP) were included in the safety population. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | bpm | Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23 |
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| Secondary | 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) | All subjects included in the study and dosed with IMP were included in the safety population. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | mm Hg | Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23 |
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| Secondary | Trough Concentration (Ctrough) of Tesofensine on Day 13, Day 14, Day 15, Day 18, Day 21 and Day 23 | Pharmacokinetic population required at least 1 quantifiable concentration, thus subjects discontinued before Day 13 were excluded. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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. |
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| Secondary | Maximum Serum Concentration (Cmax) of Metoprolol on Day 15, Day 18, and Day 21 | Pharmacokinetic (PK) population: All randomized subjects with at least 1 quantifiable tesofensine or metoprolol concentration and without major protocol deviations which could have influenced the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg/L | Day 15, Day 18 and Day 21 |
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|
|
| Secondary | Time to Cmax (Tmax) of Metoprolol on Day 15, Day 18, and Day 21 | Pharmacokinetic (PK) population: All randomized subjects with at least 1 quantifiable tesofensine or metoprolol concentration and without major protocol deviations which could have influenced the PK. | Posted | Median | Full Range | hours | Day 15, Day 18 and Day 21 |
|
|
|
| Secondary | Area Under the Concentration-time Curve From 0 to 24 h (AUC 0-24) of Metoprolol on Day 15, Day 18, and Day 21 | Pharmacokinetic (PK) population: All randomized subjects with at least 1 quantifiable tesofensine or metoprolol concentration and without major protocol deviations which could have influenced the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*μg/L | Day 15, Day 18 and Day 21 |
|
|
|
| Secondary | Heart Rate (HR) Stratified by Metoprolol Concentration | Posted | Mean | Standard Deviation | bpm | Day before dosing (Days 14, 17, 20), dosing day (Days 15, 18, 21) and two days after dosing (Days 17, 20, 23) |
|
|
|
| Secondary | 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). | Pharmacodynamic population required heart rate (HR) at baseline and at least 2 visits out of Day 15, Day 18, Day 21, thus subjects discontinued before Day 18 were excluded. The number of participants listed below is the number of subjects with an assessment at given time point. | Posted | Mean | 95% Confidence Interval | bpm | From baseline to Day 23 |
|
|
|
| Secondary | Mean of Triplicated QT Interval | Mean of triplicated QT Interval | All subjects included in the study and dosed with IMP were included in the safety population. The number of participants listed below is the number of subjects with an assessment at the specified time point. | Posted | Mean | Standard Deviation | msec | Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23 |
|
|
|
| Secondary | 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. | Posted | Number | Count of participants | 30 days prior to Screening until the Safety Follow-up phone call, up to Day 50 |
|
|
|
| 0 |
| 9 |
| 0 |
| 9 |
| 7 |
| 9 |
| EG001 | 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. | 0 | 16 | 1 | 16 | 15 | 16 |
| EG002 | 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. | 0 | 12 | 1 | 12 | 12 | 12 |
| Depression | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Nervous system disorder | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Impulse-control disorder | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
|
| Atrial tachycardia | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
|
| Palpitations | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
|
| Ventricular extrasystoles | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
|
| Foreign body sensation in eyes | Eye disorders | MedDRA (20.1) | Systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA (20.1) | Systematic Assessment |
|
| Visual impairment | Eye disorders | MedDRA (20.1) | Systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Lip swelling | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Energy increased | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Exercise tolerance | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Feeling abnormal | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Feeling cold | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Feeling hot | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Feeling of relaxation | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Mucosal dryness | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Thirst | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Limb injury | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
|
| Blood pressure increased | Investigations | MedDRA (20.1) | Systematic Assessment |
|
| Blood pressure systolic increased | Investigations | MedDRA (20.1) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
|
| Muscle rigidity | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Muscle tightness | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Aphasia | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Coordination abnormal | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Disturbance in attention | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dizziness exertional | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dizziness postural | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dysarthria | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dyskinesia | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Facial neuralgia | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Head discomfort | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Parosmia | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Psychomotor hyperactivity | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Psychomotor skills impaired | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Sensory disturbance | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Tension headache | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Tremor | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Abnormal dreams | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Euphoric mood | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Fear | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Hallucination | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Hypomania | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Illusion | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Irritability | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Listless | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Mood altered | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Mood swings | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Restlessness | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Sleep disorder | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Tension | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Thinking abnormal | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Tic | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
|
| Pollakisuria | Renal and urinary disorders | MedDRA (20.1) | Systematic Assessment |
|
| Breast discomfort | Reproductive system and breast disorders | MedDRA (20.1) | Systematic Assessment |
|
| Breast tenderness | Reproductive system and breast disorders | MedDRA (20.1) | Systematic Assessment |
|
| Menstrual discomfort | Reproductive system and breast disorders | MedDRA (20.1) | Systematic Assessment |
|
| Nasal dryness | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Pharyngeal disorder | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Yawning | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Hot flush | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
|
| Rash | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
|
| Catheter site pain | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Medical device site reaction | General disorders | MedDRA (20.1) | Systematic Assessment |
|
| Arthropod bite | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
|
| Epicondylitis | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Rheumatoid arthritis | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Trigger finger | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
|
| Dysaesthesia | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Taste disorder | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
|
| Finger repair operation | Surgical and medical procedures | MedDRA (20.1) | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
|
Not provided
Not provided
| D009930 |
| Organic Chemicals |
| D020005 | Propanols |
| D000588 | Amines |
| Day 14 |
|
|
| Day 17 |
|
|
| Day 20 |
|
|
| Day 23 |
|
|
| Metoprolol 50 mg |
|
|
| Metoprolol 100 mg |
|
|
| Change at Day 17 |
|
|
| Change at Day 20 |
|
|
| Change at Day 23 |
|
|
| Metoprolol 50 mg |
|
|
| Metoprolol 100 mg |
|
|
| HRmax Day 17 |
|
|
| HRmax Day 20; |
|
|
| HRmax Day 23 |
|
|
| HRmin Day 14 |
|
|
| HRmin Day 17 |
|
|
| HRmin Day 20 |
|
|
| HRmin Day 23 |
|
|
| Metoprolol 25 mg; HR min |
|
|
| Metoprolol 50 mg; HR max |
|
|
| Metoprolol 50 mg; HR min |
|
|
| Metoprolol 100 mg; HR max |
|
|
| Metoprolol 100 mg; HR min |
|
|
| Day 17 |
|
|
| Day 20 |
|
|
| Day 23 |
|
|
| Metoprolol 50 mg |
|
|
| Metoprolol 100 mg |
|
|
| Day -1/2h postdose |
|
|
| Day -1/4h postdose |
|
|
| Day -1/8h postdose |
|
|
| Day -1/12h postdose |
|
|
| Day 13/predose |
|
|
| Day 14/predose |
|
|
| Day 14/2h postdose |
|
|
| Day 14/4h postdose |
|
|
| Day 14/8h postdose |
|
|
| Day 14/12h postdose |
|
|
| Day 17/predose |
|
|
| Day 17/2h postdose |
|
|
| Day 17/4h postdose |
|
|
| Day 17/8h postdose |
|
|
| Day 17/12h postdose |
|
|
| Day 20/predose |
|
|
| Day 20/2h postdose |
|
|
| Day 20/4h postdose |
|
|
| Day 20/8h postdose |
|
|
| Day 20/12h postdose |
|
|
| Day 23/predose |
|
|
| Day 23/2h postdose |
|
|
| Day 23/4h postdose |
|
|
| Day 23/8h postdose |
|
|
| Day 23/12h postdose |
|
|
| Day 15/predose (metop. 25 mg) |
|
|
| Day 15/2h postdose (metop. 25 mg) |
|
|
| Day 15/4h postdose (metop. 25 mg) |
|
|
| Day 15/8h postdose (metop. 25 mg) |
|
|
| Day 15/12h postdose (metop. 25 mg) |
|
|
| Day 18/predose (metop. 25 mg) |
|
|
| Day 18/2h postdose (metop. 25 mg) |
|
|
| Day 18/4h postdose (metop. 25 mg) |
|
|
| Day 18/8h postdose (metop. 25 mg) |
|
|
| Day 18/12h postdose (metop. 25 mg) |
|
|
| Day 21/predose (metop. 25 mg) |
|
|
| Day 21/2h postdose (metop. 25 mg) |
|
|
| Day 21/4h postdose (metop. 25 mg) |
|
|
| Day 21/8h postdose (metop. 25 mg) |
|
|
| Day 21/12h postdose (metop. 25 mg) |
|
|
| Day 15/predose (metop. 50 mg) |
|
|
| Day 15/2h postdose (metop. 50 mg) |
|
|
| Day 15/4h postdose (metop. 50 mg) |
|
|
| Day 15/8h postdose (metop. 50 mg) |
|
|
| Day 15/12h postdose (metop. 50 mg) |
|
|
| Day 18/predose (metop. 50 mg) |
|
|
| Day 18/2h postdose (metop. 50 mg) |
|
|
| Day 18/4h postdose (metop. 50 mg) |
|
|
| Day 18/8h postdose (metop. 50 mg) |
|
|
| Day 18/12h postdose (metop. 50 mg) |
|
|
| Day 21/predose (metop. 50 mg) |
|
|
| Day 21/2h postdose (metop. 50 mg) |
|
|
| Day 21/4h postdose (metop. 50 mg) |
|
|
| Day 21/8h postdose (metop. 50 mg) |
|
|
| Day 21/12h postdose (metop. 50 mg) |
|
|
| Day 15/predose (metop. 100 mg) |
|
|
| Day 15/2h postdose (metop. 100 mg) |
|
|
| Day 15/4h postdose (metop. 100 mg) |
|
|
| Day 15/8h postdose (metop. 100 mg) |
|
|
| Day 15/12h postdose (metop. 100 mg) |
|
|
| Day 18/predose (metop. 100 mg) |
|
|
| Day 18/2h postdose (metop. 100 mg) |
|
|
| Day 18/4h postdose (metop. 100 mg) |
|
|
| Day 18/8h postdose (metop. 100 mg) |
|
|
| Day 18/12h postdose (metop. 100 mg) |
|
|
| Day 21/predose (metop. 100 mg) |
|
|
| Day 21/2h postdose (metop. 100 mg) |
|
|
| Day 21/4h postdose (metop. 100 mg) |
|
|
| Day 21/8h postdose (metop. 100 mg) |
|
|
| Day 21/12h postdose (metop. 100 mg) |
|
|
| DBP Day -1/2h postdose |
|
|
| DBP Day -1/4h postdose |
|
|
| DBP Day -1/8h postdose |
|
|
| DBP Day -1/12h postdose |
|
|
| DBP Day 13/predose |
|
|
| DBP Day 14/predose |
|
|
| DBP Day 14/2h postdose |
|
|
| DBP Day 14/4h postdose |
|
|
| DBP Day 14/8h postdose |
|
|
| DBP Day 14/12h postdose |
|
|
| DBP Day 17/predose |
|
|
| DBP Day 17/2h postdose |
|
|
| DBP Day 17/4h postdose |
|
|
| DBP Day 17/8h postdose |
|
|
| DBP Day 17/12h postdose |
|
|
| DBP Day 20/predose |
|
|
| DBP Day 20/2h postdose |
|
|
| DBP Day 20/4h postdose |
|
|
| DBP Day 20/8h postdose |
|
|
| DBP Day 20/12h postdose |
|
|
| DBP Day 23/predose |
|
|
| DBP Day 23/2h postdose |
|
|
| DBP Day 23/4h postdose |
|
|
| DBP Day 23/8h postdose |
|
|
| DBP Day 23/12h postdose |
|
|
| DBP Day 15/predose (metop. 25 mg) |
|
|
| DBP Day 15/2h postdose (metop. 25 mg) |
|
|
| DBP Day 15/4h postdose (metop. 25 mg) |
|
|
| DBP Day 15/8h postdose (metop. 25 mg) |
|
|
| DBP Day 15/12h postdose (metop. 25 mg) |
|
|
| DBP Day 18/predose (metop. 25 mg) |
|
|
| DBP Day 18/2h postdose (metop. 25 mg) |
|
|
| DBP Day 18/4h postdose (metop. 25 mg) |
|
|
| DBP Day 18/8h postdose (metop. 25 mg) |
|
|
| DBP Day 18/12h postdose (metop. 25 mg) |
|
|
| DBP Day 21/predose (metop. 25 mg) |
|
|
| DBP Day 21/2h postdose (metop. 25 mg) |
|
|
| DBP Day 21/4h postdose (metop. 25 mg) |
|
|
| DBP Day 21/8h postdose (metop. 25 mg) |
|
|
| DBP Day 21/12h postdose (metop. 25 mg) |
|
|
| DBP Day 15/predose (metop. 50 mg) |
|
|
| DBP Day 15/2h postdose (metop. 50 mg) |
|
|
| DBP Day 15/4h postdose (metop. 50 mg) |
|
|
| DBP Day 15/8h postdose (metop. 50 mg) |
|
|
| DBP Day 15/12h postdose (metop. 50 mg) |
|
|
| DBP Day 18/predose (metop. 50 mg) |
|
|
| DBP Day 18/2h postdose (metop. 50 mg) |
|
|
| DBP Day 18/4h postdose (metop. 50 mg) |
|
|
| DBP Day 18/8h postdose (metop. 50 mg) |
|
|
| DBP Day 18/12h postdose (metop. 50 mg) |
|
|
| DBP Day 21/predose (metop. 50 mg) |
|
|
| DBP Day 21/2h postdose (metop. 50 mg) |
|
|
| DBP Day 21/4h postdose (metop. 50 mg) |
|
|
| DBP Day 21/8h postdose (metop. 50 mg) |
|
|
| DBP Day 21/12h postdose (metop. 50 mg) |
|
|
| DBP Day 15/predose (metop. 100 mg) |
|
|
| DBP Day 15/2h postdose (metop. 100 mg) |
|
|
| DBP Day 15/4h postdose (metop. 100 mg) |
|
|
| DBP Day 15/8h postdose (metop. 100 mg) |
|
|
| DBP Day 15/12h postdose (metop. 100 mg) |
|
|
| DBP Day 18/predose (metop. 100 mg) |
|
|
| DBP Day 18/2h postdose (metop. 100 mg) |
|
|
| DBP Day 18/4h postdose (metop. 100 mg) |
|
|
| DBP Day 18/8h postdose (metop. 100 mg) |
|
|
| DBP Day 18/12h postdose (metop. 100 mg) |
|
|
| DBP Day 21/predose (metop. 100 mg) |
|
|
| DBP Day 21/2h postdose (metop. 100 mg) |
|
|
| DBP Day 21/4h postdose (metop. 100 mg) |
|
|
| DBP Day 21/8h postdose (metop. 100 mg) |
|
|
| DBP Day 21/12h postdose (metop. 100 mg) |
|
|
| SBP Day -1/predose |
|
|
| SBP Day -1/2h postdose |
|
|
| SBP Day -1/4h postdose |
|
|
| SBP Day -1/8h postdose |
|
|
| SBP Day -1/12h postdose |
|
|
| SBP Day 13/predose |
|
|
| SBP Day 14/predose |
|
|
| SBP Day 14/2h postdose |
|
|
| SBP Day 14/4h postdose |
|
|
| SBP Day 14/8h postdose |
|
|
| SBP Day 14/12h postdose |
|
|
| SBP Day 17/predose |
|
|
| SBP Day 17/2h postdose |
|
|
| SBP Day 17/4h postdose |
|
|
| SBP Day 17/8h postdose |
|
|
| SBP Day 17/12h postdose |
|
|
| SBP Day 20/predose |
|
|
| SBP Day 20/2h postdose |
|
|
| SBP Day 20/4h postdose |
|
|
| SBP Day 20/8h postdose |
|
|
| SBP Day 20/12h postdose |
|
|
| SBP Day 23/predose |
|
|
| SBP Day 23/2h postdose |
|
|
| SBP Day 23/4h postdose |
|
|
| SBP Day 23/8h postdose |
|
|
| SBP Day 23/12h postdose |
|
|
| SBP Day 15/predose (metop. 25 mg) |
|
|
| SBP Day 15/2h postdose (metop. 25 mg) |
|
|
| SBP Day 15/4h postdose (metop. 25 mg) |
|
|
| SBP Day 15/8h postdose (metop. 25 mg) |
|
|
| SBP Day 15/12h postdose (metop. 25 mg) |
|
|
| SBP Day 18/predose (metop. 25 mg) |
|
|
| SBP Day 18/2h postdose (metop. 25 mg) |
|
|
| SBP Day 18/4h postdose (metop. 25 mg) |
|
|
| SBP Day 18/8h postdose (metop. 25 mg) |
|
|
| SBP Day 18/12h postdose (metop. 25 mg) |
|
|
| SBP Day 21/predose (metop. 25 mg) |
|
|
| SBP Day 21/2h postdose (metop. 25 mg) |
|
|
| SBP Day 21/4h postdose (metop. 25 mg) |
|
|
| SBP Day 21/8h postdose (metop. 25 mg) |
|
|
| SBP Day 21/12h postdose (metop. 25 mg) |
|
|
| SBP Day 15/predose (metop. 50 mg) |
|
|
| SBP Day 15/2h postdose (metop. 50 mg) |
|
|
| SBP Day 15/4h postdose (metop. 50 mg) |
|
|
| SBP Day 15/8h postdose (metop. 50 mg) |
|
|
| SBP Day 15/12h postdose (metop. 50 mg) |
|
|
| SBP Day 18/predose (metop. 50 mg) |
|
|
| SBP Day 18/2h postdose (metop. 50 mg) |
|
|
| SBP Day 18/4h postdose (metop. 50 mg) |
|
|
| SBP Day 18/8h postdose (metop. 50 mg) |
|
|
| SBP Day 18/12h postdose (metop. 50 mg) |
|
|
| SBP Day 21/predose (metop. 50 mg) |
|
|
| SBP Day 21/2h postdose (metop. 50 mg) |
|
|
| SBP Day 21/4h postdose (metop. 50 mg) |
|
|
| SBP Day 21/8h postdose (metop. 50 mg) |
|
|
| SBP Day 21/12h postdose (metop. 50 mg) |
|
|
| SBP Day 15/predose (metop. 100 mg) |
|
|
| SBP Day 15/2h postdose (metop. 100 mg) |
|
|
| SBP Day 15/4h postdose (metop. 100 mg) |
|
|
| SBP Day 15/8h postdose (metop. 100 mg) |
|
|
| SBP Day 15/12h postdose (metop. 100 mg) |
|
|
| SBP Day 18/predose (metop. 100 mg) |
|
|
| SBP Day 18/2h postdose (metop. 100 mg) |
|
|
| SBP Day 18/4h postdose (metop. 100 mg) |
|
|
| SBP Day 18/8h postdose (metop. 100 mg) |
|
|
| SBP Day 18/12h postdose (metop. 100 mg) |
|
|
| SBP Day 21/predose (metop. 100 mg) |
|
|
| SBP Day 21/2h postdose (metop. 100 mg) |
|
|
| SBP Day 21/4h postdose (metop. 100 mg) |
|
|
| SBP Day 21/8h postdose (metop. 100 mg) |
|
|
| SBP Day 21/12h postdose (metop. 100 mg) |
|
|
| Day 14 |
|
|
| Day 23; |
|
|
| Metoprolol 25 mg |
|
|
| Metoprolol 50 mg |
|
|
| Metoprolol 100 mg |
|
|
|
| Metoprolol 100 mg |
|
|
| Metoprolol 100 mg |
|
|
| Metoprolol 100 mg |
|
|
| Metoprolol 25 mg; Two days after dosing |
|
| Metoprolol 50 mg; Day before dosing |
|
| Metoprolol 50 mg; Dosing day |
|
| Metoprolol 50 mg; Two days after dosing |
|
| Metoprolol 100 mg; Day before dosing |
|
| Metoprolol 100 mg; Dosing day |
|
| Metoprolol 100 mg; Two days after dosing |
|
| Metoprolol 50 mg |
|
|
| Metoprolol 100 mg |
|
|
| Day -1/2h postdose |
|
|
| Day -1/4h postdose |
|
|
| Day -1/8h postdose |
|
|
| Day -1/12h postdose |
|
|
| Day 13/predose |
|
|
| Day 14/predose |
|
|
| Day 14/2h postdose |
|
|
| Day 14/4h postdose |
|
|
| Day 14/8h postdose |
|
|
| Day 14/12h postdose |
|
|
| Day 17/predose |
|
|
| Day 17/2h postdose |
|
|
| Day 17/4h postdose |
|
|
| Day 17/8h postdose |
|
|
| Day 17/12h postdose |
|
|
| Day 20/predose |
|
|
| Day 20/2h postdose |
|
|
| Day 20/4h postdose |
|
|
| Day 20/8h postdose |
|
|
| Day 20/12h postdose |
|
|
| Day 23/predose |
|
|
| Day 23/2h postdose |
|
|
| Day 23/4h postdose |
|
|
| Day 23/8h postdose |
|
|
| Day 23/12h postdose |
|
|
| Day 15/predose (metop. 25 mg) |
|
|
| Day 15/2h postdose (metop. 25 mg) |
|
|
| Day 15/4h postdose (metop. 25 mg) |
|
|
| Day 15/8h postdose (metop. 25 mg) |
|
|
| Day 15/12h postdose (metop. 25 mg) |
|
|
| Day 18/predose (metop. 25 mg) |
|
|
| Day 18/2h postdose (metop. 25 mg) |
|
|
| Day 18/4h postdose (metop. 25 mg) |
|
|
| Day 18/8h postdose (metop. 25 mg) |
|
|
| Day 18/12h postdose (metop. 25 mg) |
|
|
| Day 21/predose (metop. 25 mg) |
|
|
| Day 21/2h postdose (metop. 25 mg) |
|
|
| Day 21/4h postdose (metop. 25 mg) |
|
|
| Day 21/8h postdose (metop. 25 mg) |
|
|
| Day 21/12h postdose (metop. 25 mg) |
|
|
| Day 15/predose (metop. 50 mg) |
|
|
| Day 15/2h postdose (metop. 50 mg) |
|
|
| Day 15/4h postdose (metop. 50 mg) |
|
|
| Day 15/8h postdose (metop. 50 mg) |
|
|
| Day 15/12h postdose (metop. 50 mg) |
|
|
| Day 18/predose (metop. 50 mg) |
|
|
| Day 18/2h postdose (metop. 50 mg) |
|
|
| Day 18/4h postdose (metop. 50 mg) |
|
|
| Day 18/8h postdose (metop. 50 mg) |
|
|
| Day 18/12h postdose (metop. 50 mg) |
|
|
| Day 21/predose (metop. 50 mg) |
|
|
| Day 21/2h postdose (metop. 50 mg) |
|
|
| Day 21/4h postdose (metop. 50 mg) |
|
|
| Day 21/8h postdose (metop. 50 mg) |
|
|
| Day 21/12h postdose (metop. 50 mg) |
|
|
| Day 15/predose (metop. 100 mg) |
|
|
| Day 15/2h postdose (metop. 100 mg) |
|
|
| Day 15/4h postdose (metop. 100 mg) |
|
|
| Day 15/8h postdose (metop. 100 mg) |
|
|
| Day 15/12h postdose (metop. 100 mg) |
|
|
| Day 18/predose (metop. 100 mg) |
|
|
| Day 18/2h postdose (metop. 100 mg) |
|
|
| Day 18/4h postdose (metop. 100 mg) |
|
|
| Day 18/8h postdose (metop. 100 mg) |
|
|
| Day 18/12h postdose (metop. 100 mg) |
|
|
| Day 21/predose (metop. 100 mg) |
|
|
| Day 21/2h postdose (metop. 100 mg) |
|
|
| Day 21/4h postdose (metop. 100 mg) |
|
|
| Day 21/8h postdose (metop. 100 mg) |
|
|
| Day 21/12h postdose (metop. 100 mg) |
|
|
|
| PARACETAMOL/concomitant |
|
| ANAESTHETICS, LOCAL/concomitant |
|
| IBUPROFEN/concomitant |
|
| METOPROLOL TARTRATE/concomitant |
|
| PANTOPRAZOLE/concomitant |
|
| UNACID [AMPICILLIN SODIUM;SULBACTAM SODIUM]/conco. |
|
| IBUPROFEN/prior |
|
| FOLIC ACID/concomitant |
|
| METEX [METHOTREXATE SODIUM]/concomitant |
|
| PREDNISOLONE/concomitant |
|
| METOPROLOL SUCCINATE/concomitant |
|
| HALOPERIDOL/concomitant |
|
| LORAZEPAM/concomitant |
|
| METOCLOPRAMIDE/concomitant |
|
| RISPERIDON BETA/concomitant |
|
| PARACETAMOL/prior |
|