Dose of Metoprolol Resulting in no Change in Mean Heart Rate Over 24 Hours (M24HR)
| Group | Value (mg) |
|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 10.04 |
| Cohort 2 (Tesofensine 0.50mg) | 60.95 |
| Cohort 3 (Tesofensine 0.75mg) | 147.91 |
Trial · Interventional
CompletedPhase 1Results postedRegistry dataGermany
1 trial · 1 completed · 1 with posted results
A Study to Examine the Effect of Tesofensine and Metoprolol on the 24-hour Mean Heart Rate
NCT0348871911 Jul 2018 to 6 Jun 2019
Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.
A Phase 1 Study to Examine Pharmacodynamic Interaction Between Tesofensine and Metoprolol on 24-hours Mean Heart Rate
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.
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.
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.
Outcomes the sponsor listed as primary.
Dose of Metoprolol Resulting in no Change in Mean Heart Rate Over 24 Hours (M24HR)
Time frame · Day -1 to Day 23
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.
Mean Heart Rate Over 24 Hours (M24HR) at Baseline (Day -1) and Days 14, 17, 20 and 23
Time frame · Baseline (Day -1), Days 14, 17, 20 and 23
M24HR at Baseline (Day -1) and Days 14, 17, 20 and 23.
Mean Heart Rate Over 24 Hours (M24HR) on Days 15, 18 or 21
Time frame · Days 15, 18, or 21
M24HR following each of the 3 metoprolol doses (M24HR on 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)
Time frame · Baseline (Day -1), Day 14, Day 17, Day 20, Day 23
Change in M24HR between pre-tesofensine baseline (Day -1) and after tesofensine alone (Day 14, Day 17, Day 20 and Day 23)
Change in Mean Heart Rate Over 24 Hours (M24HR) Values After Tesofensine Co-administered With Metoprolol
Time frame · Day 15, Day 18, Day 21
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.
Maximum and Minimum Heart Rate of 24 Hours (HRmax and HRmin) Values After Tesofensine Alone (Day 14, Day 17, Day 20 and Day 23)
Time frame · 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)
Maximum Heart Rate (HRmax) and Minimum Heart Rate (HRmin) Values After Tesofensine Co-administered With Metoprolol (Day 15, Day 18 and Day 21)
Time frame · 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)
Time frame · 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)
Time frame · 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)
Time frame · 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)
Time frame · 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
Time frame · 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
Time frame · Day 15, Day 18 and Day 21
Time to Cmax (Tmax) of Metoprolol on Day 15, Day 18, and Day 21
Time frame · 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
Time frame · Day 15, Day 18 and Day 21
Heart Rate (HR) Stratified by Metoprolol Concentration
Time frame · 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
Time frame · From baseline to Day 23
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).
Mean of Triplicated QT Interval
Time frame · Day -1, Day 13 [pre-dose only], Day 14, Day 15, Day 17, Day 18, Day 20, Day 21 and Day 23
Mean of triplicated QT Interval
Use of Concomitant Medication From 30 Days Prior to Screening Until Day 50
Time frame · 30 days prior to Screening until the Safety Follow-up phone call, up to Day 50
Any medicinal product, prescribed or over-the-counter (OTC), including herbal and other non-traditional remedies, was considered a concomitant medication.
Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.
| Group | Value (mg) |
|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 10.04 |
| Cohort 2 (Tesofensine 0.50mg) | 60.95 |
| Cohort 3 (Tesofensine 0.75mg) | 147.91 |
| Group | Value (bpm) | Spread |
|---|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 73.4 | 8.47 |
| Cohort 2 (Tesofensine 0.50mg) | 73.1 | 5.48 |
| Cohort 3 (Tesofensine 0.75mg) | 74.3 | 5.82 |
| Group | Value (bpm) | Spread |
|---|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 71.1 | 9.45 |
| Cohort 2 (Tesofensine 0.50mg) | 76.5 | 7.68 |
| Cohort 3 (Tesofensine 0.75mg) | 80.0 | 7.71 |
| Group | Value (bpm) | Spread |
|---|---|---|
| Cohort 1 (Tesofensine 0.25mg) | -0.9 | 2.20 |
| Cohort 2 (Tesofensine 0.50mg) | 3.5 | 4.50 |
| Cohort 3 (Tesofensine 0.75mg) | 7.0 | 5.69 |
| Group | Value (bpm) | Spread |
|---|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 2.7 | 2.87 |
| Cohort 2 (Tesofensine 0.50mg) | -2.9 | 2.25 |
| Cohort 3 (Tesofensine 0.75mg) | -2.2 | 2.05 |
| Group | Value (bpm) | Spread |
|---|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 114.4 | 11.53 |
| Cohort 2 (Tesofensine 0.50mg) | 117.5 | 10.43 |
| Cohort 3 (Tesofensine 0.75mg) | 124.2 | 17.79 |
| Group | Value (bpm) | Spread |
|---|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 107.3 | 11.93 |
| Cohort 2 (Tesofensine 0.50mg) | 117.8 | 14.32 |
| Cohort 3 (Tesofensine 0.75mg) | 120.0 | 11.73 |
| Group | Value (bpm) | Spread |
|---|---|---|
| Cohort 1 (Tesofensine 0.25mg) | 70.0 | 9.99 |
| Cohort 2 (Tesofensine 0.50mg) | 71.4 | 9.52 |
| Cohort 3 (Tesofensine 0.75mg) | 77.8 | 10.50 |
| Group | Deaths | Serious events | Other events |
|---|---|---|---|
| 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. | 0 / 9 | 0 / 9 | 7 / 9 |
| 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 |
| 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 |
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